1

• Introduction

• What is cancer?
 Definition of Cancer

Cancer is an abnormal growth of cells caused by multiple changes in

gene expression leading to dysregulated balance of cell proliferation and
cell death and ultimately evolving into a population of cells that can
invade tissues and metastasize to distant sites, causing significant
morbidity and, if untreated, death of the host. Description of Cancer
Cancer is a group of diseases of higher multicellular organisms. It is
characterized by alterations in the expression of multiple genes, leading
to dysregulation of the normal cellular program for cell division and cell
differentiation. This results in an imbalance of cell replication and cell
death that favors growth of a tumor cell population. The characteristics
that delineate a malignant cancer from a benign tumor are the abilities to
invade locally, to spread to regional lymph nodes, and to metastasize to
distant organs in the body. Clinically, cancer appears to be many
different diseases with different phenotypic characteristics.

Cancer develops when cells in a part of the body begin to grow out of
control. Even though there are many kinds of cancer, they all start
because of abnormal cells that grow out of control.

Normal body cells grow, divide, and die in an orderly fashion. During the
early years of a person's life, normal cells divide more rapidly until the
person becomes an adult. After that, cells in most parts of the body
divide only to replace worn-out or dying cells and to repair injuries.

Because cancer cells continue to grow and divide, they are different
from normal cells. Instead of dying, they outlive normal cells and
continue to form new abnormal cells.

Cancer cells often travel to other parts of the body where they begin to
grow and replace normal tissue. This process, called metastasis, occurs
as the cancer cells get into the bloodstream or lymph vessels of our
body. When cells from a cancer like breast cancer spread to another
organ like the liver, the cancer is still called breast cancer, not liver
cancer.

Cancer cells develop because of damage to DNA. This substance is in

every cell and directs all its activities. Most of the time when DNA
becomes damaged the body is able to repair it. In cancer cells, the
damaged DNA is not repaired. People can inherit damaged DNA, which
 2

accounts for inherited cancers. Many times though, a person’s DNA

becomes damaged by exposure to something in the environment, like
smoking.

Cancer usually forms as a solid tumor. Some cancers, like leukemia, do

not form tumors. Instead, these cancer cells involve the blood and
blood-forming organs and circulate through other tissues where they
grow.

Not all tumors are cancerous. Benign (non-cancerous) tumors do not

spread to other parts of the body (metastasize) and, with very rare
exceptions, are not life threatening.

Different types of cancer can behave very differently. For example, lung
cancer and breast cancer are very different diseases. They grow at
different rates and respond to different treatments. That is why people
with cancer need treatment that is aimed at their particular kind of
cancer.

Cancer is the second leading cause of death in the United States. Half of
all men and one-third of all women in the United States will develop
cancer during their lifetimes. Today, millions of people are living with
cancer or have had cancer. The risk of developing most types of cancer
can be reduced by changes in a person's lifestyle, for example, by
quitting smoking and eating a better diet. The sooner a cancer is found
and treatment begins, the better are the chances for living for many
years.

 History of cancer
 3

 Oldest descriptions of cancer

Cancer has afflicted humans throughout recorded history. It is no
surprise that from the dawn of history people have written about cancer.
Some of the earliest evidence of cancer is found among fossilized bone
tumors, human mummies in ancient Egypt, and ancient manuscripts.
Bone remains of mummies have revealed growths suggestive of the
bone cancer, osteosarcoma. In other cases, bony skull destruction as
seen in cancer of the head and neck has been found.

Our oldest description of cancer (although the term cancer was not
used) was discovered in Egypt and dates back to approximately 1600
B.C. The Edwin Smith Papyrus, or writing, describes 8 cases of tumors
or ulcers of the breast that were treated by cauterization, with a tool
called "the fire drill." The writing says about the disease, "There is no
treatment."

 Origin of the word cancer

The origin of the word cancer is credited to the Greek physician
Hippocrates (460-370 B.C.), considered the "Father of Medicine."
Hippocrates used the terms carcinos and carcinoma to describe non-
ulcer forming and ulcer-forming tumors. In Greek these words refer to a
crab, most likely applied to the disease because the finger-like spreading
projections from a cancer called to mind the shape of a crab. The Roman
physician, Celsus (28-50 B.C.), later translated the Greek term into
cancer, the Latin word for crab. Galen (130-200 A.D.), another Roman
physician, used the word oncos (Greek for swelling) to describe tumors.
Although the crab analogy of Hippocrates and Celsus is still used to
describe malignant tumors, Galen's term is now used as a part of the
name for cancer specialists -- oncologists.

 Renaissance period
During the Renaissance, beginning in the 15th century, scientists in Italy
developed a greater understanding of the human body. Scientists such
as Galileo and Newton began to use the scientific method, which later
began to be used to study disease. Autopsies, performed by Harvey
(1628), allowed an understanding of the circulation of blood through the
heart and body that had remained a mystery.

In 1761, Giovanni Morgagni of Padua was the first to do something

considered routine today. He performed autopsies to relate the patient's
illness to the pathologic findings after death. This laid the foundation for
scientific oncology, the study of cancer.
 4

The famous Scottish surgeon John Hunter (1728-1793) suggested that

some cancers might be cured by surgery and described how the
surgeon might decide which cancers to operate on. If the tumor had not
invaded nearby tissue and was "moveable," he said, "There is no
impropriety in removing it."

A century later the development of anesthesia allowed surgery to

flourish and the classic cancer operations such as radical mastectomy
were developed.

 Nineteenth century
The 19th century saw the birth of scientific oncology with the discovery
and use of the modern microscope. Rudolf Virchow, often called the
founder of cellular pathology, provided the scientific basis for the
modern pathologic study of cancer. As Morgagni had correlated the
autopsy findings observed with the unaided eye with the clinical course
of illness, so Virchow correlated the microscopic pathology.

This method not only allowed a better understanding of the damage

cancer had done to a patient but also laid the foundation for the
development of cancer surgery. Body tissues removed by the surgeon
could now be examined and a precise diagnosis made. In addition, the
pathologist could tell the surgeon whether the operation had completely
removed the tumor.

 Cancer causes
From the earliest times, physicians have wondered about the cause of
cancer. The Egyptians blamed cancers on the Gods.

Humoral theory: Hippocrates believed that the body contained 4 humors

(body fluids) -- blood, phlegm, yellow bile, and black bile. A balance of
these fluids resulted in a state of health. Any excesses or deficiencies
caused disease. An excess of black bile collecting in various body sites
was thought to cause cancer. This theory of cancer was passed on by
the Romans and was embraced by the influential doctor Galen’s medical
teaching, which remained the unchallenged standard through the Middle
Ages for over 1300 years. During this period, the study of the body,
including autopsies, was prohibited for religious reasons, thus limiting
knowledge.

Lymph theory: Among theories that replaced the humoral theory of

cancer was cancer's formation by another fluid, lymph. Life was believed
to consist of continuous and appropriate movement of the fluid parts
through solids. Of all the fluids, the most important were blood and
lymph. Stahl and Hofman theorized that cancer was composed of
fermenting and degenerating lymph varying in density, acidity, and
 5

alkalinity. The lymph theory gained rapid support. John Hunter (1723-
1792) agreed that tumors grow from lymph constantly thrown out by the
blood.

Blastema theory: In 1838, German pathologist Johannes Muller

demonstrated that cancer is made up of cells and not lymph, but he was
of the opinion that cancer cells did not arise from normal cells. Muller
proposed that cancer cells arose from budding elements (blastema)
between normal tissues. His student, Rudolph Virchow (1821-1902), the
famous German pathologist, determined that all cells, including cancer
cells, are derived from other cells.

Chronic irritation: Virchow proposed that chronic irritation was the cause
of cancer, but he falsely believed that cancers "spread like a liquid." A
German surgeon, Karl Thiersch, showed that cancers metastasize
through the spread of malignant cells and not through some unidentified
fluid.

Trauma: Despite advances in the understanding of cancer, from the late

1800s until the 1920s, cancer was thought by some to be caused by
trauma. This belief was maintained despite the failure to cause cancer in
experimental animals by injury.

Parasite theory: In the 17th and 18th centuries, some believed that
cancer was contagious. In fact, the first cancer hospital in France was
forced to move from the city in 1779 because of the fear of the spread of
cancer throughout the city.

A Nobel Prize was wrongly awarded in 1926 for scientific research

documenting stomach cancer being caused by a certain worm.
Scientists were unable to confirm this research, so they lost interest in
the parasite theory.

By the middle of the 20th century, scientists had in their hands the
instruments needed to begin solving the complex problems of chemistry
and biology presented by cancer. James Watson and Francis Crick, who
received a Nobel Prize in 1962 for their work, had discovered the exact
chemical structure of DNA, the basic material in genes.

DNA was found to be the basis of the genetic code that gives orders to
all cells. After learning how to translate this code, scientists were able to
understand how genes worked and how they could be damaged by
mutations (changes or mistakes in genes). These modern techniques of
chemistry and biology answered many complex questions about cancer.

Scientists already knew that cancer could be caused by chemicals,

radiation, and viruses, and that sometimes cancer seemed to run in
families. But as our understanding of DNA and genes increased, we
learned that it was the damage to DNA by chemicals and radiation or
introduction of new DNA sequences by viruses that often led to the
 6

development of cancer. It became possible to pinpoint the exact site of

the damage to a specific gene.

Further, scientists discovered that sometimes defective genes are

inherited and that sometimes these inherited genes are defective at the
same points that chemicals exerted their effect. In other words, most
carcinogens caused genetic damage (mutations), mutations led to
abnormal groups of cells (called clones), mutant clones evolved to even
more malignant clones over time, and the cancer progressed by more
and more genetic damage and mutations. Normal cells with damaged
DNA die; cancer cells with damaged DNA do not. The recent discovery of
this critical difference answers many questions that have troubled
scientists for many years.

During the 1970s, scientists discovered 2 important families of genes --

oncogenes and tumor suppressor genes.

Oncogenes are mutated forms of genes that cause normal cells to

grow out of control and become cancer cells. They are mutations
of certain normal genes of the cell called proto-oncogenes. Proto-
oncogenes are the genes that normally control how often a cell
divides and the degree to which it differentiates (or specializes).

Tumor suppressor genes are normal genes that slow down cell
division, repair DNA mistakes, and tell cells when to die (a
process known as apoptosis or programmed cell death). When
tumor suppressor genes don’t work properly, cells can grow out
of control, which can lead to cancer. It may be helpful to think of a
cell as a car. For it to work properly, there need to be ways to
control how fast it goes. A proto-oncogene normally functions in
a way that is similar to a gas pedal -- it helps the cell grow and
divide. An oncogene could be compared to a gas pedal that is
stuck down, which causes the cell to divide out of control. A
tumor suppressor gene is like the brake pedal on a car -- it
normally keeps the cell from dividing too quickly just as a brake
keeps a car from going too fast. When something goes wrong
with the gene, such as a mutation, cell division can get out of
control.

Slowly, medical scientists are identifying the oncogenes and tumor

suppressor genes that are damaged by chemicals or radiation and the
genes that, when inherited, can lead to cancer. For example, the
discovery during the 1990s of 2 genes that cause some breast cancers,
BRCA1 and BRCA2, represents considerable promise because many
people who have a higher probability of developing breast cancer can
now be identified.

Other genes have been discovered that are associated with some
cancers that run in families, such as cancers of the colon, rectum,
kidney, ovary, thyroid, pancreas and skin melanoma. Familial cancer is
 7

not nearly as common as spontaneous cancer, causing less than 15% of

all cancers, but it is important to understand these cancers because with
continued research in genetics we may be able to identify persons at
very high risk.

 Modern day carcinogens

More recently, other causes of cancer were discovered and documented.

In 1911 Peyton Rous, at the Rockefeller Institute in New York, described
a type of cancer (sarcoma) in chickens caused by what later became
known as the Rous sarcoma virus. He was awarded the Nobel Prize for
that work in 1968. In 1915 cancer was induced in laboratory animals for
the first time by a chemical, coal tar, applied to rabbit skin at Tokyo
University. One hundred and fifty years had passed since the most
destructive source of chemical carcinogens known to man, tobacco, was
first identified in London by the astute clinician John Hill. It was to be
many years until tobacco was "rediscovered" as a carcinogen (a
substance known or believed to cause cancer in humans).

Today we recognize and avoid many specific substances that cause

cancer: coal tars and their derivatives such as benzene, some
hydrocarbons, aniline (a substance used to make dyes), asbestos, and
others. Radiation from a variety of sources, including the sun, is known
to lead to cancer. To ensure the public's safety, the government has set
standards for many substances, such as benzene, asbestos,
hydrocarbons in the air, arsenic in drinking water, radiation, and so on.

Several viruses are now linked to cancer:

 Long-standing liver infection with the hepatitis B or C

viruses can lead to cancer of the liver.

 A variety of the herpes virus, the Epstein-Barr virus, causes

infectious mononucleosis and has been implicated in non-
Hodgkin lymphomas and nasopharyngeal cancer.

 The human immunodeficiency virus (HIV) is associated with

an increased risk of developing several cancers, especially Kaposi
Sarcoma and non-Hodgkin lymphoma.

 Human papilloma viruses (HPVs) have been linked to

several cancers, especially those of the cervix, vulva, and penis. A
test for types HPV types linked to cervical cancer was approved by
the FDA for clinical use in cervical cancer screening in 2003. A
 8

vaccine that prevents infection with 2 cancer-associated HPV

types was approved by the FDA in 2006 for use in cancer
prevention.

As of 2008, the World Health Organization's International Agency for

Research on Cancer (IARC) has identified more than 100 chemical,
physical, and biological carcinogens. Many of these associations were
recognized long before scientists understood the mechanism by which
the cancer was produced, but continuing research is discovering new
carcinogens, explaining how they cause cancer, and providing insight
into ways to prevent cancer.

 Cancer epidemiology
During the 18th century, 3 important observations were made that
launched the field of cancer epidemiology.

 Bernardino Ramazzini, an Italian doctor, reported in 1713

the virtual absence of cervical cancer and relatively high incidence
of breast cancer in nuns and wondered whether this was in some
way related to their celibate lifestyle. This observation was an
important step toward identifying and understanding the
importance of hormonal factors such as pregnancy and infections
related to sexual contact in modifying cancer risk.

 Percival Pott of Saint Bartholomew's Hospital in London

described in 1775 an occupational cancer in chimney sweeps,
cancer of the scrotum, caused by soot collecting under their
scrotum. This research led to many additional studies that
identified a number of occupational carcinogenic exposures and
led to public health measures to reduce cancer risk.

 John Hill of London was the first to recognize the dangers

of tobacco. In 1761, only a few decades after tobacco became
popular in London, he wrote a book entitled Cautions against the
Immoderate Use of Snuff.

 Results of epidemiologic research published during the

1950s and early 1960s demonstrate that smoking is a cause of
lung cancer, and lead to the US Surgeon General's 1964 report
Smoking and Health.

Epidemiologists continue their search for factors that cause cancer

(such as tobacco use, obesity, ultraviolet radiation) as well as those
offering protection against cancer (such as physical activity, healthful
diet). This research provides evidence to guide pubic health
recommendations and regulations. As molecular biologists learn more
about how factors cause of prevent cancer, this information is used in
 9

studies of molecular epidemiology, which study the interactions between

genes and external factors.

 Cancer screening and early detection

Screening refers to tests and exams used to find a disease, such as
cancer, in people who do not have any symptoms. The first screening
test to be widely used for cancer was the Pap test. The test was first
developed by George Papanicolaou as a research method in
understanding the menstrual cycle. Papanicolaou soon recognized its
potential for early detection of cervical cancer and presented his
findings in 1923. Most doctors were initially skeptical, and it was not
until the American Cancer Society promoted the test during the early
1960 that this test was widely used. Since that time, the cervical cancer
death rate in the United States has declined by about 70%. Modern
mammography methods were developed late in the 1960s and first
officially recommended by the ACS in 1976.

Current American Cancer Society guidelines include methods for early

detection of cancers of the cervix, breast, colon and rectum,
endometrium, and prostate, as well as a cancer-related checkup which,
depending on a person's age and gender, might include exams for
cancers of the thyroid, oral cavity, skin, lymph nodes, testes, and
ovaries.

 Cancer treatments:

1) Surgery
Ancient physicians and surgeons knew that cancer would usually come
back after it was removed by surgery. The Roman physician Celsus
wrote, "After excision, even when a scar has formed, none the less the
disease has returned."

Galen was a 2nd-century Roman doctor whose books were preserved for
centuries and who was thought to be the highest medical authority for
over a thousand years. Galen viewed cancer much as Hippocrates had,
and his views set the pattern for cancer management for centuries. He
considered the patient incurable after a diagnosis of cancer had been
made.

Even though medicine progressed and flourished in some ancient

civilizations, there was little progress in cancer treatment. The approach
to cancer was Hippocratic (or Galenic) for the most part. To some extent
this view that cancer cannot be cured has persisted even into the 20th
century. This has served to fuel the fear patients have of the disease.
 10

Some people, even today, consider all cancer incurable and delay
consulting a doctor until it is too late.

Treatments for cancer went through a slow process of development. The

ancients recognized that there was no curative treatment once a cancer
had spread and that intervention might be more harmful than no
treatment at all. Galen did write about surgical cures for breast cancer if
the tumor could be completely removed at an early stage. Surgery then
was very primitive with many complications, including blood loss. It
wasn't until the 19th and early 20th centuries that major advances were
made in general surgery and specifically in cancer surgery.

There were great surgeons before the discovery of anesthesia. John

Hunter, Astley Cooper, and John Warren achieved lasting acclaim for
their swift and precise surgery. But when anesthesia became available in
1846, there emerged the great surgeons whose work so rapidly
advanced the art that the next hundred years became known as "the
century of the surgeon."

Three surgeons stand out because of their contributions to the art and
science of cancer surgery: Bilroth in Germany, Handley in London, and
Halsted at Johns Hopkins. Their work led to "cancer operations"
designed to remove all of the tumor together with the lymph nodes in the
region where the tumor was located.

William Stewart Halsted, professor of surgery at Johns Hopkins

University, developed the radical mastectomy during the last decade of
the 19th century. His work was based in part on that of W. Sampson
Handley, the London surgeon who believed that cancer spread outward
by invasion from the original growth.

Halsted did not believe that cancers usually spread through the
bloodstream: "Although it undoubtedly occurs, I am not sure that I have
observed from breast cancer, metastasis which seemed definitely to
have been conveyed by way of the blood vessels." He believed that
adequate local removal of the cancer would be curative -- if the cancer
later appeared elsewhere, it was a new process. That belief led him to
develop the radical mastectomy for breast cancer. This became the basis
of cancer surgery for almost a century until the 1970s, when modern
clinical trials demonstrated that less extensive surgery is equally
effective for most women with breast cancer. Today, the radical
mastectomy is almost never performed and the "modified radical
mastectomy" is performed less frequently than before; most women with
breast cancer undergo local removal of the primary tumor (lumpectomy)
coupled with radiation therapy.

At the same time Halsted and Handley were developing their radical
operations, another surgeon was asking, "What is it that decides which
organs shall suffer in a case of disseminated cancer?" Stephen Paget,
an English surgeon, concluded that cancer cells spread by way of the
 11

bloodstream to all organs of the body but were able to grow only in a few
organs. In a brilliant leap of logic he drew an analogy between cancer
metastasis and seeds that "are carried in all directions, but they can only
live and grow if they fall on congenial soil."

Paget's conclusion that cells from a primary tumor spread through the
bloodstream but could grow only in certain, and not all, organs was an
accurate and highly sophisticated hypothesis that was confirmed by the
techniques of modern cellular and molecular biology almost a hundred
years later. This understanding of metastasis became a key element in
recognizing the limitations of cancer surgery. It eventually allowed
doctors to develop systemic treatments used after surgery to destroy
cells that had spread throughout the body and to use less mutilating
operations, for example, in treating many types of cancer. Today these
systemic treatments may also be used before surgery.

During the final decades of the twentieth century, surgeons developed

greater technical expertise in minimizing the amounts of normal tissue
removed during cancer operations. Like the trend from radical
mastectomy to lumpectomy, progress was also made in removing bone
and soft tissue tumors of the arms and legs without the need for
amputation in most cases, and in avoiding a colostomy for most patients
with rectal cancer. This progress depended not only on better
understanding of cancer as a disease and on better surgical
instruments, but also on combining surgery with chemotherapy and/or
radiation.

Until the end of the twentieth century, cancer diagnosis required

"exploratory surgery" to open the abdomen or chest so the surgeon
could take tissue samples to be tested for cancer. Starting in the 1970s,
progress in ultrasound (sonography), computed tomography (CT scans),
magnetic resonance imaging (MRI scans), and positron emission
tomography (PET scans) have replaced most exploratory operations. CT
scans and ultrasound can be used to guide biopsy needles into tumors
of internal organs.

Instruments that use fiberoptic technology and miniature video cameras

permit doctors to view the inside of the body. Surgeons can use special
surgical instruments operated through tubes inserted into the body.
Endoscopic surgery can remove tumors through tubes inserted through
body openings to reach the colon, esophagus, or bladder. Similar
instruments can also be inserted through small incisions to reach the
abdomen (laporscopic surgery) or chest (thorascopic surgery).

Less invasive ways of destroying tumors without removing them are

being studied and/or used. Cryosurgery (also called cryotherapy or
cryoablation) uses liquid nitrogen spray or a very cold probe to freeze
and kill abnormal cells. Lasers can be used to cut through tissue
(instead of using a scalpel) or to vaporize (burn and destroy) cancers of
the cervix, larynx (voice box), liver, rectum, skin and other organs.
 12

Radiofrequency ablation transmits radio waves to a small antenna

placed in the tumor to kill cancer cells by heating them.

2) Hormone therapy
Another 19th-century discovery laid the groundwork for an important
modern method to treat and prevent breast cancer. Thomas Beatson
graduated from the University of Edinburgh in 1874 and developed an
interest in the relation of the ovaries to milk formation in the breasts,
probably because he grew up near a large sheep farm in rural Scotland.
In 1878 he discovered that the breasts of rabbits stopped producing milk
after he removed the ovaries. He described his results to the Edinburgh
Medico-Chirurgical Society in 1896: "This fact seemed to me of great
interest, for it pointed to one organ holding control over the secretion of
another and separate organ."

Because the breast was "held in control" by the ovaries, Beatson

decided to test removal of the ovaries (oophorectomy) in advanced
breast cancer. He found that oophorectomy often resulted in the
improvement of breast cancer patients. He also suspected that "the
ovaries may be the exciting cause of carcinoma" of the breast. He had
discovered the stimulating effect of the female ovarian hormone
(estrogen) on breast cancer, even before the hormone itself was
discovered. His work provided a foundation for the modern use of
hormone therapy, such as tamoxifen, for the treatment and prevention of
breast cancer.

A half century after Beatson’s discovery, a urologist at the University of

Chicago, Charles Huggins, reported dramatic regression of metastatic
prostate cancer following removal of the testes. Later, drugs that
blocked male hormone were found to be effective treatment for prostate
cancer, and these drugs are now being studied to determine if they have
a role in prevention of prostate cancer.

New classes of drugs (such as aromatase inhibitors, LHRH analogs and

inhibitors, and others) have substantially changed treatment of prostate
and breast cancer. Ongoing research to better understand how
hormones influence growth of some forms of cancer has guided
progress in developing and prescribing new drugs for cancer treatment
as well as for reducing the risk of developing breast and prostate cancer.

3) Radiation
As the 19th century was drawing to a close, in 1896 a German physics
professor, Wilhelm Conrad Roentgen, presented a remarkable lecture
entitled "Concerning a New Kind of Ray." Roentgen called it the "X-ray",
with "X" being the algebraic symbol for an unknown quantity. There was
 13

immediate worldwide excitement. Within months, systems were being

devised to use X-rays for diagnosis, and within 3 years radiation was
used in the treatment of cancer.

In 1901 Roentgen received the first Nobel Prize awarded in physics.

Radiation therapy began with radium and with relatively low-voltage
diagnostic machines. In France a major breakthrough took place when it
was discovered that daily doses of radiation over several weeks would
greatly improve therapeutic response. The methods and the machines
for delivery of radiation therapy have steadily improved. Today, radiation
is delivered with great precision in order to destroy malignant tumors
while minimizing damage to adjacent normal tissue.

At the beginning of the 20th century, shortly after radiation began to be

used for diagnosis and therapy, it was discovered that radiation could
cause cancer as well as cure it. Many early radiologists used the skin of
their arms to test the strength of radiation from their radiotherapy
machines, looking for a dose that would produce a pink reaction
(erythema) that looked like sunburn. They called this the "erythema
dose," and this was considered an estimate of the proper daily fraction
of radiation. In retrospect, it is no surprise that many developed
leukemia.

Advances in radiation physics and computer technology during the last

quarter of the 20th century are making it possible to aim radiation more
precisely than in the past. Conformal radiation therapy (CRT) uses CT
images and special computers to very precisely map the location of a
cancer in 3 dimensions. The patient is fitted with a plastic mold or cast to
keep the body part still. The radiation beams are matched to the shape of
the tumor and delivered to the tumor from several directions. Intensity-
modulated radiation therapy is like CRT but along with aiming photon
beams from several directions, the intensity (strength) of the beams can
be adjusted. This gives even more control over decreasing the radiation
reaching normal tissue while delivering a higher dose to the cancer.

A related technique, conformal proton beam radiation therapy, uses a

similar approach to focusing radiation on the cancer. But instead of
using X-rays, this technique uses proton beams. Protons are parts of
 14

atoms that cause little damage to tissues they pass through but are very
effective in killing cells at the end of their path. This means that proton
beam radiation can deliver more radiation to the cancer while reducing
side effects of nearby normal tissues.

Stereotactic surgery and stereotactic radiation therapy are terms that

describe several techniques used to deliver a large, precise radiation
dose to a small tumor. The term surgery may be confusing because no
incision is actually made. The most common site being treated with this
technique is the brain. The linear accelerator, or a special machine
known as a Gamma Knife, can be used to deliver this treatment.
Research is ongoing to produce delivery systems to treat sites other
than the brain.

Intraoperative radiation therapy (IORT) is a form of treatment that

delivers radiation at the time of surgery directly to the cancer or the
adjacent tissues after the cancer has been removed. It is more
commonly used in abdominal or pelvic cancers and in cancers that have
a tendency to return. IORT minimizes the amount of tissue that is
exposed to radiation because normal tissues can be moved out of the
way during surgery and shielded, thus allowing a higher dose of
radiation to the cancer.

Chemical modifiers or radiosensitizers are substances that make cancer

more sensitive to radiation. The goal of research into these types of
substances is to develop agents that will make the tumor more sensitive
without affecting normal tissues. Research is also ongoing to find
substances that may protect normal cells from radiation.

4) Chemotherapy
The century of the surgeon had begun with the discovery of anesthesia
in 1846. Fifty years later, in 1896, Roentgen presented his famous paper
on the X-ray. During World War II, naval personnel who were exposed to
mustard gas as a result of a military action were found to have toxic
effects on the bone marrow cells that develop into blood cells. During
that same period, the U.S Army was studying a number of agents related
to mustard gas in order to develop more effective agents and to develop
protective measures. In the course of that work, a compound called
nitrogen mustard was studied and found to have substantial activity
against a cancer of the lymph nodes called lymphoma. This agent served
as the model for a long series of similar but more effective agents (called
"alkylating" agents) that killed rapidly proliferating cancer cells by
damaging their DNA.

Not long after the discovery of nitrogen mustard, Sidney Farber of

Boston demonstrated that aminopterin, a compound related to the
vitamin, folic acid, produced remission in acute leukemia in children.
Aminopterin blocked a critical chemical reaction needed for DNA
replication. That drug was the predecessor of methotrexate, a commonly
 15

used cancer treatment drug today. Since then, other researchers

discovered drugs that blocked different functions involved in cell growth
and replication. The era of chemotherapy had begun. The first cure of
metastatic cancer was obtained in 1956 when methotrexate was used to
treat a rare tumor called choriocarcinoma.

Over the years, the development and use of chemotherapy drugs have
resulted in the successful treatment of many people with cancer. Long
term remissions and even cures of many patients with Hodgkin disease
and childhood acute lymphoblastic leukemia with chemotherapy were
first reported during the 1960s, with testicular cancer following during
the next decade. Many other cancers can be controlled for long periods
of time, even if not cured, although even the most chemosenstive forms
of cancer are not always curable. Now several approaches are being
studied to improve the activity and reduce the undesirable side effects of
chemotherapy. These include:

 new drugs, new combinations of drugs, and new delivery

techniques

 novel approaches to targeting drugs more specifically at the

cancer cells (such as liposomal therapy and monoclonal antibody
therapy) to produce fewer side effects

 drugs to reduce side effects, like colony-stimulating factors,

chemoprotective agents (such as dexrazoxane and amifostine),
and antiemetics (to reduce nausea and vomiting)

 hematopoietic stem cell transplantation

 agents that overcome multidrug resistance

Liposomal therapy is a new technique that uses chemotherapy drugs

that have been packaged inside liposomes (synthetic fat globules). This
liposome, or fatty coating, helps them penetrate the cancer cells more
selectively and decreases possible side effects (such as hair loss,
nausea, and vomiting). Examples of liposomal medications are Doxil (the
encapsulated form of doxorubicin) and Daunoxome (the encapsulated
form of daunorubicin).

Early in the 20th century, the only curable cancers were small and
localized enough to be completely removed by surgery. Later, radiation
was used after surgery to control small tumor growths that were not
surgically removed. Finally, chemotherapy was added to destroy small
tumor growths that had spread beyond the reach of the surgeon and
radiotherapist. The use of chemotherapy after surgery to destroy the few
remaining cancer cells in the body is called adjuvant therapy. Adjuvant
therapy was tested first in breast cancer and found to be effective. It was
later used in colon cancer, cancer of the testis, and others.
 16

A major discovery was the advantage of multiple chemotherapeutic

agents (known as combination chemotherapy) over single agents. Some
types of very fast-growing leukemias and lymphomas (tumors involving
the cells of the bone marrow and lymph nodes, respectively) responded
extremely well to combination chemotherapy, and clinical trials led to
gradual improvement of the drug combinations used. Many of these
tumors can be cured today by appropriate combination chemotherapy.

The approach to patient treatment has become more scientific with the
introduction of clinical trials on a wide basis throughout the world.
These clinical trials compare new treatments to standard treatments and
contribute to a better understanding of treatment benefits and risks.
Clinical trials test theories about cancer learned in the basic science
laboratory and also test ideas derived from the clinical observations on
cancer patients. They are essential to continued progress.

5) Immunotherapy
Scientists’ understanding of the biology of cancer cells has led to the
development of biologic agents that mimic some of the natural signals
that the body uses to regulate growth. This cancer treatment, called
biological response modifier (BRM) therapy, biologic therapy,
biotherapy, or immunotherapy, has proven effective for several cancers
through the clinical trial process.

Some of these biologic agents, occurring naturally in the body, can now
be produced in the laboratory. Examples are interferons, interleukins,
and other cytokines. These agents are given to patients to imitate or
influence the natural immune response either by directly altering the
cancer cell growth or acting indirectly to help healthy cells control the
cancer.

One of the most exciting applications of biologic therapy has come from
identifying certain tumor targets, called antigens, and aiming an
antibody at these targets. This method was first used to localize tumors
in the body for diagnosis and more recently has been used to attack
cancer cells. Using technology first developed during the 1970s,
scientists can mass produce monoclonal antibodies that are specifically
targeted to chemical components of cancer cells. Refinements to these
methods, using recombinant DNA technology, have improved the
effectiveness and decreased the side effects of these treatments. The
first therapeutic monoclonal antibodies, rituximab (Rituxan) and
trastuzumab (Herceptin) were approved during the late 1990s for treating
lymphoma and breast cancer, respectively. At least 9 monoclonal
antibodies are already used for cancer treatment, and many more are
being studied.

Scientists are also studying vaccines to would boost the body’s immune
response to cancer cells.
 17

6) Targeted therapies
Until the late 1990s nearly all drugs used in cancer treatment (with the
notable exception of hormonal treatments) worked by killing cells that
were in the process of replicating their DNA and dividing to form 2 new
cells. These chemotherapy drugs also killed some normal cells but
fortunately, had a greater effect on cancer cells.

On the other hand, targeted therapies work by influencing the processes

that control growth division, and spread of cancer cells, as well as the
signals that cause cancer cells to naturally die (in the way normal cells
when they are too old). These targeted therapies work in several ways.

Growth signal inhibitors: Growth factors are hormone-like substances

that help tell cells when to grow and divide. Their role in fetal growth and
repair of injured tissue was first recognized during the 1960s. Later on,
they realized that abnormal forms or abnormally high levels of the same
factors contribute to the growth and spread of cancer cells. Researchers
have also started to understand how these factors are recognized by
cells, and how that recognition leads to signals inside the cells resulting
in the abnormal features of cancer cells. Changes in these signal
pathways have also been recognized as causing the abnormal behavior
of cancerous cells. During the 1980s, scientists recognized that many of
the growth factors and other substances responsible for growth factor
recognition and signaling are actually products of oncogenes. Among
the earliest targeted therapies that block growth signals are trastuzumab
(Herceptin), gefitinib (Iressa), imatinib (Gleevec), and cetuximab
(Erbitux).

Angiogenesis inhibitors: Angiogenesis is the creation of new blood

vessels. The term comes from 2 Greek words: angio, meaning "blood
vessel," and genesis, meaning "beginning." Normally, this is a healthy
process. New blood vessels, for instance, help the body heal wounds
and repair damaged body tissues. But in a person with cancer, this same
process creates new, very small blood vessels that provide a tumor with
its own blood supply and allow it to grow. Anti-angiogenesis is a form of
targeted therapy that uses drugs or other substances to stop tumors
from making new the blood vessels they need to continue growing. This
concept was first proposed by Judah Folkman in the early 1970s but it
wasn't until 2004 that the first angiogenesis inhibitor, bevicizumab
(Avastin) was approved for clinical use.

Apoptosis-inducing drugs: Apoptosis is a natural process through which

cells with DNA too damaged to repair -- such as cancer cells -- can be
forced to die. Many anticancer treatments (including radiation and
chemotherapy) cause cell changes that eventually lead to apoptosis. But
targeted drugs in this group are different, because they are aimed
specifically at the cell substances that control cell survival and death.
 18

 Cancer survivorship
Only a few decades ago, the prognosis (outlook) for people facing
cancer was not nearly as favorable as it is today. During the 1970s, the 1
out of 2 people diagnosed with cancer survived at least five years. Now,
more than 2 out of 3 survive that long. Today there are about 11 million
cancer survivors in the United States.

Now that more people are surviving cancer, more attention than ever is
focused on the quality of life for cancer survivors. Behavioral
researchers have conducted studies to learn more about the problems
survivors face. Some of these problems are medical ones, such as
permanent side effects of treatment. Others are emotional or social
challenges, like problems getting healthcare insurance, discrimination
by employers, or that some people avoid cancer survivors because they
just don’t know what to say and are afraid to ask.

Cancer was once a word that people were afraid to speak in public, and
people rarely admitted to being a cancer survivor. Now, many celebrities
and national leaders have very openly discussed their cancer
experiences.

 The twenty-first century and beyond

The growth in our knowledge of cancer biology has led to remarkable
progress in cancer prevention, early detection, and treatment in recent
years. Scientists have learned more about cancer in the last two decades
than has been learned in all the centuries preceding. This does not
change the fact, however, that all scientific knowledge is based on the
knowledge already acquired by the hard work and discovery of our
predecessors, and that much more remains to be learned.

Cancer research is currently advancing on so many fronts that it is

difficult to choose the ones to highlight here.

More targeted therapies: As more is learned about the molecular biology

of cancer, researchers will have more targets at which to aim their new
drugs. In addition to more monoclonal antibodies and small signaling
pathway inhibitors, researchers are developing new classes of
molecules such as antisense oligodeoxynucleotides and small
interfering RNA (siRNA).

Nanotechnology: New technology for producing new materials that form

extremely tiny particles is leading to very promising methods for
diagnostic imaging to more accurately demonstrate the location of
tumors, and for delivering drugs more specifically and effectively into
cancer cells.
 19

Robotoic surgery: This term refers to manipulation of surgical

instruments remotely by robotic arms and other devices controlled by a
surgeon. Robotic systems have been used for several types of cancer
surgery; radical prostatectomy is among the most common application
in surgical oncology. As mechanical and computer technology improve,
some researchers expect future systems will be able to remove tumors
more completely and with less surgical trauma than an unaided surgeon
could.

RNA expression profiling and proteomics: RNA expression profiling

permits scientists to determine relative amounts of hundreds or even
thousands or RNA molecules at one time. Knowing what proteins or RNA
molecules are present in cells can tell scientists a lot about how the cell
is behaving. In the case of cancer, it can help distinguish more
aggressive cancers from less aggressive ones, and can often help
predict which drugs the tumor is likely to respond to. Proteomic
methods are also being tested for cancer screening. For most types of
cancer, measuring the amount of one protein in the blood is not very
accurate at finding early cancers. But researchers are hopeful that
comparing the relative amounts of many proteins may be more useful,
and that knowing particular proteins are abnormally abundant and
others are less abundant can provide accurate information.

Classification of Cancer
Cancers are classified by the type of cell that resembles the tumor and,
therefore, the tissue presumed to be the origin of the tumor. These are
the histology and the location, respectively. Examples of general
categories include:

• Carcinoma: Malignant tumors derived from epithelial cells. This

group represents the most common cancers, including the common forms of
breast, prostate, lung and colon cancer.
• Sarcoma: Malignant tumors derived from connective tissue, or
mesenchymal cells.
• Lymphoma and leukemia: Malignancies derived from
hematopoietic (blood-forming) cells
• Germ cell tumor: Tumors derived from totipotent cells. In adults
most often found in the testicle and ovary; in fetuses, babies, and young
 20

children most often found on the body midline, particularly at the tip of the
tailbone; in horses most often found at the poll (base of the skull).
• Blastic tumor or blastoma: A tumor (usually malignant) which
resembles an immature or embryonic tissue. Many of these tumors are most
common in children.

 Malignant and Benign Tumors

Malignant tumors (cancers) are usually named using -carcinoma,

-sarcoma or -blastoma as a suffix, with the Latin or Greek word for the
organ of origin as the root. For instance, a cancer of the liver is called
hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For
common cancers, the English organ name is used. For instance, the
most common type of breast cancer is called ductal carcinoma of the
breast or mammary ductal carcinoma. Here, the adjective ductal refers to
the appearance of the cancer under the microscope, resembling normal
breast ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix
with the organ name as the root. For instance, a benign tumor of the
smooth muscle of the uterus is called leiomyoma (the common name of
this frequent tumor is fibroid). Unfortunately, some cancers also use the
-oma suffix, examples being melanoma and seminoma.

Signs and symptoms

Symptoms of cancer metastasis depend on the location of the tumor.
Roughly, cancer symptoms can be divided into three groups:

• Local symptoms: unusual lumps or swelling (tumor),

hemorrhage (bleeding), pain and/or ulceration. Compression of
surrounding tissues may cause symptoms such as jaundice
(yellowing the eyes and skin).

• Symptoms of metastasis (spreading): enlarged lymph

nodes, cough and hemoptysis, hepatomegaly (enlarged liver),
bone pain, fracture of affected bones and neurological symptoms.
 21

Although advanced cancer may cause pain, it is often not the first
symptom.

• Systemic symptoms: weight loss, poor appetite, fatigue and

cachexia (wasting), excessive sweating (night sweats), anemia and
specific paraneoplastic phenomena, i.e. specific conditions that
are due to an active cancer, such as thrombosis or hormonal
changes.

Every symptom in the above list can be caused by a variety of conditions

(a list of which is referred to as the differential diagnosis). Cancer may
be a common or uncommon cause of each item.

• The cell Cycle disturbances.

• The shape.
• Behavior changes (in replication
and function).
 22

• Biophysics and Biochemistry of

cancer cell.
• Apoptosis and Cancer.

• The Normal Cell and the

Cell cycle
The human body is made up of about 10 trillion cells and the ability of
each of these to produce exact replicas is an essential component of life.
In order to begin to understand how things might go wrong and cancer
might develop, it is essential to understand normal cellular processes.

 WHAT IS A CELL?

The cell is the basic unit of all living matter, whether a single celled
bacterium like Escherichia coli or a multicelled organism like a human
being. Every cell is remarkable; not only do they have the ability to carry
out complex tasks, for example uptake of nutrients and conversion to
energy, and the ability to replicate, but they also contain all the
instructions to carry out these tasks. Cells are divided into two
categories: (1) prokaryotes and (2) eukaryotes:
 23

1. Prokaryotes lack a nuclear membrane (the membrane that surrounds

the nucleus). The best-known examples of prokaryotic organisms are
bacteria. They are composed of a cell envelope, within which the
cytoplasmic region is contained. This region contains cytoplasm, which
is a fluid made up of about 70% water, the remainder comprising
enzymes that the cell has manufactured, amino acids, glucose molecules
and adenosine triphosphate (ATP). At the centre of the cell is its DNA,
which due to the lack of a nuclear membrane floats within the cytoplasm.
2. Eukaryotes contain cell organelles, each organelle has its own
structure and specific function or metabolic process to carry out.

  HOW DOES A CELL DEVELOP AND REPLICATE?

Eukaryotic cells divide to produce two identical daughter cells, each

containing exact copies of the DNA from the parent cell; in this way,
multicellular organisms are able to replace damaged or worn out cells.
The preparation for cell division occurs during interphase, the cell then
divides during mitosis, combined these processes form the cell cycle.
 24

The cell cycle, or cell-division cycle, is the series of events that takes
place in a cell leading to its division and duplication (replication). In cells
without a nucleus (prokaryotes), the cell cycle occurs via a process
termed binary fission. In cells with a nucleus (eukaryotes), the cell cycle
can be divided in two brief periods: interphase—during which the cell
grows, accumulating nutrients needed for mitosis and duplicating its
DNA—and the mitosis (M) phase, during which the cell splits itself into
two distinct cells, often called "daughter cells". The cell-division cycle is
a vital process by which a single-celled fertilized egg develops into a
mature organism, as well as the process by which hair, skin, blood cells,
and some internal organs are renewed.

To the naked eye, interphase appears to be a period of rest for the cell,
but in fact much activity is taking place. During this time, RNA is
constantly being synthesized, protein is produced and the cell is
growing in size. Scientists have determined at a molecular level that the
interphase can be divided into the following stages:

 Gap 0 (G0). Cells may leave the cell cycle for a temporary resting
period or more permanently if they have reached the end of their
development, for example neurons. Cells in this phase are often
termed quiescent and in order to enter back into the cycle they must
be stimulated by growth factors, for example platelet-derived growth
factor (PDGF). Cells that have permanently stopped dividing due to
age or accumulation of cellular damage are termed senescent.

 Gap 1 (G1). Cells increase in size, produce RNA and synthesize

protein. There is an important cell cycle control mechanism
 25

(checkpoint) activated during this stage (see Section ‘Tumour

Suppressor Genes’) that cells must pass through in order to progress
to the S phase. Synthesis phase (S phase). DNA is replicated during
this phase so that the two daughter cells produced following mitosis
will contain a copy of the DNA from the parent cell.

 Gap 2 (G2). Cells continue to grow and produce new proteins. At

the
end of G2, another important checkpoint is activated. Now the cell is
ready to enter mitosis, which is further divided into the following stages:

 Prophase. At the beginning of prophase, the nuclear

membrane breaks down and chromatin in the nucleus condenses into
chromosomes (these can be viewed under a light microscope). Each
chromosome consists of two genetically identical chromatids.
Microtubules, which are responsible for cell shape, disassemble, and
the building blocks of these are used to form the mitotic spindle.

 Prometaphase. There is now no longer a recognizable

nucleus. Some mitotic spindle fibres elongate to specific areas on the
chromosomes.

 Metaphase. Tension is applied to the spindle fibres, aligning

all the chromosomes in one plane at the centre of the cell.

 Anaphase. The chromosomes are pulled away from the central

plane towards the cell poles.

 Telophase. Chromosomes arrive at cell poles and

decondense, and the nuclear envelope reforms around the clusters at
each end of the cell, thereby forming new nuclei.

 Cytokinesis. The cell is cleaved to form two daughter cells and

microtubules reform for the cells’ entry into interphase.Cells formed
by mitosis are said to be diploid because they contain two sets of
homologous chromosomes. Another form of cell division to be aware
of is meiosis, which occurs only in reproductive cells during the
formation of gametes (sex cells). A cell dividing by meiosis duplicates
its DNA as with cells undergoing mitosis, but splits into four new cells
instead of two and contains only one copy of each chromosome.
These cells are said to be haploid.

 HOW IS THE CELL CYCLE CONTROLLED?

Cancer can be described as the uncontrolled proliferation and growth of

cells into other tissues. If we can understand the normal mechanisms
that control the cell cycle, we can begin to understand how these
controls may malfunction and cause cancer to develop. Understanding
 26

the cell cycle and its controls also allows the development of specific
and targeted therapies to treat the disease.

• CYCLINS AND CYCLIN-DEPENDENT KINASES

Many different proteins located within the cytoplasm control the cell
cycle; two of the main types are cyclins (the regulatory subunit) and
cyclin-dependent kinases (CDKs, the catalytic subunit). A cyclin joins
with a CDK to form a complex (cyclin-CDK). If a problem with the cell
cycle is detected then activation of the cyclin-CDK complex is not
completed. If there are no problems within the cell cycle then formation
of the cyclin-CDK is completed. This leads to the activation of
a transcription factor by the removal of a transcription factor inhibitor.
The transcription factor activates transcription of the genes required for
the next stage of the cell cycle, including the cyclin and CDK genes.
During the cell cycle, levels of cyclins within the cell will rise and fall but
the levels of CDKs will remain fairly constant. Activation of CDKs is a
central event in regulating the cell cycle and their activity is therefore
regulated at many different levels.

• TUMOUR SUPPRESSOR GENES

Tumour suppressor genes prevent excessive growth of a cell; the most
well known ones are p53 and the retinoblastoma (Rb) gene.

• p53
The p53 protein is essential for protecting us against cancer. More than
half of human cancers have p53 mutations and therefore no functioning
p53. p53 works by sensing DNA damage and halting the cell cycle. This
is essential, because if DNA is damaged but still replicated in S phase, it
could eventually manifest in the form of a protein mutation. By halting
the cell cycle at the G1 checkpoint, this can be prevented. So how does
this process work? Again, it comes back to the involvement of CDKs.
First, in response to a variety of stress signals, for example DNA
damage, p53 switches from an inactive state to an active state. It then
triggers transcription of the gene for p21, which is a CDK inhibitor.
Because active CDKs are needed to progress through the cell cycle, an
inactive CDK will cause the cycle to halt.
The p53 protein is also involved at the G2 checkpoint in cases, for
example, where DNA has been synthesized incorrectly. At this
checkpoint, p53 binds to E2F and prevents it from triggering
transcription of proto-oncogenes, for example c-myc and c-fos, which
are required for mitosis. Proto-oncogenes are important promoters of
normal cell growth and division; however, if they become mutated they
are known as oncogenes and can have a detrimental effect. A single
oncogene cannot cause cancer by itself but it can cause the cell cycle to
lose its inhibitory controls, thereby increasing the rate of mitosis. When
a cell loses control over mitosis, it can be the beginning of the pathway
leading to the development of cancer.
 27

Regulation of Cell Cycle

• THE CANCER CELL

Like normal tissues, the development of malignant tissues also begins at

the cellular level. However, in ways as yet not fully explained, malignant
changes result in the partial or complete breakdown of normal growth-
control mechanisms, thereby producing the tissue growths we know as
 28

cancers. The basic organization of normal cells and cancer cells is

similar. Both are composed of the same materials. Cancer cells utilize
the same nutrients and produce the same waste products as do normal
cells. Growth and multiplication of cancer cells and normal cells occur
by the same fundamental processes, and even the invasive, metastatic,
and genetically unstable properties of cancer cells are exhibited by
various normal cells at various times during normal growth. As we
examine the cancer cell, we can detect differences, but it is difficult to
determine whether an abnormal trait represents a primary characteristic
of cancer or merely a secondary side effect of malignant growths. The
plasma membrane is the site of many specialized receptors for
hormones that regulate growth and metabolism. Changes in membrane
functions usually accompany neoplastic transformation. Cancer cells
often exhibit more rapid rates of uptake of nutrients than their normal
counterparts, reflecting changes in the activity of membrane transport
mechanisms. There is also evidence that cancer cells may exhibit
abnormal responses to hormones that act at the cell surface, suggesting
critical changes in hormone receptors are involved in control of growth
and differentiation. Since hormones regulate growth, it is tempting to
postulate that a change in hypothetical receptor is a primary change of
cancer. Another important function of the plasma membrane is
recognition. On the surface of every cell are large molecules, usually
sugar-containing proteins, i.e., glycoproteins, which serve as cellular
identifying markers. Changes in these surface markers often occur
during neoplastic transformation, altering the recognition process
between different types of cells. Such changes have important
consequences, especially with respect to the metastatic ability and
immunologic properties of cancer cells. Again, it is tempting to
speculate that such changes may allow cancer cells to escape the
proper control of the immune system. Many cells contain an intricate
network of minute fibers and filaments. The fibers, called microtubules,
provide the structural support or scaffolding of cells. The filaments,
called microfilaments, are contractile and function in cell movement. The
shape and movement of cells are determined by changes in the
organization of microtubules and microfilaments, often in response to
stimuli that act at the cell surface. The dramatic changes in structure and
mobility that occur during neoplastic transformation are due to
reorganization of the intracellular network of fibers and filaments. For
example, normal fibroblasts in culture have an elongated, spindle-
shaped appearance that depends on the organization of microtubules
along the long axis of the cell. After transformation, cells assume a more
compact pleomorphic appearance, reflecting the random arrangement of
microtubules. Although cancer cells and normal cells contain many of
the same enzymes and other proteins, cancer cells often contain an
altered array of proteins when compared to their normal counterparts.
Many of the membrane proteins, such as the glycoproteins discussed
above, which function in hormone responses and recognition processes,
are altered in type and in quantity after neoplastic transformation. When
a cell divides, giving rise to two daughter cells, the chromosomes in the
nucleus are duplicated so that both daughter cells receive a complete
 29

copy of the genetic information possessed by the parent cell. The fidelity
of this process is very high for normal cells, with relatively few errors. In
contrast, reproduction of chromosomes in cancer cells is highly error
prone, as shown by the many chromosomal abnormalities seen in
cancer cells. There is evidence from studies of virally transformed cells
that the activity of certain of the regulatory proteins associated with
chromosomes may be altered during malignant transformation.
Profound changes in the biologic properties of a cell could occur by
changing the activity of the proteins that control transcription of DNA.
The fact that cancer cells often exhibit abnormal patterns of protein
synthesis suggests a failure of the mechanisms for regulating protein
synthesis within neoplastic cells. Direct and indirect evidence from many
systems suggests that when a normal cell is transformed into a cancer
cell, the primary change is genetic. The precise site or sites within the
DNA have not been identified, and it is likely that multiple sites are
involved. Our current thinking is that cells become cancerous only after
changes have occurred in several independent genes. In other words,
tumors develop only when damage accumulates in a number of genes
within a single cell. These changes include the loss or damage of tumor
suppressor genes, such as p53, and the up-regulation of embryonic
growth proteins such as the
ERB- oncogene product. According to present theory, a single
mutation in DNA would not be sufficient to produce
a transformed cancer cell. The affected cell, or its progeny, must
experience several changes before achieving a stage of malignancy.
Thus, each cancer is the end result of several alterations within a single
cell lineage or “clone” that may have taken place at any time during the
life of the affected individual or perhaps may have taken place in the
germ line. Non-dividing cells are described as being in the G0 phase.
There are four phases of the cell cycle in an actively dividing cell. Mitosis
(M phase) and the DNA synthesis phase (S phase) are separated by two
gaps (G1 and G2). The sequence is M, G1, S, G2. Important functions
take place during each phase. Furthermore, the progression from one
phase to the next is precisely regulated by regulatory proteins called
cyclins, each of which is regulated by cyclin-dependent kinase
(cdk). The genes that code for these regulatory proteins are oncogenes
and cancer suppressor genes and have been discovered to be damaged
in cancer cells, which results in a loss of control of cell division.
The critical biologic change that accompanies neoplastic transformation
is the altered response to mechanisms that control growth and
differentiation. In normal adult tissue, the number of cells is controlled
so that tissue size is proportional to the rest of the organism—
production of new cells occurs at a rate that is adjusted to compensate
for the loss of cells from the tissue. In a cancer, cell production is not
balanced with cell loss, and the cell population increases in number

•Changes in Physical Properties of

Cancer Cells
 30

Tumor cells display a characteristic set of features that distinguish them

from normal cells. These traits allow the individual cells to form a tumor
mass and eventually to metastasize to other parts of the body. We will
briefly consider the changes that affect cell functions and then discuss
some of the capabilities that must be acquired by the tumors as a whole
to enable them to grow and spread.

A wide range of changes occur during the transformation of a normal

cell to a cell capable of forming a cancerous growth. All cancer cells
acquire the ability to grow and divide in the absence of appropriate
signals and/or in the presence of inhibitory signals. There are also
detectable changes in the physical properties of the cells. These
changes include the following:

Cytoskeletal changes- The distribution and activity of the microfilaments

and microtubules may change. These alterations change the ways in
which the cell interacts with neighboring cells and alter the appearance
of the cells. Changes in the cytoskeleton also affect cell adhesion and
movement (motility).

Cell adhesion/motility- The reduction of cell:cell and cell:extracellular

matrix adhesion allows large masses of cells to form. As described in
the chapter on cell division, cancer cells do not exhibit contact inhibition
and are able to continue to grow even when surrounded by other cells.
The alterations in cell adhesion also impact on the ability of the cells to
move. Cancer cells must be able to move and migrate in order to spread,
and cell adhesion plays a major role in regulating cell movement.

Nuclear changes- The shape and organization of the nuclei of cancer cells
may be markedly different from that of the nuclei of normal cells of the
same origin. This change in appearance may be useful in the diagnosis
and staging of tumors.

Enzyme production- Cancer cells often secrete enzymes that enable them
to invade neighboring tissues. These enzymes digest away the barriers
to migration and spread of the tumor cells.
 31

•SURFACE PROPERTIES OF
CANCER CELLS

"In recent years attention has been increasingly turning to the Cell
surface as the seat of an important part of the malignant
transformation."
This is the opening sentence of a recent review by M. Abercrombie and
E. J. Ambrose entitled "The Surface Properties of Cancer Cells."' The
review is divided into two main sections:
(a) A discussion of the biological evidence for the existence of surface
peculiarities of malignant cells;
(b) A discussion of the physical evidence on what the surface
peculiarities may be.
It is a long and authoritative critical review, quoting no fewer than 152
references. In many places it is difficult reading for all except those with
special knowledge of the subject, but we call attention to it because it is
a valuable contribution to a subject of growing importance. Electron-
microscope studies of cell surfaces and biophysical researches have
built up the general conception that the outer membrane of all cells is a
relatively watertight barrier not unlike a thin film of oil through which
water and substances easily soluble in water do not readily pass.
Chemical analysis shows that this membrane contains large amounts of
phospholipids. Phospholipid membranes similar to that which encircles
the cell are found also in the cytoplasm, where they form the scaffolding
out of which are constructed many of the cell's intracellular organelles.
The electron microscope has also recorded the existence of
desmosomes in the outer cell membrane. These are dense localized
areas found on opposed cell membranes, which serve as special
attachment devices. R. J. Goldacre2 has pointed out that the basic role
of the cell membrane in cells showing amoeboid movement has been
interpreted in different ways by different observers. For example, it has
been suggested that an amoeba slides forward in the direction of
locomotion in a "rolling" movement, or that it may actively expand in the
front of the cell. R. D. Allen3 has suggested that the cytoplasm at the
front of the cell contracts and pulls the rear part of the cell after it. Other
explanations have attributed cellular motility to local differences of
surface tension only. Ambrose himself in earlier work' produced
evidence that the main locomotor mechanism in fibrocytes, when
moving on a solid substrate, is due to undulations of the cell membrane
in the region adjacent to the substrate.
 32

He found that the ruffles of the membrane were most pronounced on the
leading edge of the cell and travel backwards towards the nucleus. He
thought that undulations of the membrane could be produced by
contractile fibrils lying just within the cytoplasm and parallel to the cell
surface. These contractions seem to occur largely at random unless the
fibrils become oriented by tension or by cytoplasmic flow, so leading to
polarization of the direction of movement of the cell. In other work,
carried out with J. A. Dudgeon, D. M. Easty, and G. C. Easty, Ambrose5
suggested that the decreased adhesiveness of the surface of tumour
cells.

Schematic illustration of the subcellular structure of a typical eukaryotic cell.

Microscopic Appearance of Cancer Cells

 33

Cancer Cells Change Shape to Spread

Fast in Body
 Cancer cells change their shape to suit different
environments, switching from round to a more “elongated” shape
and back. That ability facilitates rapid spread in the body, UK
scientists say.

 Two proteins - called Rac and Rho - are responsible for the
shape switch, Institute of Cancer researchers said in the journal
Cell.

 Knowledge of how a cancer spreads could improve

treatments, experts said.

 The spread of cancer cells from the initial tumour to other

sites of the body, a process known as metastasis, is one of the
biggest problems in treatment.

 Melanoma, the most dangerous form of skin cancer, is

particularly aggressive.

 Study leader, Professor Chris Marshall, said his team had

been able to view cells in live tumours rapidly undergoing these
changes in shape.

 They discovered that when Rac is switched on it

encourages the cell to become elongated and simultaneously
 34

suppresses the activity of the competing Rho protein.

 Conversely, when cells adopt the round form, a protein

activated by Rho switches off Rac activation.

 It is thought these alternate shapes may enable tumour cells

to deal with different situations during cancer spread.

 Tests suggest that a round-shaped tumour cell may be

better equipped to survive in the bloodstream than elongated
cells.

 Professor Marshall said: "The research has found the

constant competition between two proteins called Rac and Rho is
responsible for allowing the cancer cells to change shape and
spread through the body.

 By explaining a key part of that process, our research

brings new hope for future therapies to fight cancer."

 Co-author, Dr Victoria Sanz-Moreno, said: "Until now the

conversion between different types of movement of individual
cancer cells had been observed but the key players had not been
identified.

 "We are excited to discover that the amount and the activity
of these proteins in the tumour cell regulate its shape and the
mechanism for it to move and invade surrounding tissue."

 Dr Lesley Walker, Cancer Research UK director of cancer

information, said: "Successful treatment tends to be much more
difficult if the cancer has spread.

 "This exciting study has shed light on some of the key

molecules involved in the signalling pathways that encourage
cells to move around the body.

 "Knowing more about how cancer spreads will hopefully

lead to the identification of new drug targets which will enable
scientists to develop anti-cancer drugs to block these pathways."
Metastasis

Newly discovered behavior in cancer cells signals dangerous metastasis

 35

The most aggressively malignant cancer cells have a "toggle

switch" that enables them to morph into highly mobile cells that
invade other tissues and then nest comfortably in their new
surroundings, a new study in rats suggests.

This picture of how cancer cells shift between two alternating states
(travelers and nesters) represents a new understanding of how cancer
metastasizes, or spreads to other parts of the body, said the Duke
Comprehensive Cancer Center researchers who conducted the study.

"Understanding this toggle switch might ultimately enable scientists to

find ways to stop cells from metastasizing, which is the most deadly trait
of cancer," said the study's lead investigator, Mariano Garcia-Blanco,
M.D., Ph.D., professor of molecular genetics and microbiology.

The researchers will publish their findings in the Sept. 19, 2006, issue of
the journal Proceedings of the National Academy of Sciences, now
available on line. The research was funded by the National Cancer
Institute.
 36

Until now, scientists have believed that cancer cells must transform
permanently from stationary epithelial cells into migratory mesenchymal
cells in order to metastasize.

The Duke team discovered that highly malignant cells are equal parts
epithelial and mesenchymal, transitioning between the two as their
surroundings necessitate. The proteins that the cell produces dictate
which way the cell shifts.

In a classic example of survival of the fittest, a cancer cell's ability to

toggle between epithelial and mesenchymal enables the most malignant
cells to aggressively invade and then peacefully adapt in unfamiliar
territory, the scientists said.

"The prevailing notion has been that the more mesenchymal the cancer
cells, the more mobile and metastatic they would be," Garcia-Blanco
said. "In reality, aggressive cancer cells are not homogenous, but are
extremely versatile in their ability to adapt as their survival needs shift."

The researchers discovered this transition in cancer cells when they

observed an error in "alternative splicing," a key element of the genetic
copying program inside cells. Alternative splicing determines how the
DNA is chopped into pieces and then reassembled. The order in which
DNA is reassembled determines which proteins the gene produces.

In cancer cells, the splicing machinery goes awry -- as do myriad

functions within the cells. When the splicing process proceeds one way,
the cells become mesenchymal. Spliced another way, the cells turn
epithelial.

To determine which way a cancer cell would turn, the scientists

constructed a fluorescent "reporter" -- a protein that illuminates if the
cell turns epithelial but lies dormant if the cell reverts to mesenchymal
state.

By following the reporter's illumination within cancer cells in rats, the

team viewed the very process of alternative splicing as it occurred in the
tumors. The researchers were able to visualize specific portions of DNA,
called exons, to see if they were included or excluded in the splicing
process as the cell transformed.

"We found that the regulation of alternative splicing is different in

mesenchymal versus epithelial cells," Garcia-Blanco said. "A particular
exon, FGFR2 IIIc, is silenced in mesenchymal cells but is active in
epithelial cells.

"We can visualize the genes as they are dynamically changing," he said.
"We can define the cell types by observing their splicing patterns."
 37

According to Garcia-Blanco, the cellular switch that is believed to guide

the regulation of splicing is a protein called Fox. Both mesenchymal and
epithelial cells produce Fox, but the protein is active only in epithelial
cells, Garcia-Blanco said.

Fox also may have an accomplice or "co-factor" in or around epithelial

cells that prompts it to activate, the researchers said. They speculate
that this co-factor could be activated by contact with stroma --the
supporting structural cells of a tumor -- because the stroma is where the
majority of epithelial-type cancer cells were observed. Their heavy
presence implies that the stroma may have induced the cancer cells to
revert to epithelial when they reached a new destination, so they could
stabilize to populate a new tumor site.

"Our findings validate that tumors are highly complex in their behavior
and don't necessarily need a gene mutation to alter their behavior," said
Sebastian Oltean, M.D., Ph.D., research associate and first author of the
journal article.

"Alterations in gene splicing can be much more subtle in nature but still
have a major impact on the cancer cell and can be targets of therapy."

The team's next step is to determine precisely what controls the toggle
mechanism in cancer cells, Garcia-Blanco said. Identifying the various
steps that occur during the natural progression of tumors could lead to
therapies for blocking metastasis, he said.

• Biochemistry of
Cancer Cell
Much of what we originally knew about the biochemical differences
between normal and malignant cells was discovered in their patterns of
enzymatic activity. In the 1920s, Warburg studied glycolysis in a wide
 38

variety of human and animal tumors and found that there was a general
trend toward an increased rate of glycolysis in tumor cells. He noted that
when normal tissue slices were incubated in a nutrient medium
containing glucose, but without oxygen, there was a high rate of lactic
acid production (anaerobic glycolysis); however, if they were incubated
with oxygen, lactic acid production virtually stopped. The rate of lactic
acid production was higher in tumor tissue slices in the absence of
oxygen than in normal tissues, and the presence of oxygen slowed, but
did not eliminate, lactic acid formation in the tumor slices. Warburg
concluded that cancer cells have an irreversible injury to their
respiratory mechanism, which increases the rate of lactic acid
production even in the presence of oxygen. He regarded the persistence
of this type of glycolysis as the crucial biochemical lesion in neoplastic
transformation. This old idea still has some credence in that there are
hypoxic areas in the core of tumors, where anaerobic metabolism
predominates. This has clinical implications because hypoxic cells do
not respond as well to certain anticancer drugs and radiation therapy.
Interestingly, although it was originally thought that these hypoxic areas
were only in the center of tumors and remained relatively static and
eventually became necrotic, it is now known that hypoxic areas actually
come and go in a tumor as perfusion varies and as new blood vessels
form, fade away, and then reform. Certain drugs and radiosensitizers
have been designed to take advantage of these hypoxic areas.
The mechanism for this ability of cancer cells to undergo aerobic
glycolysis appears to involve the c-myc oncogenic transcription factor.
Dang et al have shown that c-myc and the hypoxia-inducible factor 1
(HIF-1) are able to bind the lactate dehydrogenase A promoter cis-acting
elements. They hypothesize that c-myc directly activates
hypoxia/glucose-responsive elements in glycolytic enzyme genes to
increase the ability of cancer cells to maintain aerobic glycolysis.
In the early 1950s, Greenstein formulated the “convergence hypothesis”
of cancer, which states that the enzymatic activity of malignant
neoplasms tends to converge to a common pattern. Although he
recognized some exceptions to this rule, he considered the
generalization, based mostly on repeatedly transplanted tumor models,
to be valid. It is now more fully appreciated that even though cancer cells
do have some commonly increased metabolic pathways, such as those
involved in nucleic acid synthesis, there is tremendous biochemical
heterogeneity among malignant neoplasms, and that there are many
fairly well-differentiated cancers that do not have the common enzymatic
alterations he suggested. Thus, cancers do not have a universally
uniform malignant phenotype as exemplified by their enzyme patterns.
On the basis of work of about 50 years ago, which evolved from studies
on the production of hepatic cancer by feeding aminoazo dyes, the
Millers advanced the “deletion hypothesis” of cancer. This hypothesis
was based on the observation that a carcinogenic aminoazo dye
covalently bound liver proteins in animals undergoing carcinogenesis,
whereas little or no dye binding occurred with the protein of tumors
induced by the dye. They suggested that carcinogenesis resulted from
 39

“a permanent alteration or loss of protein essential for the control of

growth.”
About 10 years later, Potter suggested that the proteins lost during
carcinogenesis may be involved in the feedback control of enzyme
systems required for cell division, and he proposed the “feedback
deletion hypothesis.” In this hypothesis, Potter postulated that
“repressors” crucial to the regulation of genes involved in cell
proliferation are lost or inactivated by the action of oncogenic agents on
the cell, either by interacting with DNA to block repressor gene
transcription or by reacting directly with repressor proteins and
inactivating them. This prediction anticipated the discovery of tumor
suppressor proteins, such as p53 and RB by, about 25 years.
Biochemical studies of cancer were also aided by the so-called minimal-
deviation hepatomas developed by Morris and his colleagues. These
tumors were originally induced in rats by feeding them the carcinogens
fluorenylphthalamic acid, fluorenylacetamide compounds, or
trimethylaniline. These hepatocellular carcinomas are transplantable in
an inbred host strain of rats and have a variety of growth rates and
degrees of differentiation. They range from slowly growing, well-
differentiated, karyotypically normal cells to rapidly growing, poorly
differentiated, polyploid cells. All these tumors are malignant and
eventually kill the host. The term “minimal deviation” was coined by
Potter to convey the idea that some of these neoplasms differ only
slightly from normal hepatic parenchymal cells. The hypothesis was that
if the biochemical lesions present in the most minimally deviated
neoplasm could be identified, the crucial changes defining the malignant
phenotype could be determined. As Weinhouse has indicated, studies of
these tumors greatly advanced our knowledge of the biochemical
characteristics of the malignant phenotype, and they have ruled out
many secondary or nonspecific changes that relate more to tissue
growth rate than to malignancy.

Biochemical and biophysical changes can be summarized as:

 Changes in rate of growth
 Phenotypic Alterations in Cancer Cells
 Immortality of Transformed Cells in Culture
 Decreased Requirement for Growth Factors

 Loss of Anchorage Dependence

Most freshly isolated normal animal cells and cells from cultures of
normal diploid cells do not grow well when they are suspended in fluid
or a semisolid agar gel. If these cells make contact with a suitable
surface, however, they attach, spread, and proliferate. This type of
 40

growth is called anchorage-dependent growth. Many cell lines derived

from tumors and cells transformed by oncogenic agents are able to
proliferate in suspension cultures or in a semisolidmedium
(methylcellulose or agarose) without attachment to a surface. This is
called anchorage-independent growth.

 Loss of Cell Cycle Control and Resistance to Apoptosis

 Changes in Cell Membrane Structure and Function

 Alterations in Cell Surface Glycolipids, Glycoproteins,

Proteoglycans, and Mucins

 Modification of Extracellular Matrix Components

Cells in tissues are attached to one another and to the ECM (extracellular
matrix). Disruption of these adhesion events leads to increased cell
motility and potential invasiveness of cells through the ECM. In addition,
most cell types require attachment to the ECM for normal growth,
differentiation, and function. This attachment is responsible for what is
termed anchorage dependence. Normal cells that are detached from their
binding to the ECM undergo apoptosis, whereas tumor cells that are less
dependent on this attachment are free to proliferate, wander, and invade
tissues.

 Cell Proliferation Versus differentiation

Cancer cells are very active in proliferation, but it is not well

differentiated cells.
So, Cancer cells do not perform any of the usual functions of the normal
cell; instead, it feeds and replicates madly on the expense of normal
functioning cells.

Apoptosis
The relation between apoptosis and cancer

 Apoptosis (cell suicide)

 41

Is a normal component of the development and health of multicellular

organisms. Cells die in response to a variety of stimuli and during
apoptosis they do so in a controlled, regulated fashion.

Programmed cell death involves a series of biochemical events leading

to a characteristic cell morphology and death; in more specific terms, a
series of biochemical events that lead to a variety of morphological
changes, including blebbing (a bleb is an irregular bulge in the plasma
membrane of a cell caused by localized decoupling of the cytoskeleton from
the plasma membrane) , changes to the cell membrane such as loss of
membrane asymmetry and attachment, cell shrinkage, nuclear
fragmentation, chromatin condensation, and chromosomal DNA
fragmentation.

Processes of disposal of cellular debris whose results do not damage

the organism differentiate apoptosis from necrosis.

In contrast to necrosis, which is a form of traumatic cell death that

results from acute cellular injury, apoptosis, in general, confers
advantages during an organism's life cycle. For example, the
differentiation of fingers and toes in a developing human embryo occurs
because cells between the fingers apoptose; the result is that the digits
are separate.

Between 50 and 70 billion cells die each day due to apoptosis in the
average human adult. For an average child between the ages of 8 and 14,
approximately 20 billion to 30 billion cells die a day.

A dying cell
Research on apoptosis has increased substantially since the early
1990s. In addition to its importance as a biological phenomenon,
defective apoptotic processes have been implicated in an extensive
variety of diseases. Excessive apoptosis causes hypotrophy, such as in
ischemic damage, whereas an insufficient amount results in
uncontrolled cell proliferation, such as cancer.
 42

• Programmed cell-death (or PCD) is death of a cell in any

form, mediated by an intracellular program. In contrast to
necrosis, which is a form of cell-death that results from acute
tissue injury and provokes an inflammatory response, PCD is
carried out in a regulated process which generally confers
advantage during an organism's life-cycle.

• Functions of Apoptosis related to

cancer

• Cell termination

Apoptosis occurs when a cell is damaged beyond repair, infected with a

virus, or undergoing stressful conditions such as starvation. Damage to
DNA from ionizing radiation or toxic chemicals can also induce
apoptosis via the actions of the tumor-suppressing gene p53. The
"decision" for apoptosis can come from the cell itself, from the
surrounding tissue, or from a cell that is part of the immune system.

In these cases apoptosis functions to remove the damaged cell,

preventing it from sapping further nutrients from the organism, or
halting further spread of viral infection.

• Apoptosis also plays a role in preventing cancer. If a cell is

unable to undergo apoptosis because of mutation or biochemical
inhibition, it continues to divide and develop into a tumor. For
example, infection by papillomaviruses causes a viral gene to
interfere with the cell's p53 protein, an important member of the
apoptotic pathway. This interference in the apoptotic capability of
the cell plays a role in the development of cervical cancer.

• Homeostasis

In the adult organism, the number of cells is kept relatively constant

through cell death and division. Cells must be replaced when they
malfunction or become diseased, but proliferation must be offset by cell
 43

death. This control mechanism is part of the homeostasis required by

living organisms to maintain their internal states within certain limits.
Some scientists have suggested homeodynamics as a more accurate
term.

Homeostasis is achieved when the rate of mitosis (cell division resulting

in cell multiplication) in the tissue is balanced by the rate of cell death. If
this equilibrium is disturbed, one of two potentially fatal disorders
occurs:

• The cells divide faster than they die, resulting in the development
of a tumor.
• The cells divide slower than they die, causing cell loss.

Homeostasis involves a complex series of reactions, an ongoing

process inside an organism that calls for different types of cell signaling.
Any impairment can cause a disease. For example, dysregulation of
signaling pathway has been implicated in several forms of cancer. The
pathway, which conveys an anti-apoptotic signal, has been found to be
activated in pancreatic adenocarcinoma tissues.

This idea means that we can search for certain techniques to initiate
cancer cell apoptosis.

• Lymphocyte interactions

The development of B lymphocytes and T lymphocytes in a human body

is a complex process that creates a large pool of diverse cells and
subsequently eliminates those potentially damaging to the body.
Apoptosis is the mechanism by which the body removes both the
ineffective and the potentially damaging immature cells. In T cells,
apoptosis is initiated by the withdrawal of survival signals.

Cytotoxic T cells are able to directly induce apoptosis by opening up

pores in the target's membrane and releasing chemicals that bypass the
normal apoptotic pathway.

So we can tell briefly "why should a cell commit

suicide?"
There are two different reasons.
 44

1. Programmed cell death is as needed for proper development as

mitosis is.

Examples:

• The resorption of the tadpole tail at the time of its

metamorphosis into a frog occurs by apoptosis.
• The formation of the fingers and toes of the fetus requires
the removal, by apoptosis, of the tissue between them.
• The sloughing off of the inner lining of the uterus (the
endometrium) at the start of menstruation occurs by apoptosis.
• The formation of the proper connections (synapses)
between neurons in the brain requires that surplus cells be
eliminated by apoptosis

2. Programmed cell death is needed to destroy cells that represent a

threat to the integrity of the organism.

Examples:
Cells infected with viruses
One of the methods by which cytotoxic T lymphocytes (CTLs) kill
virus-infected cells is by inducing apoptosis. (And some viruses
mount countermeasures to thwart it)
Cells of the immune system
As cell-mediated immune responses wane (get weaker), the
effector cells must be removed to prevent them from attacking
body constituents. CTLs induce apoptosis in each other and even
in themselves. Defects in the apoptotic machinery are associated
with autoimmune diseases such as lupus erythematosus and
rheumatoid arthritis.
Cells with DNA damage
Damage to its genome can cause a cell

• to disrupt proper embryonic development leading to

birth defects
• To become cancerous.

Cells respond to DNA damage by increasing their production of

p53. P53 is a potent inducer of apoptosis. Is it any wonder that
mutations in the p53 gene, producing a defective protein, are so
often found in cancer cells (that represent a lethal threat to the
organism if permitted to live)?

Cancer cells
Radiation and chemicals used in cancer therapy induce apoptosis
in some types of cancer cells.

What makes a cell decide to commit suicide?

 45

The balance between:

• The withdrawal of positive signals; that is, signals needed

for continued survival, and
• The receipt of negative signals.

Withdrawal of positive signals

The continued survival of most cells requires that they receive

continuous stimulation from other cells and, for many, continued
adhesion to the surface on which they are growing. Some examples of
positive signals:

• growth factors for neurons

• Interleukin-2 (IL-2), an essential factor for the mitosis of
lymphocytes

Receipt of negative signals

• increased levels of oxidants within the cell

• damage to DNA by these oxidants or other agents like
o ultraviolet light
o x-rays
o chemotherapeutic drugs
• Accumulation of proteins that failed to fold properly into
their proper tertiary structure
• Molecules that bind to specific receptors on the cell surface
and signal the cell to begin the apoptosis program. These death
activators include:
o Tumor necrosis factor-alpha (TNF-α) that binds to the
TNF receptor;
o Lymphotoxin (also known as TNF-β) that also binds to
the TNF receptor;
o Fas ligand (FasL), a molecule that binds to a cell-
surface receptor named Fas (also called CD95).

• The process of cell death

Upon receiving specific signals instructing the cells to undergo
apoptosis a number of distinctive changes occur in the cell. A family
of proteins known as caspases are typically activated in the early
stages of apoptosis. These proteins breakdown or cleave key cellular
components that are required for normal cellular function including
structural proteins in the cytoskeleton and nuclear proteins such as
 46

DNA repair enzymes. The caspases can also activate other

degradative enzymes such as DNases, which begin to cleave the DNA
in the nucleus.
Apoptotic cells display distinctive morphology during the apoptotic
process. This can be seen in the image below which shows a
trophoblast cell undergoing apoptosis.

 Typically, the cell begins to shrink following the cleavage of

lamins and actin filaments in the cytoskeleton (A).
 The breakdown of chromatin in the nucleus often leads to
nuclear condensation and in many cases the nuclei of apoptotic cells
take on a "horse-shoe" like appearance (B).
 Cells continue to shrink (C), packaging themselves into a
form that allows for their removal by macrophages. These
phagocytic cells are responsible for clearing the apoptotic cells from
tissues in a clean and tidy fashion that avoids many of the problems
associated with necrotic cell death. In order to promote their
phagocytosis by macrophages, apoptotic cells often ungergo plasma
membrane changes that trigger the macrophage response. One
such change is the translocation of phosphatidylserine from the
inside of the cell to the outer surface.
 The end stages of apoptosis are often characterised by the
appearance of membrane blebs (D) or blisters process. Small
vesicles called apoptotic bodies are also sometimes observed (D,
arrow).

The Mechanisms of Apoptosis can be summarized

There are 3 different mechanisms by which a cell commits suicide by
apoptosis.
 47

1. One generated by signals arising within the cell;

2. another triggered by death activators binding to receptors at the
cell surface:
o TNF-α
o Lymphotoxin
o Fas ligand (FasL)
3. A third that may be triggered by dangerous reactive oxygen
species.

Explanation
 There are a number of mechanisms through which
apoptosis can be induced in cells. The sensitivity of cells to
any of these stimuli can vary depending on a number of
factors such as the expression of pro- and anti-apoptotic
proteins (eg. the Bcl-2 proteins or the Inhibitor of Apoptosis
Proteins), the severity of the stimulus and the stage of the cell
cycle. Some of the major stimuli that can induce apoptosis are
outlined in the illustration below.

• In some cases the apoptotic stimuli comprise extrinsic signals

such as the binding of death inducing ligands to cell surface
receptors called death receptors. These ligands can either be
soluble factors or can be expressed on the surface of cells such
as cytotoxic T lymphocytes. The latter occurs when T-cells
recognise damaged or virus infected cells and initiate apoptosis in
 48

order to prevent damaged cells from becoming neoplastic

(cancerous) or virus-infected cells from spreading the infection.
Apoptosis can also be induced by cytotoxic T-lymphocytes using
the enzyme granzyme.

• In other cases apoptosis can be initiated following intrinsic

signals that are produced following cellular stress. Cellular stress
may occur from exposure to radiation or chemicals or to viral
infection. It might also be a consequence of growth factor
deprivation or oxidative stress caused by free radicals. In general
intrinsic signals initiate apoptosis via the involvement of the
mitochondria. The relative ratios of the various bcl-2 proteins can
often determine how much cellular stress is necessary to induce
apoptosis.

Caspases and apoptosis

The caspases are a family of proteins that are one of the main executors
of the apoptotic process. They belong to a group of enzymes known as
cysteine proteases and exist within the cell as inactive pro-forms or
zymogens. These zymogens can be cleaved to form active enzymes
following the induction of apoptosis.

Induction of apoptosis via death receptors typically results in the

activation of an initiator caspase such as caspase 8 or caspase 10.
These caspases can then activate other caspases in a cascade. This
cascade eventually leads to the activation of the effector caspases, such
as caspase 3 and caspase 6. These caspases are responsible for the
cleavage of the key cellular proteins, such as cytoskeletal proteins, that
leads to the typical morphological changes observed in cells undergoing
apoptosis.

These morphological changes stimulate macrophages to engulf the

apoptotic cell.

Caspases and chromatin breakdown

One of the hallmarks of apoptosis is the cleavage of chromosomal DNA
into nucleosomal units. The caspases play an important role in this
process by activating DNases, inhibiting DNA repair enzymes and
breaking down structural proteins in the nucleus.

1) Inactivation of enzymes involved in DNA repair.

The enzyme poly (ADP-ribose) polymerase, or PARP, was one of the first
proteins identified as a substrate for caspases. PARP is involved in
repair of DNA damage and functions by catalyzing the synthesis of poly
 49

(ADP-ribose) and by binding to DNA strand breaks and modifying

nuclear proteins. The ability of PARP to repair DNA damage is prevented
following cleavage of PARP by caspase-3.

2) Breakdown of structural nuclear proteins.

Lamins are intra-nuclear proteins that maintain the shape of the nucleus
and mediate interactions between chromatin and the nuclear membrane.
Degradation of lamins by caspase 6 results in the chromatin
condensation and nuclear fragmentation commonly observed in
apoptotic cells.

3) Fragmentation of DNA.

The fragmentation of DNA into nucleosomal units - as seen in DNA

laddering assays - is caused by an enzyme known as CAD, or caspase
activated DNase. Normally CAD exists as an inactive complex with ICAD
(inhibitor of CAD). During apoptosis, ICAD is cleaved by caspases, such
as caspase 3, to release CAD. Rapid fragmentation of the nuclear DNA
follows.

• Apoptosis and Cancer

Some viruses associated with cancers use tricks to prevent apoptosis of
the cells they have transformed.

• Several human papilloma viruses (HPV) have been

implicated in causing cervical cancer. One of them produces a
protein (E6) that binds and inactivates the apoptosis promoter
p53.
• Epstein-Barr Virus (EBV), the cause of mononucleosis and
associated with some lymphomas
o produces a protein similar to Bcl-2
o produces another protein that causes the cell to
increase its own production of Bcl-2. Both these actions
make the cell more resistant to apoptosis (thus enabling a
cancer cell to continue to proliferate).

Even cancer cells produced without the participation of viruses may

have tricks to avoid apoptosis.

• Some B-cell leukemias and lymphomas express high levels

of Bcl-2, thus blocking apoptotic signals they may receive. The
high levels result from a translocation of the BCL-2 gene into an
enhancer region for antibody production.
• Melanoma (the most dangerous type of skin cancer)cells avoid
apoptosis by inhibiting the expression of the gene encoding Apaf-
1.
 50

• Some cancer cells, especially lung and colon cancer cells,

secrete elevated levels of a soluble "decoy" molecule that binds to
FasL, plugging it up so it cannot bind Fas. Thus, cytotoxic T cells
(CTL) cannot kill the cancer cells.
• Other cancer cells express high levels of FasL, and can kill
any cytotoxic T cells (CTL) that try to kill them because CTL also
express Fas (but are protected from their own FasL).

Steps of Apoptosis
 51

The Apoptotic Pathway

Induced Apoptosis in Cancer therapy

The role of apoptosis in cancer development and emerging treatment
strategies has rapidly expanded over the past few years. The novel
discovery in the apoptotic pathways and their relevant molecules
provides us not only the knowledge how tumors develop but also the
opportunity to design new therapeutic tools to prevent or inhibit the
growth of tumors with minimal side-effects.

In healthy subjects, apoptosis is a normal and continuous process with

complex physiological controls. However, due to various environmental
and endogenous factors this process becomes out of control or
develops in a manipulated direction in cancers. The imbalance between
the pro-apoptosis and anti-apoptosis is often a two-side coin. With a
shift in favour of the latter, cells may growth uncontrollably.
 52

The goals of chemotherapy (and radiotherapy) are to eliminate tumor cell

targets by promoting cell death. In recent years, a major focus has been
placed on programmed cell death or apoptosis as the primary
mechanism of cell killing.
This means that cell death (apoptosis) and growth arrest (senescence)
represent the critical elements of tumor cellresponses to various forms
of cancer therapy.
Example : conventional therapies, such as standard cytotoxic drugs and
radiation
more recent therapies, such as monoclonal antibodies and targeting of
specific receptor and signaling pathways
developing modalities, such as photodynamic therapy.
 53

Expected Causes of Cancer

 54

Introduction
Perhaps the most important question in cancer biology is what causes
the cellular alterations that produce a cancer. The answer to this
question has been elusive (difficult). If the actual cause of these
alterations were known, the elimination of factors that produce cancer
and the development of better treatment modalities would likely follow.
Cancer prevention might become a reality. A cancerous growth has a
number of predictable properties. The incidence rates of various cancers
are strongly related to environmental factors and lifestyle, and cancers
have certain growth characteristics, among which are the abilities to
grow in an uncontrolled manner, invade surrounding tissues, and
metastasize (invade non-adjacent tissues). Also, when viewed
microscopically, cancer cells appear to be less well differentiated than
their normal counterparts and to have certain distinguishing features,
such as large nuclei and nucleoli. Most cancers arise from a single clone
of cells, whose precursor may have been altered by insult with a
carcinogen. In most cases cancer is a disease of aging. The average age
at diagnosis is over 65 and malignant cancers arise from a lifetime
accumulation of ‘‘hits’’ on a person’s DNA. These hits may result from
genetic susceptibility to environmental agents such as chemicals;
radiation; or viral, bacterial, or parasitic infections; or from
endogenously generated agents such as oxygen radicals. It is often said
that we would all get cancer if we lived long enough. There is frequently
a long latent period, in some cases 20 years or more, between the
initiating insult and the appearance of a clinically detectable tumor.
During this time, cellular proliferation (to multiply very quickly) must
occur, but it may originally be limited by host defenses or lack of access
to the host’s blood supply. During the process of tumor progression,
however, escape from the host’s defense mechanisms and
vascularization (to supply with vessels) of the growing tumor ultimately
occur. The genetic instability of cancer cells leads to the emergence of a
more aggressively growing tumor frequently characterized by the
appearance of poorly differentiated cells with certain properties of a
more embryonic phenotype. During tumor progression, considerable
biochemical heterogeneity becomes manifest in the growing tumor and
its metastases, even though all the neoplastic cells may have arisen
originally from a single deranged cell. Any theory that seeks to explain
the initiation of cancer and its progression must take these observations
into consideration.

Cancer is a diverse class of diseases which differ widely in their causes

and biology. Any organism, even plants, can acquire cancer. Nearly all
known cancers arise gradually, as errors build up in the cancer cell and
its progeny - anything which replicates (our cells) - will probabilistically
suffer from errors (mutations). Unless error correction and prevention is
properly carried out, the errors will survive, and might be passed along
 55

to daughter cells. Normally, the body safeguards against cancer via

numerous methods, such as: apoptosis, helper molecules (some DNA
polymerases), possibly senescence (diploid cells lose the ability to
divide), etc. However these error-correction methods often fail in small
ways, especially in environments that make errors more likely to arise
and propagate. For example, such environments can include the
presence of disruptive substances called carcinogens, or periodic injury
(physical, heat, etc.), or environments that cells did not evolve to
withstand, such as hypoxia . Cancer is thus a progressive disease, and
these progressive errors slowly accumulate until a cell begins to act
contrary to its function in the animal.
The errors which cause cancer are often self-amplifying, eventually
compounding at an exponential rate. For example:

• A mutation in the error-correcting machinery of a cell might

cause that cell and its children to accumulate errors more rapidly
• A mutation in signaling (endocrine) machinery of the cell
can send error-causing signals to nearby cells
• A mutation might cause cells to become neoplastic
(Neoplasia is the abnormal proliferation of cells), causing them to
migrate and disrupt more healthy cells
• A mutation may cause the cell to become immortal (see
telomeres), causing them to disrupt healthy cells forever

Thus cancer often explodes in something like a chain reaction caused by

a few errors, which compound into more severe errors. Errors which
produce more errors are effectively the root cause of cancer, and also
the reason that cancer is so hard to treat: even if there were
10,000,000,000 cancerous cells and one killed all but 10 of those cells,
those cells (and other error-prone precancerous cells) could still self-
replicate or send error-causing signals to other cells, starting the
process over again. This rebellion-like scenario is an undesirable
survival of the fittest, where the driving forces of evolution itself work
against the body's design and enforcement of order. In fact, once cancer
has begun to develop, this same force continues to drive the
progression of cancer towards more invasive stages, and is called clonal
evolution.

Research about cancer causes often falls into the following categories:

• Agents (e.g. viruses) and events (e.g. mutations) which

cause or facilitate genetic changes in cells destined to become
cancer.
• The precise nature of the genetic damage, and the genes
which are affected by it.
• The consequences of those genetic changes on the biology
of the cell, both in generating the defining properties of a cancer
 56

cell, and in facilitating additional genetic events which lead to

further progression of the cancer.

What causes cancer?

This will tells us about what actually causes cancer. There is information
about:

• The many causes of cancer

• Cancer-causing substances (carcinogens)
• Age
• Genetic make up
• The immune system
• Bodyweight, diet and physical activity
• Day to day environment
• Viruses

Each cancer is thought to first start from one abnormal cell. What seems
to happen is that certain vital genes which control how cells divide and
multiply are damaged or altered. This makes the cell abnormal. If the
abnormal cell survives it may multiply 'out of control' into a malignant
tumor.

We all have a risk of developing cancer. Many cancers seem to develop

for no apparent reason. However, certain risk-factors are known to
increase the chance that one or more of your cells will become abnormal
and lead to cancer. Risk factors include the following:

The many causes of cancer

There are about 200 different types of cancer. They can start in any type
of body tissue. What affects one body tissue may not affect another. For
example, tobacco smoke that you breathe in may help to cause lung
cancer. Overexposing your skin to the sun could cause a melanoma on
your leg. But the sun won't give you lung cancer and smoking won't give
you melanoma.

Apart from infectious diseases, most illnesses are 'multifactorial'.

Cancer is no exception. Multifactorial means that there are many factors
involved. In other words, there is no single cause for any one type of
cancer.

Cancer-causing substances (carcinogens)

A carcinogen is something (chemical, radiation, etc) which can damage a
cell and make it more likely to turn into a cancerous cell. Cancer
pathogenesis is traceable back to DNA mutations that impact cell growth
and metastasis. Substances that cause DNA mutations are known as
mutagens, and mutagens that cause cancers are known as carcinogens.
 57

Particular substances have been linked to specific types of cancer as a

general rule, the more the exposure to a carcinogen, the greater the risk.

Mutation: chemical carcinogens

Well known examples include:

• Tobacco smoke: If you smoke, you are more likely to develop cancer
of the lung, mouth, throat, esophagus, bladder and pancreas.
Smoking is thought to cause about a quarter of all cancers.
Tobacco is responsible for about one in three of all cancer deaths
in the developed world, and about one in five worldwide. However,
the numbers of smokers worldwide is still rising, leading to what
some organizations have described as the tobacco epidemic. The
heavier you smoke, the greater the risk. If you stop smoking, your
risk goes down considerably. The incidence of lung cancer is
highly correlated with smoking. Tobacco smoking is associated
with many forms of cancer, and causes 90% of lung cancer. About
1 in 10 smokers die from lung cancer.

Tobacco smoke contains over fifty known carcinogens, including

nitrosamines and polycyclic aromatic hydrocarbons so, it is a powerful
carcinogen. But not everyone who smokes gets lung cancer. So there
must be other factors at work as well as carcinogens.

• Workplace chemicals: such as asbestos, benzene,

formaldehyde, etc. If you have worked with these without
protection you have an increased risk of developing certain
cancers. For example, a cancer called mesothelioma is linked to
prolonged exposure to asbestos fibers.

Many mutagens are also carcinogens, but some carcinogens are not
mutagens. Alcohol is an example of a chemical carcinogen that is not a
mutagen. Such chemicals may promote cancers through stimulating the
rate of cell division. Faster rates of replication leaves less time for repair
enzymes to repair damaged DNA during DNA replication, increasing the
likelihood of a mutation.

Can people get cancer from being exposed to benzene?

The International Agency for Research on Cancer (IARC), after

examining many scientific studies, concluded that benzene does cause
cancer in humans. Occupational studies of workers exposed to high
levels of benzene have shown that benzene causes leukemia, a cancer of
the bone marrow (where blood cells are made).

 Can formaldehyde causes cancer?

 58

Although the short-term health effects of formaldehyde exposure are

well known, less is known about its potential long-term health effects. In
1980, laboratory studies showed that exposure to formaldehyde could
cause nasal cancer in rats. This finding raised the question of whether
formaldehyde exposure could also cause cancer in humans. In 1987, the
U.S. Environmental Protection Agency (EPA) classified formaldehyde as
a probable human carcinogen under conditions of unusually high or
prolonged exposure. Since that time, some studies of humans have
suggested that formaldehyde exposure is associated with certain types
of cancer.

 Why is there concern that hair dyes may cause cancer?

Over 5,000 different chemicals are used in hair dye products, some of
which are reported to be carcinogenic (cancer-causing) in animals.
Because so many people use hair dyes, scientists have tried to
determine whether exposure to the chemicals in hair coloring products
is associated with an increased risk of cancer in people.

Early hair dye formulations contained chemicals, including aromatic

amines that were found to cause cancer in animals. In the mid- to late
1970s, however, manufacturers changed the components in dye
products to eliminate some of these chemicals. It is not known whether
some of the chemicals still used in hair dyes can cause cancer. Given
the widespread use of hair dye products, even a small increase in risk
may have a considerable public health impact.

Over the years, some epidemiologic (population) studies have found an

increased risk of bladder cancer in hairdressers and barbers. A 2008
report of the Working Group of the International Agency for Research on
Cancer (IARC) concluded that some of the chemicals these workers are
exposed to occupationally are "probably carcinogenic to humans".

Although some studies have linked the personal use of hair dyes with
increased risks of certain cancers of the blood and bone marrow, such
as non-Hodgkin lymphoma (NHL) and leukemia, other studies have not
shown such links. Studies of breast and bladder cancer have also
produced conflicting results. Relatively few studies have been published
about the association of hair dye use with the risk of other cancers.
Based on its review of the evidence, IARC concluded that personal use
of hair dyes is "not classifiable as to its carcinogenicity to humans".

Mutation: ionizing radiation

Radiation is a carcinogen. For example, exposure to radioactive

materials and nuclear 'fallout' can increase the risk of leukemia and
other cancers. Too much sun exposure and sunburn (radiation from UVA
and UVB) increase your risk of developing skin cancer. The larger the
dose of radiation, the greater the risk of developing cancer. But
 59

note: the risk from small doses such as from a single X-ray test is very
small. Sources of ionizing radiation, such as radon gas, can cause
cancer. Prolonged exposure to ultraviolet radiation from the sun can
lead to melanoma and other skin malignancies.

Non-ionizing radio frequency radiation from mobile phones and other

similar RF sources has also been proposed as a cause of cancer, but
there is currently little established evidence of such a link.

magnetic field exposures in humans, at home or at work, are linked to

increased cancer risk.

• How does radon cause cancer?

Radon decays quickly, giving off tiny radioactive particles. When
inhaled, these radioactive particles can damage the cells that line the
lung. Long-term exposure to radon can lead to lung cancer, the only
cancer proven to be associated with inhaling radon. Cigarette smoking is
the most common cause of lung cancer. Radon represents a far smaller
risk for this disease, but it is the second leading cause of lung cancer in
the United States. Scientists estimate that approximately 15,000 to
22,000 lung cancer deaths per year are related to radon.

Although the association between radon exposure and smoking is not

well understood, exposure to the combination of radon gas and cigarette
smoke creates a greater risk for lung cancer than either factor alone. The
majority of radon-related cancer deaths occur among smokers.

• Why is there concern that cellular telephones may cause

cancer?

There are three main reasons:

• Cellular telephones emit radiofrequency (RF) energy (radio

waves), which is a form of radiation that is under investigation for
its effects on the human body.

• Cellular telephone technology emerged in Europe in the

1980s but did not come into widespread use in the United States
until the 1990s. The technology is rapidly changing, so there are
few long-term studies of the effects of RF energy from cellular
telephones on the human body.
• The number of cellular telephone users has increased
rapidly. As of December 2008, there were more than 270 million
subscribers to cellular telephone service in the United States,
according to the Cellular Telecommunications and Internet
 60

Association. This is an increase from 110 million users in 2000 and

208 million users in 2005.

For these reasons, it is important to learn whether RF energy from

cellular telephones affects human health.

• Age:
Most types of cancer become more common as we get older. This is
because the changes that make a cell become cancerous in the first
place take a long time to develop. There have to be a number of changes
to the genes within a cell before it turn into a cancer cell. These changes
can happen by accident when the cell is dividing. Or they can happen
because the cell has been damaged by carcinogens and the damage is
then passed on to future 'daughter' cells when that cell divides. The
longer we live, the more time there is for genetic mistakes to happen in
our cells.

The older you become, the more likely that you will develop a cancer.
This is probably due to an accumulation of damage to cells in the
body over time. Also, the body's defences and resistance against
abnormal cells may become less good as you become older. For
example, the ability to repair damaged cells, and the immune
system which may destroy abnormal cells, may become less
efficient with age. So, eventually one damaged cell may manage to
survive and multiply 'out of control' into a cancer. Most cancers
develop in older people.

• Genetic make up
There need to be a number of genetic mutations within a cell before it
becomes cancerous. Sometimes a person is born with one of these
mutations already. This doesn't mean they will definitely get cancer. But
with one mutation from the start, it makes it more likely statistically that
they will develop cancer during their lifetime. Doctors call this 'genetic
predisposition'.

The BRCA1 and BRCA2 breast cancer genes are examples of genetic
predisposition. Women who carry one of these faulty genes have a
higher chance of developing breast cancer than women who do not.

The BRCA genes are good examples for another reason. Most women
with breast cancer do not have a mutated BRCA1 or BRCA 2 gene. Less
than 5% of all breast cancer is due to these genes. So although women
with one of these genes are individually more likely to get breast cancer,
most breast cancer is not caused by a high risk inherited gene fault.
 61

This is true of other common cancers where some people have a genetic
predisposition - for example, colon (large bowel) cancer.

Researchers are looking at the genes of people with cancer in a study

called SEARCH. They also hope to find out more about how other factors
might interact with genes to increase the risk of cancer.

Some cancers have a strong genetic link. For example, in certain

childhood cancers the abnormal gene or genes which may trigger a cell
to become abnormal and cancerous are inherited. Other types of cancer
may have some genetic factor which is less clear-cut. It may be that in
some people their genetic make-up means that they are less resistant to
the effect of carcinogens or other factors such as diet.

• Heredity
Most forms of cancer are sporadic, meaning that there is no inherited
cause of the cancer. There are, however, a number of recognized
syndromes where there is an inherited predisposition to cancer, often
due to a defect in a gene that protects against tumor formation. Famous
examples are:

• certain inherited mutations in the genes BRCA1 and BRCA2

are associated with an elevated risk of breast cancer and ovarian
cancer
• tumors of various endocrine organs in multiple endocrine
neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as
osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors)
due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of
the APC gene that leads to early onset of colon carcinoma.
• Hereditary nonpolyposis colorectal cancer (HNPCC, also
known as Lynch syndrome) can include familial cases of colon
cancer, uterine cancer, gastric cancer, and ovarian cancer, without
a preponderance of colon polyps.
• Retinoblastoma, when occurring in young children, is due to
a hereditary mutation in the retinoblastoma gene.
• Down syndrome patients, who have an extra chromosome
21, are known to develop malignancies such as leukemia and
testicular cancer, though the reasons for this difference are not
well understood.

• The immune system dysfunction:

 62

People with a poor immune system have an increased risk of developing

certain cancers. For example, people with AIDS, or people on
immunosuppressive therapy. People who have problems with their
immune systems are more likely to get some types of cancer. This group
includes people who

• Have had organ transplants and take drugs to suppress

their immune systems to stop organ rejection
• Are born with rare medical syndromes which affect their
immunity
• Have HIV or AIDS

HIV is associated with a number of malignancies, including Kaposi's

sarcoma, non-Hodgkin's lymphoma, and HPV-associated malignancies
such as anal cancer and cervical cancer. AIDS-defining illnesses have
long included these diagnoses. The increased incidence of malignancies
in HIV patients points to the breakdown of immune surveillance as a
possible etiology of cancer. Certain other immune deficiency states (e.g.
common variable immunodeficiency and IgA deficiency) are also
associated with increased risk of malignancy.

The types of cancers that affect these groups of people fall into two,
overlapping groups:

• Cancers that are caused by viruses, such as cervical cancer

and other cancers of the genital or anal area, some lymphomas,
liver cancer and stomach cancer
• Lymphomas

Chronic infections or transplanted organs can continually stimulate cells

to divide. This continual cell division means that immune cells are more
likely to develop genetic faults and develop into lymphomas.

• Bodyweight, diet and physical activity

Lifestyle factors
The vast majority of cancer risk factors are environmental or lifestyle-
related in nature, leading to the claim that cancer is a largely preventable
disease. Examples of modifiable cancer risk factors include alcohol
consumption (associated with increased risk of oral, esophageal, breast,
and other cancers), smoking (although 20% of women with lung cancer
have never smoked, versus 10% of men), physical inactivity (associated
with increased risk of colon, breast, and possibly other cancers), and
being overweight / obese (associated with colon, breast, endometrial,
and possibly other cancers). Based on epidemiologic evidence, it is now
thought that avoiding excessive alcohol consumption may contribute to
reductions in risk of certain cancers; however, compared with tobacco
exposure, the magnitude of effect is modest or small and the strength of
 63

evidence is often weaker. Other lifestyle and environmental factors

known to affect cancer risk (either beneficially or detrimentally) include
certain sexually transmitted diseases (such as those conveyed by the
human papillomavirus), the use of exogenous hormones, exposure to
ionizing radiation and ultraviolet radiation, and certain occupational and
chemical exposures.

Every year, at least 200,000 people die worldwide from cancer related to
their workplace. Millions of workers run the risk of developing cancers
such as lung cancer and mesothelioma from inhaling asbestos fibers
and tobacco smoke, or leukemia from exposure to benzene at their
workplaces. Currently, most cancer deaths caused by occupational risk
factors occur in the developed world. It is estimated that approximately
20,000 cancer deaths and 40,000 new cases of cancer each year in the
U.S. are attributable to occupation.

Diet and other lifestyle factors may increase or decrease the risk of
developing cancer. For example:

• If you eat a lot of fruit and vegetables you have a reduced

risk of developing certain cancers. The exact way in which they
protect against cancer is not fully understood. These foods are
rich in vitamins and minerals, and also contain chemicals called
'anti-oxidants'. They may protect against damaging chemicals that
get into the body. We should all eat at least five portions of fruit
and vegetables per day (some experts recommend even more).
• Eating too much fatty food possibly increases the risk of
developing certain cancers.
• The risk of developing certain cancers is increased by:
obesity, lack of regular exercise, and drinking a lot of alcohol.

Cancer experts estimate that maintaining a healthy bodyweight, making

changes to our diet and taking regular physical activity could prevent
about one in three deaths from cancer in the UK. In the western world,
many of us eat too much red and processed meat and not enough fresh
fruit and vegetables. This type of diet is known to increase the risk of
cancer. Drinking alcohol can also increase the risk of developing some
types of cancer.

Sometimes foods or food additives are blamed for directly causing

cancer and described as 'carcinogenic'. This is often not really true.
Sometimes a food is found to contain a substance that can cause cancer
but in such small amounts that we could never eat enough of it to do any
harm. And some additives may actually protect us.

Vitamins
The idea that cancer can be prevented through vitamin supplementation
stems from early observations correlating human disease with vitamin
deficiency, such as pernicious anemia with vitamin B12 deficiency, and
 64

scurvy with Vitamin C deficiency. This has largely not been proven to be
the case with cancer, and vitamin supplementation is largely not proving
effective in preventing cancer. The cancer-fighting components of food
are also proving to be more numerous and varied than previously
understood, so patients are increasingly being advised to consume
fresh, unprocessed fruits and vegetables for maximal health benefits.

Epidemiological studies have shown that low vitamin D status is

correlated to increased cancer risk. However, the results of such studies
need to be treated with caution, as they cannot show whether a
correlation between two factors means that one causes the other (i.e.
correlation does not imply causation). The possibility that Vitamin D
might protect against cancer has been contrasted with the risk of
malignancy from sun exposure. Since exposure to the sun enhances
natural human production of vitamin D, some cancer researchers have
argued that the potential deleterious malignant effects of sun exposure
are far outweighed by the cancer-preventing effects of extra vitamin D
synthesis in sun-exposed skin. In 2002, Dr. William B. Grant claimed that
23,800 premature cancer deaths occur in the US annually due to
insufficient UVB exposure (apparently via vitamin D deficiency). This is
higher than 8,800 deaths occurred from melanoma or squamous cell
carcinoma, so the overall effect of sun exposure might be beneficial.
Another research group estimates that 50,000–63,000 individuals in the
United States and 19,000 - 25,000 in the UK die prematurely from cancer
annually due to insufficient vitamin D.

The case of beta-carotene provides an example of the importance of

randomized clinical trials. Epidemiologists studying both diet and serum
levels observed that high levels of beta-carotene, a precursor to vitamin
A, were associated with a protective effect, reducing the risk of cancer.
This effect was particularly strong in lung cancer. This hypothesis led to
a series of large randomized clinical trials conducted in both Finland and
the United States (CARET study) during the 1980s and 1990s. This study
provided about 80,000 smokers or former smokers with daily
supplements of beta-carotene or placebos. Contrary to expectation,
these tests found no benefit of beta-carotene supplementation in
reducing lung cancer incidence and mortality. In fact, the risk of lung
cancer was slightly, but not significantly, increased by beta-carotene,
leading to an early termination of the study.

Results reported in the Journal of the American Medical Association

(JAMA) in 2007 indicate that folic acid supplementation is not effective in
preventing colon cancer, and folate consumers may be more likely to
form colon polyps.

Hormonal imbalances
Some hormones can act in a similar manner to non-mutagenic
carcinogens in that they may stimulate excessive cell growth. A well-
 65

established example is the role of hyper estrogenic states in promoting

endometrial cancer.

• Day to day environment

By environmental causes we mean what is around you each day that
may help to cause cancer. This could include

• Tobacco smoke
• The sun
• Natural and man made radiation
• Work place hazards
• Asbestos

Tobacco
Most people know that smoking is a major risk factor for lung cancer.
But it may also increase the risk of

• Mouth cancer
• Pharyngeal cancer (the pharynx is behind the nose - some
come under mouth cancers and some are nasopharyngeal
cancers)
• Cancer of the larynx (also called laryngeal or voice box
cancer)

because smoke passes over these areas as it is breathed in.

Smoking also increases the risk of

• Cancer of the esophagus (gullet)

• Stomach cancer

because some smoke is swallowed.

 66

Smoking is also linked to

• Cancer of the pancreas

• Liver cancer
• Cancer of the cervix
• Acute myeloid leukemia

because some carcinogens from the smoke get into the bloodstream and
circulate around the body.

Smoking is also linked to kidney cancer and bladder cancer because the
carcinogens in the blood are filtered into the urine.

The more you smoke, the younger you start, and the longer you keep on
smoking, the more likely you are to get cancer.

Long term exposure to environmental tobacco smoke at home or at work

increases the risk of lung cancer. It also increases the risk of cancer of
cancer of the larynx and pharyngeal cancer. Exposure to environmental
tobacco smoke in childhood may cause bladder cancer later in life.

The sun
Most skin cancers are largely caused by over exposing your skin to
ultraviolet radiation from the sun. There is more of a risk if you

• Are fair skinned

• Have a lot of moles
• Have a relative who has had melanoma or non-melanoma
skin cancer

Non-melanoma skin cancer is linked to more or less constant sun

exposure over the years. So it is common in white people who live in hot
countries such as South Africa and Australia. But melanoma (the most
dangerous form of skin cancer) is linked to exposing untanned skin to
the sun in relatively short bursts (for example, going to a hot country for
two weeks and frying on the beach). This is thought to be particularly
dangerous in babies, children and young adolescents. To reduce your
risk of melanoma

• Use at least factor 15 sun cream

• Cover up with a hat, long sleeved shirt and trousers or sit in
the shade between 11am and 3pm when the sun is strongest
• Don't let your skin burn
• Sun beds can also increase the risk of skin cancer and it is
best not to use them at all.
 67

Other types of radiation

Other types of radiation can help to cause cancer. We are all exposed to
radiation each day. There is natural radiation from the earth and space,
radiation from the nuclear power and weapons industries, and radiation
from medical tests (X-rays).

Radiation helps to cause cancer by damaging the genes in body cells

and causing gene mutations. These may or may not lead to cancer, but
the more radiation we are exposed to, the greater the chance that a
mutation will occur that could make a cancer develop.

Radiotherapy is a very important treatment for many cancers. But having

radiotherapy can increase the risk of another cancer developing in the
future. Doctors minimise the amount of radiation patients are exposed to
as much as possible. Getting another cancer later because of having had
radiotherapy is quite rare. If you are having radiotherapy it is important
to remember that the most important thing for you is to treat the cancer
you already have. For many cancers, radiotherapy is the best way to do
this.

Work place hazards

Some people risk being exposed to a cancer causing substance
(carcinogen) because of the work that they do. For example, workers in
the chemical dye industry have been found to have a higher incidence
than normal of bladder cancer. If at all possible, once a substance is
known to be a cancer risk, it is no longer used. If a possibly carcinogenic
substance has to be used, then there are strict regulations covering how
it is handled so that workers are protected from it. Contact the
Environmental Protection Agency for information about how to protect
yourself at work.

Asbestos
Asbestos is included here because it is such a well known cause of
cancer - particularly a cancer called mesothelioma, which most
commonly affects the pleura (covering of the lungs). Asbestos is
made up of tiny fibres which can be breathed in. There are different
types of asbestos. All types are now banned in the UK. But white
asbestos was still in use up until 1999 (mostly in the car industry in
brake linings). There is usually a very long time between exposure
to asbestos and developing cancer - typically about 20 to 30 years
or more.
 68

• Infection
Viruses
Some viruses are linked to certain cancers. For example, people with
persistent infection with the hepatitis B virus or the hepatitis C virus
have an increased risk of developing cancer of the liver. Another
example is the link between the human papilloma virus (HPV virus) and
cervical cancer. Most (possibly all) women who develop cervical cancer
have been infected with a strain (sub-type) of the HPV virus at some
point in their life. But, most viruses and viral infections are not linked to
cancer.

Viruses can help to cause some cancers. But this does not mean that
these cancers can be caught like an infection. What happens is that the
virus can cause genetic changes in cells that make them more likely to
become cancerous.

These cancers and viruses are linked

• Cervical cancer, and other cancers of the genital and anal

area, and the genital wart virus, HPV
• Primary liver cancer and the Hepatitis B and C viruses
• Lymphomas and the Epstein-Barr Virus
• T cell leukemia in adults and the Human T cell leukemia
virus
• HPV also probably leads to oropharyngeal cancer and non
melanoma skin cancers in some people

There will be people with primary liver cancer and with T cell leukemia
who haven't had the related virus. But infection increases their risk of
getting that particular cancer. With cervical cancer, scientists now
believe that everyone with an invasive cervical cancer has had an HPV
infection beforehand.

Many people can be infected with a cancer causing virus, and never get
cancer. The virus only causes cancer in certain situations. Many women
get a high risk HPV infection, but never develop cervical cancer. Another
example is Epstein-Barr virus (EBV). These are some facts about EBV

• It is very common - most people are infected with EBV

• People who catch it late in life get glandular fever and have
an increased risk of lymphoma
• In sub-Saharan Africa, EBV infection and repeated attacks
of malaria together cause a cancer called Burkitt's lymphoma in
children
 69

• In China, EBV infection (together with other unknown

factors) causes nasopharyngeal cancer
• In people with AIDs and transplant patients EBV can cause
lymphoma
• About 4 out of 10 cases of Hodgkin's lymphoma and a
quarter of cases of Burkitt lymphoma (a rare type of non
Hodgkin's lymphoma) seem to be related to EBV infection

How viruses are thought to cause cancer?

Viruses that are known to cause cancer such as HPV (cervical cancer),
Hepatitis B (liver cancer), and EBV (a type of lymphoma), are all DNA
viruses. It is thought that when the virus infects a cell, it inserts a part of
its own DNA near the cell growth genes, causing cell division. The group
of changed cells that are formed from the first cell dividing all have the
same viral DNA near the cell growth genes. The group of changed cells
are now special because one of the normal controls on growth has been
lost.

Depending on their location, cells can be damaged through radiation

from sunshine, chemicals from cigarette smoke, and inflammation from
bacterial infection or other viruses. Each cell has a chance of damage, a
step on a path toward cancer. Cells often die if they are damaged,
through failure of a vital process or the immune system; however,
sometimes damage will knock out a single cancer gene. In an old
person, there are thousands, tens of thousands or hundreds of
thousands of knocked-out cells. The chance that any one would form a
cancer is very low.

When the damage occurs in any area of changed cells, something

different occurs. Each of the cells has the potential for growth. The
changed cells will divide quicker when the area is damaged by physical,
chemical, or viral agents. A vicious circle has been set up: Damaging the
area will cause the changed cells to divide, causing a greater likelihood
that they will suffer knock-outs.

This model of carcinogenesis is popular because it explains why

cancers grow. It would be expected that cells that are damaged through
radiation would die or at least be worse off because they have fewer
genes working; viruses increase the number of genes working.

One concern is that we may end up with thousands of vaccines to

prevent every virus that can change our cells. Viruses can have different
effects on different parts of the body. It may be possible to prevent a
number of different cancers by immunizing against one viral agent. It is
likely that HPV, for instance, has a role in cancers of the mucous
membranes of the mouth.

Bacterial infection
 70

Bacterial infections have not been thought of as cancer causing agents

in the past. But studies have shown that people who have helicobacter
pylori infection of their stomach develop inflammation of the stomach
lining, which increases the risk of stomach cancer. Helicobacter pylori
infection can be treated with a combination of antibiotics.

Research is also looking at whether substances produced by particular

types of bacteria in the digestive system can increase the risk of bowel
cancer or stomach lymphomas. Some researchers think that particular
bacteria may produce cancer causing substances in some people. But
research into this issue is at an early stage.

If bacteria do play a part in causing cancer this could be important in

cancer prevention. Bacterial infections can often be cured with
antibiotics, so getting rid of the infection could be a way to reduce the
risk of these types of cancer.

Other causes
Excepting the rare transmissions that occur with pregnancies and only a
marginal few organ donors, cancer is generally not a transmissible
disease. The main reason for this is tissue graft rejection caused by MHC
incompatibility. In humans and other vertebrates, the immune system
uses MHC antigens to differentiate between "self" and "non-self" cells
because these antigens are different from person to person. When non-
self antigens are encountered, the immune system reacts against the
appropriate cell. Such reactions may protect against tumor cell
engraftment by eliminating implanted cells. In the United States,
approximately 3,500 pregnant women have a malignancy annually, and
transplacental transmission of acute leukemia, lymphoma, melanoma
and carcinoma from mother to fetus has been observed. The
development of donor-derived tumors from organ transplants is
exceedingly rare. The main cause of organ transplant associated tumors
seems to be malignant melanoma, that was undetected at the time of
organ harvest, though other cases exist. In fact, cancer from one
organism will usually grow in another organism of that species, as long
as they share the same histocompatibility genes, proven using mice;
however this would never happen in a real-world setting except as
described above.

In non-humans, a few types of cancer have been found to be caused by

transmission of the tumor cells themselves. This phenomenon is seen in
dogs with Sticker's sarcoma, also known as canine transmissible
venereal tumor, as well as Devil facial tumor disease in Tasmanian
devils.

Most cancers are probably due to a combination of factors

 71

Not everybody who comes into contact with a carcinogen or has an

unhealthy lifestyle will develop cancer. For example, not all smokers
develop cancer of the lung. In fact, we are all probably exposed to low
doses of carcinogens a lot of the time.

The body has certain mechanisms which may protect us from

developing cancer. For example, it is thought that many cells which are
damaged by carcinogens can repair themselves. Also, the body's
immune system may be able to destroy some types of abnormal cells
before they multiply into a tumor. Perhaps one carcinogen may only
damage one gene, and two or more genes may need to be damaged or
altered to trigger the cells to multiply 'out of control'.

In many cases it is likely that a combination of factors such as genetic

make-up, exposure to a carcinogen, age, diet, the state of your immune
system, etc, play a part to trigger a cell to become abnormal, and allow it
to multiply 'out of control' into a cancer

Pathophysiology
Cancers are caused by a series of mutations. Each mutation alters the
behavior of the cell somewhat.

Cancer is fundamentally a disease of regulation of tissue growth. In

order for a normal cell to transform into a cancer cell, genes which
regulate cell growth and differentiation must be altered. Genetic changes
can occur at many levels, from gain or loss of entire chromosomes to a
mutation affecting a single DNA nucleotide. There are two broad
categories of genes which are affected by these changes. Oncogenes
may be normal genes which are expressed at inappropriately high levels,
or altered genes which have novel properties. In either case, expression
of these genes promotes the malignant phenotype of cancer cells.
Tumor suppressor genes are genes which inhibit cell division, survival,
or other properties of cancer cells. Tumor suppressor genes are often
disabled by cancer-promoting genetic changes. Typically, changes in
many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic

changes which may contribute to the generation of cancer cells. Most of
these changes are mutations, or changes in the nucleotide sequence of
genomic DNA. Aneuploidy, the presence of an abnormal number of
chromosomes, is one genomic change which is not a mutation, and may
involve either gain or loss of one or more chromosomes through errors
in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a

chromosome. Genomic amplification occurs when a cell gains many
copies (often 20 or more) of a small chromosomal locus, usually
containing one or more oncogenes and adjacent genetic material.
Translocation occurs when two separate chromosomal regions become
 72

abnormally fused, often at a characteristic location. A well-known

example of this is the Philadelphia chromosome, or translocation of
chromosomes 9 and 22, which occurs in chronic myelogenous leukemia,
and results in production of the BCR-abl fusion protein, an oncogenic
tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions,

which may occur in the promoter of a gene and affect its expression, or
may occur in the gene's coding sequence and alter the function or
stability of its protein product. Disruption of a single gene may also
result from integration of genomic material from a DNA virus or
retrovirus, and such an event may also result in the expression of viral
oncogenes in the affected cell and its descendants.
 73

The relation between The Telomerase

Enzyme and Cancer
 Telomerase and Immortality

The search for immortality has long been a quest of the human spirit.
Whether it manifests as a belief in some sort of spiritual afterlife or in
prolonging our mortal lives, humanity seems to find the ending of
consciousness a horrid thought. Naturally, the mechanisms for why
people grow old and die would gain a huge amount of attention by both
researchers and the non-scientific community. Many scientists believe
the key to mortality has already been found, and it is located at the ends
of our chromosomes.

Research has discovered that regions of repetitive DNA stretches called

telomeres found on the ends of our DNA strands are cut shorter every
time they are copied. Eventually the telomeres are worn away and genes
near the end of the chromosomes are lost which contain protein
instructions the body desperately needs to survive. Some believe that it
is this slow yet eventual erosion of the ends of our chromosomes that
leads to aging. The discoveries in this area will have a huge impact on
more than just showing the way to a possible fountain of youth. Cancer
research and cloning may also hinge on developments in the field of
telomere research.

Telomeres exist as the body’s way of solving a problem with DNA

replication. DNA is replicated by the use of an enzyme called DNA
polymerase.

DNA polymerase functions to copy our chromosomal DNA, using an

existing DNA "parental" strand as a template. The polymerase performs
this feat by attaching nucleotides to polymerize a new "daughter" DNA
strand in complement to the parental strand. Adenine (A) is added to the
 74

new strand complementary to thymine (T) while guanine (G) is added

complementary to cytosine (C), and visa versa. There are two main
problems with the capabilities of the DNA polymerase. The first is that it
can’t start from scratch (from the beginning). There must be a segment
of the new strand from which the polymerase can begin attaching new
nucleotides. The use of primers easily solves this problem. These
primers are RNA fragments that bind by random assortment
complementary to sites on the parent strand of DNA, and must be in
place before the DNA polymerase can begin copying the parent strand.

 Replication by DNA polymerase

(Replication shortens the Chromosome)

The second problem caused by DNA polymerase during replication is

much more difficult for cells to surpass. DNA polymerase can only work
in a 5’ to 3’ direction. The terms 5’ and 3’ refer to the sugar molecule in
the sugar/phosphate DNA backbone. The numbers relate to the carbon in
that ring of sugar. 5’ is the fifth carbon in that ring. 3’ is the third. In order
for the polymerase to attach a new complementary nucleotide, an
alcohol (-OH) group must be available on the 3’ carbon of the sugar
molecule. That is the site where the polymerase attaches the phosphate
group of the next nucleotide. This phosphate group is subsequently
attached to the 5’ carbon of the new nucleotide’s sugar group. The
polymerase can therefore only work from the direction of the previously
attached 5’ carbon to the 3’ carbon, which has the –OH group available
for the attachment of the next nucleotide. The problem with this
 75

unidirectional movement lies with the primers, for they can’t stay in the
new strand because they are RNA, and not DNA. Removal of these RNA
primers is really not a problem when they are located in the middle of the
new daughter strand. There will be a 5’ carbon available for a DNA
polymerase to fill in the gap that remained after primer removal.
However, the problem lies at the beginning each chromosome. A primer
was necessary to provide a 5’ carbon for the beginning of synthesis, yet
once it is removed, an upstream 5’ carbon is not available from which a
polymerase can attach nucleotides and fill in the gap. Therefore,
because the nucleotides are are not replaced after removal of the first
primer at the beginning of every chromosome, every time the
chromosome replicates the daughter strand will be shorter than the
parental strand. Studies have shown that the length of a chromosome
shortens by about 50 nucleotides every time it replicates. The damage
isn’t huge compared to the overall length of a chromosome, but it does
mean the chromosome is mortal in that it is slowly being eaten away at
the ends with every cell division. If any of these 50 nucleotides contains
the instruction to begin the transcription of a gene, that gene and the
protein it encodes will never be usable by the body again.

The body’s natural cure to this dilemma is the production of expendable

nucleotides at the 3’ end of every chromosome. These "cannon fodder"
nucleotides are called telomeres. Telomeres are repetitive hexameric (6
base pair) sequences of DNA. In humans this repeated G-rich sequence
is AGGGTT. These sequences are 1000-1700 base pairs long at the
beginning of a mammalian life. Cells seldom survive past about 50
divisions in vitro, which most researchers ascribe to the deletion of too
many genes in the process of replication.

Oddly, these telomeres are not encoded in the initial DNA resulting from
egg fertilization. What this means is that the telomeres must be added
later in development. In 1985 Elizabeth Blackburn and Carol Greider
discovered a new DNA polymerase which can add telomeres to DNA.
This polymerase, called telomerase, is a ribonucleoprotein present in the
very early stages of development. Telomerase activity stops in later
development, as it is only required to put the telomeres in place once.
Ribonucleoproteins contain RNA, which telomerase uses as a template
to synthesize the hexameric DNA telomeres. Because telomerase is a
polymerase that copies an RNA template (its own) into DNA, it is a
reverse transcriptase. A reverse transcriptase is so named because it is
capable of writing codes of DNA from an RNA template which is the
reverse of transcription. Reverse transcriptases have gained a lot of
fame because they are used by retroviruses, notably HIV, for viral
replication.
 76

Telomerase mechanism
Telomerase binds to the 3’ end of a chromosome and lines its own RNA
template so that a few of its RNA base pairs are complementary to that of
the strand. Another segment of the ribozyme hangs over the edge
providing a template for the synthesis of the telomeres (CCUAAC).
Telomerase synthesizes the hexomeric sequence and then translocates
to a new 3’ recognition site, which is within the hexanucleotide it just
produced, and repeats the procedure. A normal DNA polymerase and
primer can then complete the complementary strand’s 5’ end with all of
the new hexomeric repeats--all except the last bit of course. The exact
details of telomerase function are currently under research, but its
currently understood mechanism as a DNA polymerase that carries its
own template appears quite unique and phenomenal.

Could the "Fountain of Youth," simply be a shot of telomerase? Some

research hints that this might be a good start to combat aging. For
example, recent studies have shown that mice deficient in the gene for
encoding telomerase RNA (mTR) developed liver cirrhosis sooner and
regenerated much slower than normal mice. These same mice also
showed improved liver function upon receiving gene delivery of
telomerase. In the future, it may be possible to induce telomerase to
reset aging cells back to their chromosomal state during a person’s
young and vibrant 20’s. However, in most cases the addition of
telomerase into somatic cells late in development would be a death
sentence. Cell death (apoptosis) is often a good thing in the body. If
some cells didn’t die, some tissues would never stop growing.
Apoptosis is a crucial tool used by the body to maintain proper
development. Certain cells must die at certain times or else the entire
organism will perish.

Another aging-related subject that telomere research might prove helpful

to is cloning research. Cloning researchers have found that
unfortunately the telomeres of cloned animals (such as the famed cloned
sheep named "Dolly") are much shorter than a counterpart of the same
developmental "age". Even though cloning technology has attained
successful birth rates as high as 80%, most of these clones die before
 77

even reaching adulthood. Shortened telomeres appear to be the most

likely cause of these deaths. Research seeks to uncover a means of
safely extending the telomeres of the clones. Some may hope that the
solution to the clone problem will eventually bring about a magic youth
potion to humanity.

Besides the prevention of age-related health problems, another

motivating drive for telomerase research is to develop effective cancer
treatments. Scientists are attempting to destroy the telomeres by
eradicating telomerase activity in cancer cells. The purpose is to limit the
number of divisions possible in these cells. Normal somatic cells have
no telomerase present in them because the expression of the telomerase
gene is shut down early in life. Because these cells live a long time in the
body, the telomeres created early in life are long enough to serve them
for the number of divisions they need to make during the lifetime of the
organism. However, cancer cells are defined by unbridled cell division,
and therefore it is the telomerase which allows cancer cells to continue
their unhindered proliferation and subsequent immortality. One of the
mutations that leads to a cell becoming cancerous is one that disrupts
the cells ability to shut down telomerase expression. Cancer researchers
have become very interested in designing drugs that target and
inactivate telomerase, for if telomerase could be inactivated this would
lead to cancer cells becoming mortal again and stop them in their tracks.

Although using telomere research for finding a treatment for cancer is a

popular concept that everyone supports, the idea of significantly
extending life is much more controversial. With the population of Earth
bulging proudly over 6 billion souls one has to ponder if human
immortality would be a blessing at this point in time. Endless life could
be to society what cell immortality is to the body.

• Telomeres, Telomerase and Cancer

An unusual enzyme called telomerase acts on parts of chromosomes
known as telomeres. The enzyme has recently been found in many
human tumors and is being eyed as a new target for cancer therapy.

Often in nature things are not what they seem. A rock on the seafloor
may be a poisonous fish; a beautiful flower in a garden may be a
carnivorous insect lying in wait for prey. This misleading appearance
extends to certain components of cells, including chromosomes-the
strings of linear DNA that contain the genes. At one time, the DNA at the
ends of chromosomes seemed to be static. Yet in most organisms that
have been studied, the tips, called telomeres, are actually ever changing;
they shorten and lengthen repeatedly.
During the past 15 years, investigation of this unexpected flux has
produced a number of surprising discoveries. In particular, it has led to
 78

identification of an extraordinary enzyme named telomerase that acts on

telomeres and is thought to be required for the maintenance of many
human cancers. This last finding has sparked much speculation that
drugs able to inhibit the enzyme might combat a wide array of
malignancies. The research also opens the possibility that changes in
telomere length over time may sometimes play a role in the aging of
human cells.
Modern interest in telomeres and telomerase has its roots in
experiments carried out in the 1930s by two remarkable geneticists:
Barbara McClintock, then at the University of Missouri at Columbia, and
Hermann J. Muller, then at the University of Edinburgh. Working
separately and with different organisms, both investigators realized that
chromosomes bore a special component at their ends that provided
stability. Muller coined the term "telomere," from the Greek for "end"
(telos) and "part" (meros). McClintock noted that without these end caps,
chromosomes stick to one another, undergo structural changes and
misbehave in other ways. These activities threaten the survival and
faithful replication of chromosomes and, consequently, of the cells
housing them.
It was not until the 1970s, however; that the precise makeup of the
telomere was determined. In 1978 one of us (Blackburn), then working
with Joseph G. Gall of Yale University, found that the telomeres in
Tetrahymena, a ciliated, single-cell pond dweller, contained an extremely
short, simple sequence of nucleotides-TTGGGG-repeated over and over.
(Nucleotides are the building blocks of DNA; they are generally denoted
as single letters representing the chemical bases that distinguish one
nucleotide from another. The base in T nucleotides is thymine; that in G
nucleotides is guanine.)
Since then, scientists have characterized the telomeres in a host of
creatures, including animals, plants and microorganisms. As is true of
Tetrahymena, virtually all telomeres-including those of mice, humans
and other vertebrates contain repeated short subunits often rich in T and
G nucleotides [see "The Human Telomere," by Robert K. Moyzis;
Scientific American, August 1991]. For instance, human and mouse
telomeres feature the sequence TTAGGG; those of roundworms feature
TTAGGC. (A stands for adenine, C for cytosine.)

The following section will teach you the basics of telomeres and
telomerase. It will also introduce you to the potential applications of
current telomerase research. Words in italics are defined in the glossary.
At the end of some paragraphs, you may view a short animation that will
help describe what you just read.

What are telomeres and telomerase?

 79

To better understand telomeres and telomerase, let's first review

some basic principles of biology and genetics. The human body is an
organism formed by adding many organ systems together. Those organ
systems are made of individual organs. Each organ contains tissues
designed for specific functions like absorption and secretion. Tissues are
made of cells that have joined together to perform those special
functions. Each cell is then made of smaller components called
organelles, one of which is called the nucleus. The nucleus contains
structures called chromosomes that are actually "packages" of all the
genetic information that is passed from parents to their children. The
genetic information or "genes" are really just a series of base pairs
called Adenine (A), Guanine (G), Cytosine (C), and Thymine (T). These
base pairs make up our cellular alphabet and create the sequences, or
instructions needed to form our bodies. In order to grow and age, our
bodies must duplicate their cells. This process is called mitosis. Mitosis
is a process that allows one "parent" cell to divide into two new
"daughter" cells. During mitosis, cells make copies of their genetic
material. Half of the genetic material goes to each new daughter cell. To
make sure that information is successfully passed from one generation
to the next, each chromosome has a special protective cap called a
telomere located at the end of its "arms". Telomeres are controlled by
the presence of the enzyme telomerase. Now that we have covered some
basics, let's explore telomeres, telomerase, and their importance to you!

A telomere is a repeating DNA sequence (TTAGGG) at the end of the

body's chromosomes. The telomere can reach a length of 15,000 base
pairs. Telomeres function by preventing chromosomes from losing base
pair sequences at their ends. They also stop chromosomes from fusing
to each other. However, each time a cell divides, some of the telomere is
lost (usually 25-200 base pairs per division). When the telomere becomes
too short, the chromosome reaches a "critical length" and can no longer
replicate. This means that a cell becomes "old" and dies by a process
called apoptosis. Telomere activity is controlled by two mechanisms:
erosion and addition. Erosion, as mentioned, occurs each time a cell
divides. Addition is determined by the activity of telomerase.

Telomerase, also called telomere terminal transferase, is an enzyme

made of protein and RNA subunits that elongates chromosomes by
adding TTAGGG sequences to the end of existing chromosomes.
Telomerase is found in fetal tissues, adult germ cells, and also tumor
cells. Telomerase activity is regulated during development and has a
very low, almost undetectable activity in somatic (body) cells. Because
these somatic cells do not regularly use telomerase, they age. The result
of aging cells is an aging body. If telomerase is activated in a cell, the
cell will continue to grow and divide. This "immortal cell" theory is
important in two areas of research: aging and cancer.

Cellular aging, or senescence, is the process by which a cell becomes

old and dies. It is due to the shortening of chromosomal telomeres to the
point that the chromosome reaches a critical length. Cellular aging is
 80

analogous to a wind up clock. If the clock stays wound, a cell becomes

immortal and constantly produces new cells. If the clock winds down,
the cell stops producing new cells and dies. Our cells are constantly
aging. Being able to make the body's cells live forever certainly creates
some exciting possibilities. Telomerase research could therefore yield
important discoveries related to the aging process.

Cancer cells are a type of malignant cell. The malignant cells multiply
until they form a tumor that grows uncontrollably. Telomerase has been
detected in human cancer cells and is found to be 10-20 times more
active than in normal body cells. This provides a selective growth
advantage to many types of tumors. If telomerase activity was to be
turned off, then telomeres in cancer cells would shorten, just like they do
in normal body cells. This would prevent the cancer cells from dividing
uncontrollably in their early stages of development. In the event that a
tumor has already thoroughly developed, it may be removed and anti-
telomerase therapy could be administered to prevent relapse. In
essence, preventing telomerase from performing its function would
change cancer cells from "immortal" to "mortal".

Knowing what we have just learned about telomeres and telomerase,

it can be said that scientists are on the verge of discovering many of
telomerase's secrets. In the future, their research in the area of
telomerase could uncover valuable information to combat aging, fight
cancer, and even improve the quality of medical treatment in other areas
such as skin grafts for burn victims bone marrow transplants, and heart
disease. Who knows how far this could go?

 The Cancer Connection

 Some investigators suspect that the loss of proliferative capacity

observed in human cells lacking telomerase may have evolved not to
make us decrepit but to help us avoid cancer.

 Cancers arise when a cell acquires multiple genetic mutations that

together cause the cell to escape from normal controls on replication
and migration. As the cell and its offspring multiply uncontrollably,
they can invade and damage nearby tissue.

 Some may also break away and travel to parts of the body where
they do not belong, establishing new malignancies (metastases) at
distant sites. In theory, a lack of telomerase would retard the growth
of tumors by causing continually dividing cells to lose their telomeres
and to succumb before they did much damage. If cancer cells made
telomerase, they would retain their telomeres and would potentially
 81

survive indefinitely.

 The notion that telomerase might be important to the maintenance

of human cancers was discussed as early as 1990. But the evidence
did not become compelling until recently. In 1994 Christopher M.
Counter, Silvia Bacchetti, Harley and their colleagues at McMaster
showed that telomerase was active not only in cancer-cell lines
maintained in the cancer-cell lines maintained in the laboratory but in
ovarian tumors in the human body. Later that year groups led by
Harley, who had moved to Geron Corporation in Menlo Park, Calif.,
and by Jerry W. Shay of the University of Texas Southwestern Medical
Center at Dallas detected telomerase in 90 of 101 human tumor
samples (representing 12 tumor types) and in none of 50 samples of
normal somatic tissue (representing four tissue types).

 Even before such evidence was obtained, however, researchers

had begun exploring some of the details of how telomerase might
contribute to cancer. That work suggests telomerase probably
becomes active after a cell has already lost its brakes on proliferation.
The first clue was an initially mystifying discovery made
independently by Titia de Lange, now at the Rockefeller University,
and by Hasrie's group. In 1990 these investigators reported that
telomeres in human tumors were shorter than telomeres in the normal
surrounding tissue-sometimes dramatically so.

 Studies by Greider's, Bacchetri's and Harley's laboratories

explained why the telomeres were so small. The teams had induced
normal cells from humans to make a viral protein causing cells to
ignore the alarm signals that usually warn them to stop dividing. The
treated cells continued to proliferate long after they would normally
enter senescence. In most of the cells, telomeres shortened
drastically, and no telomerase was detected; eventually death ensued.
Some cells, however, persisted after their siblings died and became
immortal. In these immortal survivors, telomeres were maintained at a
strikingly short length, and telomerase was present.

 These outcomes imply that telomeres in cancer cells are small

because cells synthesize telomerase only after they have already
begun to replicate uncontrollably; by then, the cells have presumably
lost a substantial number of telomeric subunits. When the enzyme is
finally activated, it stabilizes the severely clipped telomeres, allowing
overly prolific cells to become immortal.
 82

The Telomere

These findings and others have led to an attractive but still

hypothetical model for the normal and malignant activation of
telomerase by the human body. According to this model,
telomerase is made routinely by cells of the germ line in the
.developing embryo

Once the body is fully formed, however, telomerase is repressed

in many somatic cells, and telomeres shorten as such cells
.reproduce

When telomeres decline to a threshold level, a signal is emitted

.that prevents the cells fromdividing further
If, however, cancer-promoting genetic mutations block issuance
of such safety signals or allow cells to ignore them, cells will
bypass normal senescence and continue to divide. They will also
presumably continue to lose telomeric sequences and to
undergo chromosomal alterations that allow further, possibly
carcinogenic mutations to arise. When telomeres are completely
 83

or almost completely lost, cells may reach a point at which they

.crash and die
But if the genetic derangements of the pre-crisis period lead to
the manufacture of telomerase, cells will not completely lose
their telomeres. Instead the shortened telomeres will be rescued
and maintained. In this way, the genetically disturbed cells will
.gain the immortality characteristic of cancer
This scenario has generally been borne out by the evidence,
although, once again, things may not be entirely as they seem.
Some advanced tumors lack telomerase, and some somatic cells-
notably the white blood cells known as macrophages and
lymphocytes-have recently been found to make the enzyme.
Nevertheless, on balance, the collected evidence suggests that
many tumor cells require telomerase in order to divide
.indefinitely

 Hereditary Cancer

Hereditary cancer is a cancer that has developed as a result of a gene

mutation passed down from a parent to a child. Inheriting a gene
mutation does not necessarily mean that person will develop cancer, but
.increases their risk factor

Research and studies have found that certain gene mutations increase
the chances of a person to develop certain kinds of cancers, depending
on family history. Remember, cancer is not inherited, only the gene that
.increases the risk factor of developing it

 What is genetic testing?

Genetic testing is the use of laboratory tests to get a more accurate risk
of developing a hereditary cancer. Tests depend on the cancer being
.investigated
Genetic testing in never required. Many questions are answered through
genetic counseling. It is a personal decision between you and your
.physician

Keep in mind that genetic testing can help you make more informed
medical decisions about your healthcare, depending on the findings of
.the test

Genetic cause of cancer

 84

Cancer has become the most fatal disorder these days. Genetically
Cancer can be looked upon as a problem with differentiation and
development. When normal cells of animals differentiate, there are
control mechanisms to regulate their growth and division. When cells
multiply, they become crowded and start touching each other. This
surface contact results in inhibition of cell movement and division.

On the other hand, cells which continue to divide and give rise to a
tissue mass referred to as tumour. These can also invade other tissues
and tumours can arise in new locations, this is cancer. The genetic
information is present in codon form and due to the attack of X-rays,
viruses and chemical mutagens these codons get change. Epstein-barr,
herpes virus and Papilloma virus are main cancer causing viruses. Many
cancers appear essentially due to the activation of a set of genes
referred to as ONCOGENES.

There are about 20 viral genes, which are known to cause cancer. These
genes are called VIRAL ONCOGENES. Surprisingly, each VIRAL
ONCOGENES has a homologous base sequence in the DNA of the
normal animal cells. This sequence is named PROTOONCOGENE.
PROTOONCOGENES control the production of proteins, which stimulate
the growth and cell division. PROTOONCOGENES turned on to cause
cancer and this happens in 2 ways -

1. A PROTOONCOGENE is placed next to a gene that is not

normally next to it and this boosts its expression.
2. PROTOONCOGENE is moved from its normal position on a
chromosome and placed next to a gene, which is normally very
active.

Many PROTOONCOGENES are involved in normal growth and

development of cells. In cancer this normal function is subverted so that
the PROTOONCOGENES are slightly altered or broken into fragments or
amplified and are transferred to a new chromosomal location. These
ONCOGENES now come under an altered environment and different
regulatory controls. All these changes result in altered genomic
 85

complement and lead to the formation of abnormal proteins, which now

are responsible for the uncontrolled growth, which is cancerous.

 Chromosomes and cancer

Normal human cells contain 46 chromosomes. Changes in this number

as well as structural chromosomal abnormalities are common in the
majority of tumors. The first consistent chromosome abnormality to be
recognized was the Philadelphia chromosome seen in chronic myeloid
leukemia. Since then many other changes have been found, including
loss or gain of whole chromosomes or parts of chromosomes and
chromosomal translocations. These changes are nonrandom events and
generally are somatically acquired alterations. Some may be primary
events occurring early in the development of the tumor and are likely to
be an important event in its development. Others are secondary events
and may have a role in the subsequent behavior of the tumor. In
addition, many other random changes in the chromosome complement
are also found due to the instability of the tumor cell.
Loss of chromosomal material can often result in the deletion of a tumor
suppressor gene. Duplication of a region can lead to over-expression of
an oncogene.
Molecular analysis of translocation breakpoint has led to the
identification of a number of genes adjacent to the breakpoints which
have been implicated in the initiation and progression of tumors.
Studies of chromosome translocations led to the identification of a
number of oncogenes.

 Oncogene

An oncogene is a gene that, when mutated or expressed at high levels,

helps turn a normal cell into a tumor cell.

Many abnormal cells normally undergo a programmed form of death

(apoptosis). Activated oncogenes can cause those cells to survive and
proliferate instead. Most oncogenes require an additional step, such as
mutations in another gene, or environmental factors, such as viral
infection, to cause cancer. Since the 1970s, dozens of oncogenes have
been identified in human cancer. Many cancer drugs target those DNA
sequences and their products.

 Proto-oncogene

A proto-oncogene is a normal gene that can become an oncogene due to

mutations or increased expression. Proto-oncogenes code for proteins
that help to regulate cell growth and differentiation. Proto-oncogenes are
often involved in signal transduction and execution of mitogenic signals,
usually through their protein products. Upon activation, a proto-
oncogene (or its product) becomes a tumor-inducing agent, an
 86

oncogene. Examples of proto-oncogenes include RAS, WNT, MYC, ERK,

and TRK.

 Inherited vs. sporadic (that happens only

occasionally) cancer

Cancers can be classified into four main groups on the basis of the
genetic defect:

(1) The majority of cancers is sporadic and is caused by

environmental factors such as chemicals and radiation. Mutations
in these tumors are found only in the cancer tissue itself.

(2) Some cancers, without a recognizable genetic basis, show

clustering in families and may represent an underlying
susceptibility to environmental carcinogens. Care has to be taken
when looking at this group as it is possible to have apparent
clustering of cancers in families due to the shared environment of
family members rather than because of a genetic defect.

(3) A small proportion of cancers have a clearly defined

genetic cause. This means that screening at-risk family members
is immediately possible, thereby preventing unnecessary
morbidity and mortality. In addition, the genes involved have a
wider importance as the genes which cause the inherited form of
the disease are often the same as those which are implicated in
the sporadic form of the disease. Their study can therefore help in
the understanding of the more common forms of the cancer. The
classic example of this is the APC gene which is responsible for
the inherited condition familial adenomatous polyposis (FAP) and
which is also the earliest gene to be mutated in the development
of sporadic colorectal cancer. The main exception to this principle
is familial breast cancer which is caused by defects in the BRCA1
and BRCA2 genes. Defects in these genes have not so far been
observed in sporadic breast cancer. In cancers with a true genetic
basis, the causative mutation is found in all the cells of the body.
This group can be recognized by an earlier age of onset, multiple
cancers in individuals and by segregation of the disease through
the family in a Mendelian manner.

(4) Individuals with some conditions, generally termed

chromosome breakage syndromes because of the increased
chromosome fragility seen in cultured cells, for example those
from xeroderma pigmentosum and ataxia telangiectasia, have an
increased risk of cancers although the incidence of cancers is not
close to the levels seen in patients in group 3.
 87

• Diagnosis
Most cancers are initially recognized either because signs or symptoms
appear or through screening. Neither of these lead to a definitive
diagnosis, which usually requires the opinion of a pathologist, a type of
physician (medical doctor) who specializes in the diagnosis of cancer
and other diseases. People with suspected cancer are investigated with
medical tests. These commonly include:

 Blood tests
 X-rays
 CT scans
 Endoscopy.

A multi-slice CT scanner

• Tumor marker
A tumor marker is a substance found in the blood, urine, or body tissues
that can be elevated in cancer, among other tissue types. There are
many different tumor markers, each indicative of a particular disease
process, and they are used in oncology to help detect the presence of
cancer. An elevated level of a tumor marker can indicate cancer;
however, there can also be other causes of the elevation.

• Description
 88

Tumor markers can be produced directly by the tumor or by non-tumor

cells as a response to the presence of a tumor.

Koepke outlines a hierarchy of clinical laboratory tests, from least to

most informative. As used in oncology, they are as follows:

• Screening for common cancers on a population basis

Example: elevated prostate specific antigen suggests prostate cancer.

• Monitoring of cancer survivors after treatment

Example: elevated AFP in a child previously treated for teratoma

suggests relapse with endodermal sinus tumor.

• Diagnosis of specific tumor types, particularly in certain

brain tumors and other instances where biopsy is not feasible.

The term tumor antigen is sometimes interchangeably used for tumor

marker.

• Classification
Tumor markers can be classified in two groups: Cancer-specific markers
and tissue-specific markers.

Cancer-specific markers
Cancer-specific markers are related to the presence of certain cancerous
tissue. Because there is a large overlap between the many different
tumor tissue types and the markers produced these markers might not
be specific in making a diagnosis. They can, however, be useful in the
follow-up of treated patients to describe progress of the disease or
response to treatment. A few examples of these markers are CEA, CA19-
9, CA125.

An example of a cancer-specific marker, CEA, or carcinoembryonic

antigen, is a blood-borne protein, first noted to be produced by tumors
of the gastrointestinal system. Further investigation showed that it was
produced by the occasional lung and breast cancer case, meaning that
an elevated level does not necessarily mean a bowel cancer. However, in
a patient with a history of a treated bowel cancer, a rising CEA level can
be an early sign of recurring bowel cancer. This usually occurs before
the site of return can be identified on imaging or examination and so
many oncologists question the wisdom of doing a blood test for CEA
when the end result is bad news that alarms the patient. Nevertheless, a
sequence of steady low CEA readings can provide much needed
reassurance to the post-operative patient. Also, a rising sequence of
 89

CEA readings should alert the physician to the need for diagnostic tests
such as PET scans.

Tissue-specific markers
Tissue-specific markers are related to specific tissues which have
developed cancer. Generally speaking, these substances are not
specifically related to the tumor, and may be present at elevated levels
when no cancer is present. But unlike the previous group, elevated
levels point to a specific tissue being at fault. Examples include PSA,
beta-HCG - (Human chorionic gonadotropin), AFP - (Alpha-fetoprotein),
AFP-L3 - (a lectin-reactive AFP) and Thyroglobulin. For example, if a man
has an elevated PSA, a search for prostate cancer will be undertaken. If
an individual has an elevated level of beta-HCG, AFP or AFP-L3%, a
search for a testicular or liver cancer, respectively, will be made.

PSA (Prostate specific antigen) is produced by the normal prostate. It is a

protein enzyme called a serine protease that usually acts as an
anticoagulant to keep semen liquid. Only small amounts leak into the
circulation in normal circumstances. Enlarged prostates leak more
substantial amounts, and cancerous prostates also leak substantial
amounts. An accurate way to tell if an elevated PSA level results from
cancer is to biopsy the prostate.

β-hCG: Elevated levels cannot prove the presence of a tumor, and low
levels do not rule it out (an exception is in males who do not naturally
produce β-hCG). Nevertheless, elevated βhCG levels fall after successful
treatment (e.g. surgical intervention or chemotherapy), and a recurrence
can often be detected by the finding of rising levels.

CA15-3: Elevated CA15-3, in conjunction with alkaline phosphatase, was

shown to increase chances of early recurrence in breast cancer.
90
 91

• Management of cancer
Cancer can be treated by surgery, chemotherapy, radiation therapy,
immunotherapy, monoclonal antibody therapy or other methods. The
choice of therapy depends upon the location and grade of the tumor and
the stage of the disease, as well as the general state of the patient
(performance status). A number of experimental cancer treatments are
also under development.

Complete removal of the cancer without damage to the rest of the body
is the goal of treatment. Sometimes this can be accomplished by
surgery, but the propensity of cancers to invade adjacent tissue or to
spread to distant sites by microscopic metastasis often limits its
effectiveness. The effectiveness of chemotherapy is often limited by
toxicity to other tissues in the body. Radiation can also cause damage to
normal tissue.

Because "cancer" refers to a class of diseases, it is unlikely that there

will ever be a single "cure for cancer" any more than there will be a
single treatment for all infectious diseases.

•Types of therapies (summarized)

• Surgery
In theory, non-hematological cancers can be cured if entirely removed by
surgery, but this is not always possible. When the cancer has
metastasized to other sites in the body prior to surgery, complete
surgical excision is usually impossible. In the Halstedian model of
cancer progression, tumors grow locally, and then spread to the lymph
nodes, then to the rest of the body. This has given rise to the popularity
of local-only treatments such as surgery for small cancers. Even small
localized tumors are increasingly recognized as possessing metastatic
potential.

Examples of surgical procedures for cancer include mastectomy for

breast cancer and prostatectomy for prostate cancer. The goal of the
surgery can be either the removal of only the tumor, or the entire organ.
A single cancer cell is invisible to the naked eye but can regrow into a
new tumor, a process called recurrence. For this reason, the pathologist
will examine the surgical specimen to determine if a margin of healthy
tissue is present, thus decreasing the chance that microscopic cancer
cells are left in the patient.

In addition to removal of the primary tumor, surgery is often necessary

for staging, e.g. determining the extent of the disease and whether it has
metastasized to regional lymph nodes. Staging is a major determinant of
prognosis and of the need for adjuvant therapy.
 92

Occasionally, surgery is necessary to control symptoms, such as spinal

cord compression or bowel obstruction. This is referred to as palliative
treatment.

•Radiation therapy
Radiation therapy (also called radiotherapy, X-ray therapy, or irradiation)
is the use of ionizing radiation to kill cancer cells and shrink tumors.
Radiation therapy can be administered externally via external beam
radiotherapy (EBRT) or internally via brachytherapy. The effects of
radiation therapy are localised and confined to the region being treated.
Radiation therapy injures or destroys cells in the area being treated (the
"target tissue") by damaging their genetic material, making it impossible
for these cells to continue to grow and divide. Although radiation
damages both cancer cells and normal cells, most normal cells can
recover from the effects of radiation and function properly. The goal of
radiation therapy is to damage as many cancer cells as possible, while
limiting harm to nearby healthy tissue. Hence, it is given in many
fractions, allowing healthy tissue to recover between fractions.

Radiation therapy may be used to treat almost every type of solid tumor,
including cancers of the brain, breast, cervix, larynx, lung, pancreas,
prostate, skin, stomach, uterus, or soft tissue sarcomas. Radiation is
also used to treat leukemia and lymphoma. Radiation dose to each site
depends on a number of factors, including the radiosensitivity of each
cancer type and whether there are tissues and organs nearby that may
be damaged by radiation. Thus, as with every form of treatment,
radiation therapy is not without its side effects.

•Chemotherapy
Chemotherapy is the treatment of cancer with drugs ("anticancer drugs")
that can destroy cancer cells. In current usage, the term "chemotherapy"
usually refers to cytotoxic drugs which affect rapidly dividing cells in
general, in contrast with targeted therapy (see below). Chemotherapy
drugs interfere with cell division in various possible ways, e.g. with the
duplication of DNA or the separation of newly formed chromosomes.
Most forms of chemotherapy target all rapidly dividing cells and are not
specific to cancer cells, although some degree of specificity may come
from the inability of many cancer cells to repair DNA damage, while
normal cells generally can. Hence, chemotherapy has the potential to
harm healthy tissue, especially those tissues that have a high
replacement rate (e.g. intestinal lining). These cells usually repair
themselves after chemotherapy.

Because some drugs work better together than alone, two or more drugs
are often given at the same time. This is called "combination
 93

chemotherapy"; most chemotherapy regimens are given in a

combination.

The treatment of some leukaemias and lymphomas requires the use of

high-dose chemotherapy, and total body irradiation (TBI). This treatment
ablates the bone marrow, and hence the body's ability to recover and
repopulate the blood. For this reason, bone marrow, or peripheral blood
stem cell harvesting is carried out before the ablative part of the therapy,
to enable "rescue" after the treatment has been given. This is known as
autologous stem cell transplantation. Alternatively, hematopoietic stem
cells may be transplanted from a matched unrelated donor (MUD).

•Targeted therapies
Targeted therapy, which first became available in the late 1990s, has had
a significant impact in the treatment of some types of cancer, and is
currently a very active research area. This constitutes the use of agents
specific for the deregulated proteins of cancer cells. Small molecule
targeted therapy drugs are generally inhibitors of enzymatic domains on
mutated, overexpressed, or otherwise critical proteins within the cancer
cell. Prominent examples are the tyrosine kinase inhibitors imatinib
(Gleevec/Glivec) and gefitinib (Iressa).

Monoclonal antibody therapy is another strategy in which the

therapeutic agent is an antibody which specifically binds to a protein on
the surface of the cancer cells. Examples include the anti-HER2/neu
antibody trastuzumab (Herceptin) used in breast cancer, and the anti-
CD20 antibody rituximab, used in a variety of B-cell malignancies.

Targeted therapy can also involve small peptides as "homing devices"

which can bind to cell surface receptors or affected extracellular matrix
surrounding the tumor. Radionuclides which are attached to these
peptides (e.g. RGDs) eventually kill the cancer cell if the nuclide decays
in the vicinity of the cell. Especially oligo- or multimers of these binding
motifs are of great interest, since this can lead to enhanced tumor
specificity and avidity.

Photodynamic therapy (PDT) is a ternary treatment for cancer involving a

photosensitizer, tissue oxygen, and light (often using lasers). PDT can
be used as treatment for basal cell carcinoma (BCC) or lung cancer; PDT
can also be useful in removing traces of malignant tissue after surgical
removal of large tumors.

•Immunotherapy
Cancer immunotherapy refers to a diverse set of therapeutic strategies
designed to induce the patient's own immune system to fight the tumor.
 94

Contemporary methods for generating an immune response against

tumours include intravesical BCG immunotherapy for superficial bladder
cancer, and use of interferons and other cytokines to induce an immune
response in renal cell carcinoma and melanoma patients. Vaccines to
generate specific immune responses are the subject of intensive
research for a number of tumours, notably malignant melanoma and
renal cell carcinoma. Sipuleucel-T is a vaccine-like strategy in late
clinical trials for prostate cancer in which dendritic cells from the patient
are loaded with prostatic acid phosphatase peptides to induce a specific
immune response against prostate-derived cells.

Allogeneic hematopoietic stem cell transplantation ("bone marrow

transplantation" from a genetically non-identical donor) can be
considered a form of immunotherapy, since the donor's immune cells
will often attack the tumor in a phenomenon known as graft-versus-
tumor effect. For this reason, allogeneic HSCT leads to a higher cure rate
than autologous transplantation for several cancer types, although the
side effects are also more severe.

•Hormonal therapy
The growth of some cancers can be inhibited by providing or blocking
certain hormones. Common examples of hormone-sensitive tumors
include certain types of breast and prostate cancers. Removing or
blocking estrogen or testosterone is often an important additional
treatment. In certain cancers, administration of hormone agonists, such
as progestogens may be therapeutically beneficial.

•Angiogenesis inhibitors
Angiogenesis inhibitors prevent the extensive growth of blood vessels
(angiogenesis) that tumors require to survive. Some, such as
bevacizumab, have been approved and are in clinical use. One of the
main problems with anti-angiogenesis drugs is that many factors
stimulate blood vessel growth in cells normal or cancerous. Anti-
angiogenesis drugs only target one factor, so the other factors continue
to stimulate blood vessel growth. Other problems include route of
administration, maintenance of stability and activity and targeting at the
tumor vasculature.

•Symptom control
Although the control of the symptoms of cancer is not typically thought
of as a treatment directed at the cancer, it is an important determinant of
the quality of life of cancer patients, and plays an important role in the
 95

decision whether the patient is able to undergo other treatments.

Although doctors generally have the therapeutic skills to reduce pain,
nausea, vomiting, diarrhea, hemorrhage and other common problems in
cancer patients, the multidisciplinary specialty of palliative care has
arisen specifically in response to the symptom control needs of this
group of patients. This is an especially important aspect of care for
those patients whose disease is not a good candidate for other forms of
treatment. As most treatments for cancer involve significantly
unpleasant side effects, a patient with little realistic hope of a cure may
choose to seek palliative care only, eschewing more radical therapies in
exchange for a prolonged period of normal living.

Pain medication, such as morphine and oxycodone, and antiemetics,

drugs to suppress nausea and vomiting, are very commonly used in
patients with cancer-related symptoms. Improved antiemetics such as
ondansetron and analogues, as well as aprepitant have made aggressive
treatments much more feasible in cancer patients.

Chronic pain due to cancer is almost always associated with continuing

tissue damage due to the disease process or the treatment (i.e. surgery,
radiation, chemotherapy). Although there is always a role for
environmental factors and affective disturbances in the genesis of pain
behaviors, these are not usually the predominant etiologic factors in
patients with cancer pain. Furthermore, many patients with severe pain
associated with cancer are nearing the end of their lives and palliative
therapies are required. Issues such as social stigma of using opioids,
work and functional status, and health care consumption are not likely to
be important in the overall case management. Hence, the typical strategy
for cancer pain management is to get the patient as comfortable as
possible using opioids and other medications, surgery, and physical
measures. Doctors have been reluctant to prescribe narcotics for pain in
terminal cancer patients, for fear of contributing to addiction or
suppressing respiratory function. The palliative care movement, a more
recent offshoot of the hospice movement, has engendered more
widespread support for preemptive pain treatment for cancer patients.

Fatigue is a very common problem for cancer patients, and has only
recently become important enough for oncologists to suggest treatment,
even though it plays a significant role in many patients' quality of life.
 96

• Cancer and pregnancy

The incidence of concurrent cancer during pregnancy has risen due to
the increasing age of pregnant mothers and due to the incidental
discovery of maternal tumors during prenatal ultrasound examinations.

Cancer treatment needs to be selected to do least harm to both the

woman and her embryo/fetus. In some cases a therapeutic abortion may
be recommended.

Radiation therapy is generally out of the question, and chemotherapy

always poses the risk of miscarriage and congenital malformations.
Little is known about the effects of medications on the child.

Even if a drug has been tested as not crossing the placenta to reach the
child, some cancer forms can harm the placenta and make the drug pass
over it anyway. Some forms of skin cancer may even metastasize to the
child's body.

Diagnosis is also made more difficult, since computed tomography is

infeasible because of its high radiation dose. Still, magnetic resonance
imaging works normally. However, contrast media cannot be used, since
they cross the placenta.

As a consequence of the difficulties to properly diagnose and treat

cancer during pregnancy, the alternative methods are either to perform a
Cesarean section when the child is viable in order to begin a more
aggressive cancer treatment, or, if the cancer is malignant enough that
the mother is unlikely to be able to wait that long, to perform an abortion
in order to treat the cancer.
 97

• Cancer Chemotherapy
Normally, your cells grow and die in a controlled way. Cancer cells keep
forming without control. Chemotherapy is drug therapy that can stop
these cells from multiplying. However, it can also harm healthy cells,
which causes side effects.

During chemotherapy you may have no side effects or just a few. The
kinds of side effects you have depend on the type and dose of
chemotherapy you get. Side effects vary, but common ones are nausea,
vomiting, tiredness, pain and hair loss. Healthy cells usually recover
after chemotherapy, so most side effects gradually go away.

Your course of therapy will depend on the cancer type, the

chemotherapy drugs used, the treatment goal and how your body
responds. You may get treatment every day, every week or every month.
You may have breaks between treatments so that your body has a
chance to build new healthy cells. You might take the drugs by mouth, in
a shot or intravenously.

• History of cancer chemotherapy

The use of minerals and plant-based medicines are believed to date back
to prehistoric medicine.

The first use of drugs to treat cancer, however, was in the early 20th
century, although it was not originally intended for that purpose.
Mustard gas was used as a chemical warfare agent during World War I
and was studied further during World War II. During a military operation
in World War II, a group of people were accidentally exposed to mustard
gas and were later found to have very low white blood cell counts. It was
reasoned that an agent that damaged the rapidly-growing white blood
cells might have a similar effect on cancer. Therefore, in the 1940s,
several patients with advanced lymphomas (cancers of certain white
blood cells) were given the drug by vein, rather than by breathing the
irritating gas. Their improvement, although temporary, was remarkable.
That experience led researchers to look for other substances that might
have similar effects against cancer. As a result, many other drugs have
been developed to treat cancer, and drug development since then has
exploded into a multibillion-dollar industry, although the principles and
limitations of chemotherapy discovered by the early researchers still
apply.

• Principles of Chemotherapy
 98

Cancer is the uncontrolled growth of cells coupled with malignant

behavior: invasion and metastasis. Cancer is thought to be caused by
the interaction between genetic susceptibility and environmental toxins.

In the broad sense, most chemotherapeutic drugs work by impairing

mitosis (cell division), effectively targeting fast-dividing cells. As these
drugs cause damage to cells they are termed cytotoxic. Some drugs
cause cells to undergo apoptosis (so-called "programmed cell death").

Scientists have yet to identify specific features of malignant and immune

cells that would make them uniquely targetable (barring some recent
examples, such as the Philadelphia chromosome as targeted by
imatinib). This means that other fast-dividing cells, such as those
responsible for hair growth and for replacement of the intestinal
epithelium (lining), are also often affected. However, some drugs have a
better side effect profile than others, enabling doctors to adjust
treatment regimens to the advantage of patients in certain situations.

As chemotherapy affects cell division, tumors with high growth fractions

(such as acute myelogenous leukemia and the aggressive lymphomas,
including Hodgkin's disease) are more sensitive to chemotherapy, as a
larger proportion of the targeted cells are undergoing cell division at any
time. Malignancies with slower growth rates, such as indolent
lymphomas, tend to respond to chemotherapy much more modestly.

Drugs affect "younger" tumors (i.e., more differentiated) more effectively,

because mechanisms regulating cell growth are usually still preserved.
With succeeding generations of tumor cells, differentiation is typically
lost, growth becomes less regulated, and tumors become less
responsive to most chemotherapeutic agents. Near the center of some
solid tumors, cell division has effectively ceased, making them
insensitive to chemotherapy. Another problem with solid tumors is the
fact that the chemotherapeutic agent often does not reach the core of the
tumor. Solutions to this problem include radiation therapy (both
brachytherapy and teletherapy) and surgery.

Over time, cancer cells become more resistant to chemotherapy

treatments. Recently, scientists have identified small pumps on the
surface of cancer cells that actively move chemotherapy from inside the
cell to the outside. Research on p-glycoprotein and other such
chemotherapy efflux pumps, is currently ongoing. Medications to inhibit
the function of p-glycoprotein are undergoing testing as of June, 2007 to
enhance the efficacy of chemotherapy.

• Types of chemotherapeutic drugs

The majority of chemotherapeutic drugs can be divided in to alkylating
agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase
 99

inhibitors, and other antitumour agents. All of these drugs affect cell
division or DNA synthesis and function in some way.

Some newer agents do not directly interfere with DNA. These include
monoclonal antibodies and the new tyrosine kinase inhibitors e.g.
imatinib mesylate (Gleevec or Glivec), which directly targets a molecular
abnormality in certain types of cancer (chronic myelogenous leukemia,
gastrointestinal stromal tumors). These are examples of targeted
therapies.

In addition, some drugs that modulate tumor cell behaviour without

directly attacking those cells may be used. Hormone treatments fall into
this category.

Where available, Anatomical Therapeutic Chemical Classification System

codes are provided for the major categories.

Alkylating agents (L01A)

Alkylating agents are so named because of their ability to add alkyl
groups to many electronegative groups under conditions present in
cells. Cisplatin and carboplatin, as well as oxaliplatin, are alkylating
agents. They impair cell function by forming covalent bonds with the
amino, carboxyl, sulfhydryl, and phosphate groups in biologically
important molecules.

Other agents are mechlorethamine, cyclophosphamide, chlorambucil,

ifosfamide. They work by chemically modifying a cell's DNA.

Anti-metabolites (L01B)
Anti-metabolites masquerade as purine ((azathioprine, mercaptopurine))
or pyrimidine - which become the building blocks of DNA. They prevent
these substances from becoming incorporated in to DNA during the "S"
phase (of the cell cycle), stopping normal development and division.
They also affect RNA synthesis. Due to their efficiency, these drugs are
the most widely used cytostatics.

Plant alkaloids and terpenoids (L01C)

These alkaloids are derived from plants and block cell division by
preventing microtubule function. Microtubules are vital for cell division,
and, without them, cell division cannot occur. The main examples are
vinca alkaloids and taxanes.

Vinca alkaloids (L01CA)

 100

Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly

of tubulin into microtubules (M phase of the cell cycle). They are derived
from the Madagascar periwinkle, Catharanthus roseus (formerly known
as Vinca rosea). The vinca alkaloids include:

• Vincristine
• Vinblastine
• Vinorelbine
• Vindesine

Podophyllotoxin (L01CB)
Podophyllotoxin is a plant-derived compound which is said to help with
digestion as well as used to produce two other cytostatic drugs,
etoposide and teniposide. They prevent the cell from entering the G1
phase (the start of DNA replication) and the replication of DNA (the S
phase). The exact mechanism of its action is not yet known.

The substance has been primarily obtained from the American Mayapple
(Podophyllum peltatum). Recently it has been discovered that a rare
Himalayan Mayapple (Podophyllum hexandrum) contains it in a much
greater quantity, but, as the plant is endangered, its supply is limited.
Studies have been conducted to isolate the genes involved in the
substance's production, so that it could be obtained recombinantly.

Taxanes (L01CD)
The prototype taxane is the natural product paclitaxel, originally known
as Taxol and first derived from the bark of the Pacific Yew tree.
Docetaxel is a semi-synthetic analogue of paclitaxel. Taxanes enhance
stability of microtubules, preventing the separation of chromosomes
during anaphase.

Topoisomerase inhibitors (L01CB and L01XX)

Topoisomerases are essential enzymes that maintain the topology of
DNA. Inhibition of type I or type II topoisomerases interferes with both
transcription and replication of DNA by upsetting proper DNA
supercoiling.

• Some type I topoisomerase inhibitors include

camptothecins: irinotecan and topotecan.
• Examples of type II inhibitors include amsacrine, etoposide,
etoposide phosphate, and teniposide. These are semisynthetic
derivatives of epipodophyllotoxins, alkaloids naturally occurring
in the root of American Mayapple (Podophyllum peltatum).

Antitumour antibiotics (L01D)

 101

These include the immunosuppressant dactinomycin (which is used in

kidney transplantations), doxorubicin, epirubicin, bleomycin and others.

•Chemotherapy and its side effects

Many people fear chemotherapy because they have heard that it can
have uncomfortable side effects. But side-effect management has come
a long way over the last few decades. Today, many side effects once
associated with chemotherapy can be prevented or controlled. With
some types of chemotherapy, you may experience only minimal side
effects. And chemotherapy may be your best option for a successful
outcome. You can help achieve a successful outcome by understanding
how side effects can impact your treatment. Learn how best to manage
chemotherapy side effects.

Chemotherapy is the general term for any treatment involving the use of
chemical agents to stop cancer cells from growing. Chemotherapy can
eliminate cancer cells at sites great distances from the original cancer.
As a result, chemotherapy is considered a systemic treatment.

More than half of all people diagnosed with cancer receive

chemotherapy. For millions of people, chemotherapy helps treat their
cancer effectively, enabling them to enjoy full, productive lives.

A chemotherapy regimen (a treatment plan and schedule) usually

includes drugs to fight cancer plus drugs to help support completion of
the cancer treatment. To get the most from chemotherapy, it's important
to stick to a schedule of treatment.

 How Chemotherapy Works

Chemotherapy is designed to kill cancer cells. Chemotherapy can be

administered through a vein, injected into a body cavity, or delivered
orally in the form of a pill, depending on which drug is used.

Chemotherapy works by destroying cancer cells; unfortunately, it cannot

tell the difference between a cancer cell and some healthy cells. So
chemotherapy eliminates not only the fast-growing cancer cells but also
other fast-growing cells in your body, including, hair and blood cells.

Some cancer cells grow slowly while others grow rapidly. As a result,
different types of chemotherapy drugs target the growth patterns of
specific types of cancer cells. Each drug has a different way of working
and is effective at a specific time in the life cycle of the cell it targets.
Your doctor will determine the chemotherapy drug that is right for you.
To understand more about the different ways chemotherapy is given,
read about how people receive chemotherapy.
 102

 Discussing the Effectiveness of Cancer Treatment

Understand the goals and risks of each treatment option so you can
work with your doctor to decide which treatment is best for you. Balance
potential benefits against the risks of treatment.

Some risks of cancer treatments may include time away from family and
friends, uncomfortable side effects, or long-term complications. Cancer
treatment may be inconvenient, prolonged, or unavailable close to home.
These are important considerations when evaluating treatment options,
but they are not typically mentioned in medical journals reporting the
results and benefits of new treatments.

 Importance of Dose and Schedule

Your doctor will develop a treatment plan scientifically designed for you,
based on your type of cancer, its stage of advancement, and your overall
health. It will consist of specific chemotherapy agents, at specific doses
and intervals. These are called your scheduled cycles. Generally,
treatments are given daily, weekly, or monthly. Your doctor will help you
determine the most effective treatment schedule for you.

The goal is to make your chemotherapy as effective, timely, and

problem-free as possible. But while your chemotherapy treatment works
to fight your cancer, it also can cause side effects such as a lowered
white blood cell count. A low white blood cell count means your immune
system isn't as strong as it could be, which can increase your risk of
infection. It also can require your doctor to change your dose or
schedule of your chemotherapy.

A chemotherapy-induced low white blood cell count, caused by healthy

cells lost during chemotherapy, is an expected side effect of many
chemotherapy drugs. A low white blood cell count typically occurs after
the administration of certain types of chemotherapy and may continue
for several days. To help reduce side effects like low white blood cell
count that may interfere with your treatment schedule, learn more about
managing chemotherapy side effects.

Under certain circumstances, your doctor may decide your body is too
weak to receive chemotherapy. A low white blood cell count can
temporarily disrupt your cancer treatment or result in having your
chemotherapy dose decreased.

 Chemotherapy Side Effects

 103

Scientists have made a great deal of progress in developing therapies to

help prevent and manage the side effects of chemotherapy. Newer
supportive care treatments have led to vast improvements in the
management of symptoms associated with cancer treatment. Some
people don't experience side effects at all, and you are unlikely to
experience all the side effects you read about below. Although
chemotherapy is designed to treat cancer cells, unfortunately, it often
affects parts of your body not directly affected by the cancer itself. This
undesired result is referred to as a complication of treatment, or a side
effect.

Side effects may be acute (short-term), chronic (long-term), or

permanent. Side effects may cause inconvenience, discomfort, and even
death.

Additionally, certain side effects may prevent doctors from delivering the
prescribed dose of chemotherapy at the specific time and schedule of
the treatment plan. In certain cancers, the expected outcome from
chemotherapy is based on delivering the full chemotherapy dose on
schedule so it is important to understand chemotherapy cycles and
schedules.

Side effects from chemotherapy can include pain, diarrhea, constipation,

mouth sores, hair loss, nausea and vomiting, as well as blood-related
side effects. In this section, you can learn more about the importance of
diagnosing and monitoring blood-related side effects. These may include
low infection fighting white blood cells count (neutropenia), low red blood
cells count (anemia), and low platelets count (thrombocytopenia).

CBC and Related Side Effects

The CBC, or complete blood count, helps your doctor look for side effects of
chemotherapy, which may include changes in the three types of cells in
your blood. Because chemotherapy kills fast-growing blood cells as well
as cancer cells, side effects involving your blood are an expected result
of chemotherapy. Your first step in understanding blood-related side
effects, is knowing CBC, or your complete blood count.

Side effects involving blood include the following:

1. Neutropenia
Neutropenia (new-troh-PEE-nee-ah) is the scientific name for a low
infection-fighting white blood cell count. A low white blood cell count
may leave your body vulnerable to infection and too weak to receive
chemotherapy according to your doctors' treatment schedule. This
could lead your doctor to delay your current treatment or reduce your
doses until your count reaches sufficient levels. Infection can lead to
hospitalization. To help reduce the risk of treatment delays due to
 104

blood-related side effects, find out more about the risks associated with
low white cell blood count.

2. Anemia
Anemia is the scientific name for a low red blood cell count. Because
red blood cells carry oxygen, a low red blood cell count may mean
there is not enough oxygen circulating in your body. This condition
can be effectively managed with one of several treatments, including
prescription medicines, and/or blood transfusions, if necessary.

3. Thrombocytopenia
Thrombocytopenia (throm-boh-sy-toh-PEE-nee-ah) is the scientific
name for a low platelet count. A low platelet count may cause you to
experience bruising or excessive bleeding. Learn more about the risks
of low platelet count.

All of these side effects may be related to your chemotherapy. All are
diagnosed through your CBC test. You can manage them to help
reduce the possibility that they will compromise your treatment.

 Other Chemotherapy Side Effects.

Chemotherapy may produce other side effects. Side effects occur

because most cancer treatments cannot distinguish between cancer
cells and normal, healthy cells. For example, chemotherapy damages
rapidly dividing cells, a hallmark of cancer cells. In the process, healthy
cells that are also rapidly dividing, such as blood cells and the cells
lining the mouth and GI tract are also damaged.

Side effects of treatment cause inconvenience, discomfort, and

occasionally may even be fatal. Additionally, side effects may also
prevent doctors from delivering the prescribed dose of therapy at the
specific time and schedule decided in the treatment plan. It is important
to understand that the expected outcome from therapy is based on
delivering treatment at the dose and schedule of the treatment plan. In
other words, side effects not only cause discomfort and unpleasantness,
but may also limit a patient’s ability to achieve the best outcome from
treatment by preventing the delivery of therapy at its optimal dose and
time.

In the rest of this section you can learn more about the following side
effects and how to manage them:

 Hair Loss
 Nausea and Vomiting
 Mouth Sores
 Constipation
 105

 Diarrhea
 Pain
 Numbness and Tingling
 Forgetfulness and Inability to Concentrate
 Reproductive and Sexual Side Effects

About low white blood cell counts

Chemotherapy can weaken your natural defenses

Chemotherapy (also known as chemo) works by killing fast-growing

cancer cells. Unfortunately, chemotherapy drugs can’t always tell the
difference between cancer cells and fast-growing healthy cells, including
red and white blood cells. As a result, one of the most serious potential
side effects of many types of chemotherapy drugs is a low white blood
cell count. Chemo that causes this side effect is described as
myelosuppressive, because it suppresses your production of white
blood cells. A low number of a specific type of white blood cells called
neutrophils,—also known as neutropenia can put some patients at risk
for severe infections and may interrupt chemo treatment. In fact,
complications associated with a low white blood cell count are the most
common causes of dose reductions or delays in chemotherapy.

A sufficient white blood cell count may enable your doctors to

administer chemotherapy according to their treatment schedule.

The fewer number of white blood cells you have and the longer you
remain without enough, the more at risk you become for developing a
potentially life-threatening infection.

Therefore, your doctor may need to delay chemo treatment or reduce

your chemotherapy dose until your white blood cell count increases and
the possibility of infection is reduced.

• Choosing the suitable chemotherapeutic drug and

side effects

How chemotherapy kills cancer cells

Chemotherapy damages dividing cells. You can have chemotherapy
either as an injection into the bloodstream or have it as tablets or
capsules. The drugs circulate all round the body in the bloodstream and
damage any cells that are dividing. Body tissues are made of billions of
 106

individual cells. Once we are fully grown, most of the body's cells don't
divide much. They spend most of their time in a resting state and only
divide if they need to repair damage. When cells divide they split into
two, identical new cells.

So, where there was 1 cell, there are now 2 and these then divide to
make 4 and then 8 and so on. And cancer cells divide much more often
than most normal cells. This is how tumours grow and form lumps. Cells
in the process of dividing are more at risk of being damaged by
chemotherapy. Chemotherapy damages part of the control centre inside
each cell that makes cells divide. Or it interrupts the chemical processes
involved in cell division. The damaged cells then die.

There is more detailed information about how normal cells grow and
about how cancer cells differ from normal cells in the about cancer
section of CancerHelp UK.

How chemotherapy kills dividing cells

Chemotherapy damages cells as they divide. In the centre of each living
cell is a dark blob, called the nucleus. The nucleus is the control centre
of the cell. It contains chromosomes, which are made up of genes. These
genes have to be copied exactly each time a cell divides into 2 to make
new cells.
 107

Chemotherapy damages the genes inside the nucleus of cells. Some

drugs damage cells at the point of splitting. Some damage them while
they are busy making copies of all their genes before they split. Cells
that are at rest (most normal cells, for instance) are much less likely to
be damaged by chemo. You may have a combination of different
chemotherapy drugs. The combination will include chemo drugs that
damage cells at different stages in the process of cell division. With
more than one type of drug, there is more chance of killing more cells.

The fact that chemo drugs kill dividing cells helps to explain why
chemotherapy causes side effects. It affects healthy body tissues where
the cells are constantly growing and dividing. The skin, bone marrow,
hair follicles and lining of the digestive system are examples of these.
Your hair is always growing. Your bone marrow is constantly producing
blood cells. The cells of your skin and the lining of your digestive system
are constantly renewing themselves. These tissues have dividing cells
and they can be damaged by chemotherapy.

But, normal cells can replace the healthy cells that are damaged by
chemotherapy. So the damage to healthy cells doesn't usually last. Most
side effects disappear once your treatment is over, and some only
happen during the days while you are actually having the drugs (for
example, sickness or diarrhoea).

How well chemotherapy works

The chance of the chemotherapy curing your cancer depends on the
type of cancer you have

• With some types of cancer, most people are cured by

chemotherapy
• With other types of cancer, fewer people are completely
cured

Examples of cancers where chemotherapy works very well are testicular

cancer and Hodgkin's lymphoma.

With some cancers, chemotherapy can't cure the cancer on its own. But
it can help in combination with other types of treatment. Many people
with breast or bowel cancer, for example, have chemotherapy after
surgery to help lower the risk of the cancer coming back.

With some cancers, if a cure is unlikely, your doctor may still suggest
chemotherapy to
 108

• Shrink the cancer

• Relieve your symptoms
• Give you a longer life by controlling the cancer or putting it
into remission

What remission means

Remission is a word doctors often use when talking about cancer or
leukaemia. It means there is no sign of the cancer. Doctors can be
reluctant to say that a cancer is 'cured' because some cancers can come
back years later. The more time that goes by, the less likely it is that a
cancer will come back. But there is still that small chance. So doctors
use the word 'remission'. You may hear your doctor talk about complete
remission and partial remission.

Complete remission means that the cancer or leukaemia can't be

detected on scans, X-rays, or blood tests etc.

Partial remission means the treatment has killed some of the cells, but
not all. The cancer has shrunk, but can still be seen on scans and
doesn't appear to be growing. The treatment may have stopped the
cancer from growing, or made it smaller so that other treatments are
more likely to help, such as surgery or radiotherapy.

 What Causes Side Effects?

Because cancer cells may grow and divide more rapidly than normal
cells, many anticancer drugs are made to kill growing cells. But certain
normal, healthy cells also multiply quickly, and chemotherapy can affect
these cells, too. This damage to normal cells causes side effects. The
fast-growing, normal cells most likely to be affected are blood cells
forming in the bone marrow and cells in the digestive tract (mouth,
stomach, intestines, esophagus), reproductive system (sexual organs),
and hair follicles. Some anticancer drugs may affect cells of vital organs,
such as the heart, kidney, bladder, lungs, and nervous system.

You may have none of these side effects or just a few. The kinds of side
effects you have and how severe they are, depend on the type and dose
of chemotherapy you get and how your body reacts. Before starting
chemotherapy, your doctor will discuss the side effects that you are
most likely to get with the drugs you will be receiving. Before starting the
treatment, you will be asked to sign a consent form. You should be given
all the facts about treatment including the drugs you will be given and
their side effects before you sign the consent form.
 109

 How Long Do Side Effects Last?

Normal cells usually recover when chemotherapy is over, so most side
effects gradually go away after treatment ends, and the healthy cells
have a chance to grow normally. The time it takes to get over side effects
depends on many things, including your overall health and the kind of
chemotherapy you have been taking.

Most people have no serious long-term problems from chemotherapy.

However, on some occasions, chemotherapy can cause permanent
changes or damage to the heart, lungs, nerves, kidneys, reproductive or
other organs. And certain types of chemotherapy may have delayed
effects, such as a second cancer, that show up many years later. Ask
your doctor about the chances of any serious, long-term effects that can
result from the treatment you are receiving (but remember to balance
your concerns with the immediate threat of your cancer).

The side effects of chemotherapy can be unpleasant, but they must be

measured against the treatment's ability to destroy cancer. Medicines
can help prevent some side effects such as nausea. Sometimes people
receiving chemotherapy become discouraged about the length of time
their treatment is taking or the side effects they are having. If that
happens to you, talk to your doctor or nurse. They may be able to
suggest ways to make side effects easier to deal with or reduce them.

Below you will find suggestions for dealing with some of the more
common side effects of chemotherapy.

• Fatigue
• Nausea & Vomiting
• Pain
• Hair Loss
• Anemia
• Infection
• Blood Clotting Problems
• Mouth, Gum and Throat Problems
• Diarrhea and Constipation
• Nerve and Muscle Effects
• Effects on Skin and Nails
• Radiation Recall
• Kidney and Bladder Effects
• Flu-Like Symptoms
• Fluid Retention
• Effects on Sexual Organs and Sexuality
 110

•Treatment Options
As we have seen before, there are many treatment options, but
unfortunately most of them have severe side effects like those side
effects of chemotherapy and Radiotherapy.

But there are other ways which are designed to reduce those side effects
by tools of high specificity i.e. recognize and attack cancer cells only,
and scientists are trying to achieve this as possible as they can.

From those types of therapies we will discuss (Photodynamic therapy

and biological therapy).

Photodynamic therapy
Photodynamic therapy (PDT), matured as a feasible medical technology
in the 1980s at several institutions throughout the world, is a third-level
treatment for cancer involving three key components: a photosensitizer,
light, and tissue oxygen. It is also being investigated for treatment of
psoriasis, and is an approved treatment for wet macular degeneration.
 111

•History
The German physician Friedrich Meyer–Betz performed the first study
with what was first called photoradiation therapy (PRT) with porphyrins
in humans in 1913. Meyer–Betz tested the effects of haematoporphyrin-
PRT on his own skin.
Thomas Dougherty of Roswell Park Cancer Center, among others
worldwide, became a highly visible advocate and educator. Early
patients were treated at Roswell, Los Angeles Children's Hospital, Los
Angeles County Hospital, and other clinics and Hospitals in the USA and
overseas.
It was John Toth, as product manager for Cooper Medical Devices
Corp/Cooper Lasersonics, who acknowledged the "photodynamic
chemical effect" of the therapy with early clinical argon dye lasers and
wrote the first "white paper" renaming the therapy as "Photodynamic
Therapy" (PDT). This was done to support efforts in setting up 10 clinical
sites in Japan where the term "radiation" had negative connotations.
PDT received even greater interest as result of Thomas Dougherty
helping expand clinical trials and forming the International
Photodynamic Association, in 1986.

•Mechanism of action
A photosensitizer is a chemical compound that can be excited by light of
a specific wavelength. This excitation uses visible or near-infrared light.
In photodynamic therapy, either a photosensitizer or the metabolic
precursor of one is administered to the patient. The tissue to be treated
is exposed to light suitable for exciting the photosensitizer. Usually, the
photosensitizer is excited from a ground singlet state to an excited
singlet state. It then undergoes intersystem crossing to a longer-lived
excited triplet state. One of the few chemical species present in tissue
with a ground triplet state is molecular oxygen. When the
photosensitizer and an oxygen molecule are in proximity, an energy
transfer can take place that allows the photosensitizer to relax to its
ground singlet state, and create an excited singlet state oxygen
molecule. Singlet oxygen is a very aggressive chemical species and will
very rapidly react with any nearby biomolecules. (The specific targets
depend heavily on the photosensitizer chosen.) Ultimately, these
destructive reactions will kill cells through apoptosis or necrosis.
This mechanism is identical to the mechanism of the disease
Erythropoietic protoporphyria, which causes blistering in response to
sun exposure due to a genetic defect in the same metabolic pathway.

• Example: treatment of skin cancer

 112

As an example, consider PDT as a treatment for basal cell carcinoma

(BCC). BCC is the most common form of skin cancer in humans.
Conventional treatment of BCC involves surgical excision, cryogenic
treatment with liquid nitrogen, or localized chemotherapy with 5-
fluorouracil or other agents.
A PDT treatment would involve the following steps.
• A photosensitizer precursor (aminolevulinic acid
( ALA ) or methyl aminolevulinate (MAL)) is applied.
• A waiting period of a few hours is allowed to elapse,
during which time
o ALA will be taken up by cells, and
o ALA will be converted by the cells to
protoporphyrin IX, a photosensitizer (see
Porphyrin).
• The physician shines a bright red light (from an array
of light-emitting diodes or a diode laser) on the area to be
treated. The light exposure lasts a few minutes to a few
tens of minutes.
o Protoporphyrin IX absorbs light, exciting
it to an excited singlet state;
o Intersystem crossing occurs, resulting in
excited triplet protoporphyrin IX;
o Energy is transferred from triplet
protoporphyrin IX to triplet oxygen, resulting
in singlet (ground state) protoporphyrin IX and
excited singlet oxygen;
o Singlet oxygen reacts with biomolecules,
fatally damaging some cells in the treatment
area.
• Within a few days, the exposed skin and carcinoma
will scab over and flake away.
• In a few weeks, the treated area has healed, leaving
healthy skin behind. For extensive malignancies, repeat
treatments may be required. It is also common to
experience pain from the area treated.
• After the treatment the patient will need to avoid
excessive exposure to sunlight for a period of time.
Treatment of internal organs may be achieved through the use of
endoscopes and fiber optic catheters to deliver light, and intravenously-
administered photosensitizers.
A great deal of research and clinical study is now underway to determine
optimal combinations of photosensitizers, light sources, and treatment
parameters for a wide variety of different cancers.

•Advantages and limitations

Unlike chemotheraphy for cancer the effect of PDT can be localised.
Specificity of treatment is achieved in three ways.
 113

• First, light is delivered only to tissues that a physician

wishes to treat. In the absence of light, there is no
activation of the photosensitizer and no cell killing.
• Second, photosensitizers may be administered in
ways that restrict their mobility. In our example, ALA was
only applied to the area to be treated.
• Finally, photosensitizers may be chosen which are
selectively absorbed at a greater rate by targeted cells.
ALA is taken up much more rapidly by metabolically active
cells. Since malignant cells tend to be growing and
dividing much more quickly than healthy cells, the ALA
targets the unhealthy cells.
PDT can be much cheaper than the alternative radiotherapy or surgical
operation and after care. Post operative recovery is typically hours or
days rather than weeks.
A major limitation of PDT is that the light needed to activate most
photosensitizers can not penetrate through more than one third of an
inch (1 cm) of tissue using standard laser technology and low powered
LED technolgy. Laser application of PDT is limited to the treatment of
tumours on or under the skin, or on the lining of some internal organs.
Moreover it is less effective in treatment of large tumours and metastasis
for the same reason. However new high powered LED technology has
been lab tested to provide a depth of 2 inches from surface in a
simulated breast tissue. Also hollow needles have been used by some
units to get the light into deeper tissues.

•Photosensitizers
A wide array of photosensitizers for PDT exist. Some examples include
aminolevulinic acid ( ALA ), Silicon Phthalocyanine Pc 4, m-
tetrahydroxyphenylchlorin (mTHPC), and mono-L-aspartyl chlorin e6
(NPe6). Several photosensitizers are also commercially available, such
as Photofrin, Visudyne, and LS11. Although these photosensitizers can
be used for wildly different treatments, they all aim to achieve certain
characteristics:
• High absorption at long wavelengths
o Tissue is much more transparent at higher
wavelengths (~700-850 nm). Absorbing at longer
wavelengths would allow the light to penetrate
deeper, and allow the treatment of larger tumors.
• High singlet oxygen quantum yield
• Low photobleaching
• Natural fluorescence
o Many optical dosimetry techniques, such
as fluorescence spectroscopy, depend on the
drug being naturally fluorescent
• High chemical stability
• Low dark toxicity
 114

o The photosensitizer should not be

harmful to the target tissue until the treatment
beam is applied.
• Preferential uptake in target tissue

The major difference between different types of photosensitizers is in the

parts of the cell that they target. Unlike in radiation therapy, where
damage is done by targeting cell DNA, most photosensitizers target
other cell structures. For example, mTHPC has been shown to localize in
the nuclear envelope and do its damage there. In contrast, ALA has been
found to localize in the mitochondria and Methylene Blue in the
lysosomes.
Photomedicine is an interdisciplinary branch of medicine that involves
the study and application of light with respect to health and disease.
Photomedicine may be related to the practice of various fields of
medicine including dermatology, surgery, dentistry, optical diagnostics,
cardiology, and oncology.

• Biological Treatment
Biological therapy has many names, including "immunologic therapy,"
"immunotherapy," or "biotherapy."

Biological therapy uses the body's immune system to help kill cancer
cells. Types of biological therapy include the following:

 Interferon
 Interleukin
 Monoclonal antibodies
 Colony-stimulating factors
 Cytokines
 Vaccines

The Immune system and Cancer

Immune system plays a critical role in controlling and eliminating
infectious organisms, including many pathogenic bacteria and viruses.
 115

More controversial has been the debate pertaining to whether the

immune system can effectively control tumor growth and metastases.

However, many studies suggest that appropriate activation of the

immune system can lead to tumor regressions in experimental animal
models. Thus, there is significant interest in harnessing the immune
system for the treatment of tumors.

The main focus of immunotherapy has been on T lymphocytes, since

they have been shown to be the major effector cells in various animal
tumor models. Removal of T cells typically eliminates the antitumor
activity of most therapeutic approaches, while conversely, the adoptive
transfer of tumor-reactive T cells mediates regression of malignant
lesions. Furthermore, in several histologically distinct types of human
tumors, the degree of T-cell infiltrate demonstrated a positive correlation
with patient survival, suggesting a role for these cells in controlling
malignant growth.

Tumors are Immunogenic

Tumor immunology in the past decade has made great gains: We know
now that tumors are immunogenic. We know that T cells can function at
the single cell level, because they are able to leave the endothelium and
migrate into tissues where they can clonally expand until the antigen is
eradicated. The most exciting aspect of stimulating an endogenous
immune response, however, is the potential to initiate long-term
immunologic memory.

This represents a dramatic shift in how cancer is treated. If we can focus

this type of immunologic memory, targeting immunogenic proteins
involved in malignant transformations, we may be able to prevent
relapse(to be infected again). Of course, relapse is one of the major
problems in long-term survival of cancer patients. Some patients can
initially respond to chemotherapy, surgery, or radiation therapy, but
tumors may recur.

 Tumor antigen

Tumor antigen is a substance produced in tumor cells that triggers an

immune response in the host. Tumor antigens are useful in identifying
tumor cells and are potential candidates for use in cancer therapy.

 Mechanism of tumor antigenesis

Normal proteins in the body are not antigenic because of self-tolerance,

a process in which self-reacting cytotoxic T lymphocytes (CTLs) and
autoantibody-producing B lymphocytes are culled "centrally" in primary
lymphatic tissue (bone marrow) and "peripherally" in secondary
lymphatic tissue (mostly thymus for T-cells and spleen/lymph nodes for
 116

B cells). Thus any protein that is not exposed to the immune system
triggers an immune response. This may include normal proteins that are
well sequestered from the immune system, proteins that are normally
produced in extremely small quantities, proteins that are normally
produced only in certain stages of development, or proteins whose
structure is modified due to mutation.

 Classification of Tumor Antigens

Initially they were broadly classified into two categories based on their
pattern of expression: Tumor-Specific Antigens, which are present only on
tumor cells and not on any other cell and Tumor-Associated Antigens,
which are present on some tumor cells and also some normal cells

This classification, however, is imperfect because many antigens

thought to be tumor-specific turned out to be expressed on some normal
cells as well. The modern classification of tumor antigens is based on
their molecular structure and source.

Accordingly they can be classified as:

1. Products of Mutated Oncogenes and Tumor Suppressor Genes

2. Products of Other Mutated Genes
3. Overexpressed or Aberrantly Expressed Cellular Proteins
4. Tumor Antigens Produced by Oncogenic Viruses

5. Oncofetal Antigens
6. Altered Cell Surface Glycolipids and Glycoproteins
7. Cell Type-Specific Differentiation Antigens

Cancer immunology
Cancer immunology is the study of interactions between the immune
system and cancer cells (also called tumors or malignancies). It is also a
growing field of research that aims to discover innovative cancer
immunotherapies to treat and retard progression of this disease. The
immune response, including the recognition of cancer-specific antigens
is of particular interest in this field as knowledge gained drives the
development of new vaccines and antibody therapies. For instance in
2007, Ohtani published a paper finding tumour infiltrating lymphocytes
to be quite significant in human colorectal cancer. The host was given a
better chance at survival if the cancer tissue showed infiltration of
inflammatory cells, in particular lymphocytic reactions. The results
yielded suggest some extent of anti-tumour immunity is present in
colorectal cancers in humans.
 117

Over the past 10 years there has been notable progress and an
accumulation of scientific evidence for the concept of cancer
immunosurveillance and immunoediting based on:

(i) protection against development of spontaneous and

chemically-induced tumors in animal systems and
(ii) Identification of targets for immune recognition of human
cancer.

In 1999, a rat with immunity to cancer was discovered by Dr. Zheng Cui.

• Significant progress has been made in the past

several decades in our Understanding of the host immune
response to tumors. This has included:

(1) Identification of antigens expressed on human tumors as well as

epitopes from these proteins that can serve as targets for the CD4+ and
CD8+ T-cell populations;

(2) Defining and characterizing antigen presenting cells (e.g., dendritic

cells), and the co-stimulatory requirements for effective peptide
presentation;

(3) Identifying the role various cytokines play in regulating cellular and
humoral immune responses; and

(4) Understanding the intracellular signaling pathways that control T and

APC differentiation, effector functional and survival.

Immunosurveillance
Cancer immunosurveillance is a theory formulated in 1957 by Burnet and
Thomas, who proposed that lymphocytes act as sentinels in recognising
and eliminating continuously arising, nascent transformed cells. Cancer
immunosurveillance appears to be an important host protection process
that inhibits carcinogenesis and maintains regular cellular homeostasis.
It has also been suggested that immunosurveillance primarily functions
as a component of a more general process of cancer immunoediting.

Immunoediting
Immunoediting is a process by which a person is protected from cancer
growth and the development of tumour immunogenicity by their immune
system. It has three main phases: elimination, equilibrium and escape.
 118

 Immunity and Cancer

The immune system provides one of the body's main defenses
against cancer. When normal cells turn into cancer cells, some of the
antigens on their surface change. These new or altered antigens flag
immune defenders, including cytotoxic T cells, natural killer cells,
and macrophages.

According to one theory, patrolling cells of the immune system provide

continuing bodywide surveillance, spying out and eliminating cells that
undergo malignant transformation. Tumors develop when the
surveillance system breaks down or is overwhelmed. Some tumors may
elude the immune defenses by hiding or disguising their tumor antigens.
Alternatively, tumors may survive by encouraging the production of
suppressor T cells; these T cells act as the tumor's allies, blocking
cytotoxic T cells that would normally attack it.

Blood tests show that people can develop antibodies to many types of
tumor antigens (although the antibodies may not actually be effective in
fighting the tumor). Skin testing (similar to skin testing for tuberculosis)
has demonstrated that tumors provoke cellular immunity as well.
Furthermore, studies indicated that cancer patients have a better
prognosis when their tumors are infiltrated with many immune cells.
Immune responses may underlie the spontaneous disappearance of
some cancers.

Tests using antibodies derived from batches of human serum can detect
various tumor-associated antigens-including carcinoembryonic antigen
(CEA) and alphafetoprotein (AFP)-in blood samples. Because such
antigens develop not only in cancer but in other diseases as well, the
antibody tests are not useful for cancer screening in the general
population. They are however, valuable in monitoring the course of
disease and the effectiveness of treatment in patients known to have
cancer.
 119

Scientists have developed monoclonal antibodies (Hybridoma Technology)

that are targeted specifically at tumor antigens. Linked to radioactive
substances, these antibodies can be used to track down and reveal
hidden cancer metastases within the body. Monoclonal antitumor
antibodies are also being used experimentally to treat cancer-either in
their native form or as immunotoxins, linked to natural toxins, anticancer
drugs, or radioactive substances.

Other efforts to attack cancer through the immune system center on

stimulating or replenishing the patient's immune responses with
substances known as biological response modifiers. Among these are
interferons (now obtained through genetic engineering) and interleukins.
In some cases biological response modifiers are injected directly into
the patient; in other cases they are used in the laboratory to transform
some of the patient's own lymphocytes into tumor-hungry cells known
as lymphokine-activated killer (LAK) cells and tumor-infiltrating
lymphocytes (TILS), which are then injected back into the patient.
Researchers are even using structures from the tumor cells themselves
to construct custom-made anticancer "vaccines."

• Immunotherapy Cancer Treatment

The concept of immunotherapy is based on the body's natural defense
system, which protects us against a variety of diseases. Although we are
less aware of it, the immune system also works to aid our recovery from
many illnesses.
For many years, physicians believed that the immune system was
effective only in combating infectious diseases caused by such invading
agents as bacteria and viruses. More recently, we have learned that the
immune system may play a central role in protecting the body against
cancer and in combating cancer that has already developed. This latter
role is not well understood, but there is evidence that in many cancer
patients the immune system slows down the growth and spread of
tumors. The body's ability to develop an immune reaction to tumors may
help determine which patients are cured of cancer using conventional
therapies, including surgery, radiation and drugs.
One immediate goal of research in cancer immunology is the
development of methods to harness and enhance the body's natural
tendency to defend itself against malignant tumors. Immunotherapy
represents a new and powerful weapon in the arsenal of anticancer
treatments.
Immunotherapy seems to offer great promise as a new dimension in
cancer treatment, but it is still very much in its infancy. Immunotherapies
involving certain cytokines and antibodies have now become part of
standard cancer treatment. Other examples of immunotherapy remain
 120

experimental. Although many clinical trials of new forms of

immunotherapy are in progress, an enormous amount of research
remains to be done before the findings can be widely applied.
Immunotherapy of cancer began about one hundred years ago when Dr.
William Coley, at the Sloan-Kettering Institute, showed that he could
control the growth of come cancers and cure a few advanced cancers
with injections of a mixed vaccine of streptococcal and staphylococcal
bacteria known as Coley's toxin. The tuberculosis vaccine, Bacillus
Calmette-Guerin (BCG), developed in 1922, is known to stimulate the
immune system and is now used to treat bladder cancers.
Many years of research have finally produced the first successful
examples of immunotherapies for cancer. Sometimes referred to as
biological response modifiers or as biological therapies, these new
treatments-such as interferons and other cytokines, monoclonal
antibodies, and vaccine therapies-have generated renewed interest and
research activity in immunology.

 Immunotherapy for cancer is essentially the stimulation of the

immune system via a variety of reagents such as vaccines, infusion
of T cells, or cytokines. These reagents act through one of several
mechanisms:

1) By stimulating the antitumor response, either by increasing the

number of effector cells or by producing one or more soluble mediators
such as lymphokines;

2) By decreasing suppressor mechanisms;

3) By altering tumor cells to increase their immunogenicity and make

them more susceptible to immunologic defenses; and

4) By improving tolerance to cytotoxic drugs or radiotherapy, such as

stimulating bone marrow function with granulocyte colony-stimulating
factor (G-CSF).

The basic premise of immunotherapy for cancer, then, is to stimulate

the immune system in some way to treat and even prevent cancer.
Historical data show that the immune system clearly plays a role in
cancer progression. For example, immunosuppression is associated
with cancer development. In fact, cancer is 100 times more likely to
occur in people who take immunosuppressive medications (e.g., for
organ transplant or rheumatic disease) than in people with normal
immune function.3
 121

 Components used in Cancer

Immunotherapy

• Interferons and Other Cytokines

Interferons belong to a group of proteins known as cytokines. They are
produced naturally by white blood cells in the body (or in the laboratory)
in response to infection, inflammation, or stimulation. They have been
used as a treatment for certain viral diseases, including hepatitis B.
Interferon-alpha was one of the first cytokines to show an antitumor
effect, and it is able to slow tumor growth directly, as well as help to
activate the immune system. Interferon-alpha has been approved by the
FDA and is now commonly used for the treatment of a number of
cancers, including multiple myeloma, chronic myelogenous leukemia,
hairy cell leukemia, and malignant melanoma. Interferon-beta and
interferon-gamma are other types of interferons that have been
investigated.
Other cytokines with antitumor activity include the interleukins (e.g.,
IL-2) and tumor necrosis factor. IL-2 is frequently used to treat kindey
cancer and melanoma.
Some of the problems with these cytokines, including many of the
interferons and interleukins, are their side effects, which include malaise
and flu-like syndromes. When given at a high dose, the side effets can be
greatly magnified.

•Monoclonal Antibodies

Another important biological therapy involves antibodies against cancer

cells or cancer-associated targets. Monoclonal antibodies are artificial
antibodies against a particular target (the "antigen") and are produced in
the laboratory. The original method involved hybridoma cells (a fusion of
two different types of cells) that acted as factories of antibody
production. A major advance in this field was the ability to convert these
antibodies, which originally were made from mouse hybridomas, to
"humanized" antibodies tha more closely resemble our natural
antibodies. Even newer techniques can be used to generate human
antibodies from genetically engineered mice or bacteria containing
human antibody genes. Monoclonal antibodies have been widely used in
scientific studies of cancer, as well as in cancer diagnosis.
As therapy for cancer, monoclonal antibodies can be injected into
patients to seek out the cancer cells, potentially leading to disruption of
cancer cell activities or to enhancement of the immune response
againast the cancer. This strategy has been of great interest since the
original invention of monoclonal antibodies in the 1970s. After many
 122

years of clinical testing, researchers have proven that improved

monoclonal antibodies can be used effectively to help treat certain
cancers. An antibody called rituximab (Rituxan) can be useful in the
treatment of non-Hodgkin's lymphoma, while trastuzumab (Herceptin) is
useful against certain breast cancers. Other new monoclonal antibodies
are undergoing active testing.

Researchers also are studying ways of linking cytotoxic drugs, toxins, or

radioisotopes to monoclonal antibodies to enhance their effectiveness
against cancer cells. In this case, the antibodies would function as a
targeted delivery mechanism; the result would be like a "guided missile,"
capable of seeking out a specific target-a cancer cell.

•Cancer Vaccines
The term cancer vaccine refers to a vaccine that either prevents
infections with cancer-causing viruses, treats existing cancer or
prevents the development of cancer in certain high risk individuals. (The
ones that treat existing cancer are known as therapeutic cancer
vaccines.)

Some cancers, such as cervical cancer and some liver cancers, are
caused by viruses, and traditional vaccines against those viruses, such
as HPV vaccine and Hepatitis B vaccine, will prevent those cancers.

Scientists have also been trying to develop vaccines against existing

cancers. But there is no such vaccine that can cure a person having
cancer. Some researchers believe that cancer cells routinely arise and
are destroyed by the healthy immune system; cancer forms when the
immune system fails to destroy them. One approach to cancer
vaccination is to separate proteins from cancer cells and immunize
cancer patients against those proteins, in the hope of stimulating an
immune reaction that would kill the cancer cells. Therapeutic cancer
vaccines are being developed for the treatment of breast, lung, colon,
skin, kidney, prostate, and other cancers.

Biological therapy or immunotherapy is now considered a fourth

modality of cancer treatment, and examples such as interferon and
monoclonal antibodies have become part of standard cancer treatment.
Many types of immunotherapy, such as cancer vaccines, remain
experimental. Vaccines have revolutionized public health by preventing
the development of many important infectious diseases, including polio,
small pox, and diphtheria. It has been much more difficult to develop
effective vaccines to prevent cancer, or to treat patients who already
have cancer. Attempts to develop such cancer vaccines, despite many
decades of experimental work, have yet to yield proven results. In spite
of this, a notable increase in interest has been generated by recent
 123

advances in the areas of immunology and cancer biology, which have

led to more sophisticated and promising vaccine strategies than those
previously available. Cancer vaccines typically consist of a source of
cancer-associated material (antigen), along with other components, to
further stimulate the immune response against the antigen. The
challenge has been to find better antigens, as well as to package the
antigen in such a way as to enhance the patient's immune system to
fight cancer cells that have the antigen.
Increasingly, cancer vaccines have been shown to be capable of
improving the immune response against particular antigens. The result
of this immunologic effect is not always sufficient to reverse the
progression of cancer. However, cancer vaccines have been generally
well tolerated, and they may provide useful anticancer effects in some
situations. For example, in malignant lymphoma, a number of laboratory
studies have indicated that vaccination using lymphoma-associated
proteins called idiotype can stimulate the immune systems of mice
sufficiently to help them resist the development of lymphomas.
In clinical trials, idiotype vaccines continue to be tested and have been
associated with indications of clinical benefit in some lymphoma
patients. In malignant melanoma, a wide variety of vaccine strategies
have been introduced into clinical trials, and some have been found to
stimulate the immune response against the cancer.
Cancer vaccines continue to be evaluated in these diseases as well as
most other cancer types. The many new strategies for vaccine
construction and immune stimulation may lead to the emergence of
clinically useful cancer vaccines. An example of one exciting new
approach being tested in melanoma and other cancers is the use of
dendritic cell vaccines. Dendritic cells help to turn on the immune
response.
 124

Internet resources
www.nature.com

www.wikipedia.com

http://www.cancersupportivecare.com/immunotherapy.html

www.chemotherapy.com

http://www.neulasta.com/index.jsp

http://faculty.plattsburgh.edu/donald.slish/Telomerase.html

http://www.sciencedirect.com/

http://www.cancer.org/docroot/CRI/content/CRI_2_6x_the_history_of_ca
ncer_72.asp
 125

Text books
 The Biology of Cancer, Second Edition, Edited by
JANICE GABRIEL

 CANCER BIOLOGY, FOURTH EDITION

Raymond W. Ruddon, M.D., Ph.D.
University of Michigan Medical School
Ann Arbor, Michigan

 Apoptosis, Senescence, and Cancer

Edited by
David A. Gewirtz
Shawn E. Holt
Steven Grant
 Molecular Biology of Cancer
Second edition
F.Macdonald
C.H.J.Ford
A.G.Casson

 CANCER IMMUNOTHERAPY AT THE CROSSROADS

HOW TUMORS EVADE IMMUNITY AND WHAT CAN BE
DONE
Edited by
JAMES H. FINKE, PhD
and
RONALD M. BUKOWSKI, MD
126