‫تحت اشراف‪:‬‬

‫أ‪.‬د‪ /‬عبد هللا الشنواني‬

‫اعداد‪:‬‬
‫أحمد ايهاب محمد عبد الوهاب‬
‫أحمد جمال أحمد غريب‬
‫أحمد حازم محمد الصغير‬
‫أحمد حسن أحمد عبد الرحمن‬
‫أحمد حسين مغاوري السعدني‬
‫أحمد خالد محمد محمود‬
‫أحمد سامي صبحي عبد العال‬
‫أحمد سعيد شربيني محمد‬
 Content
History Of Cancer ................................. 2

Etiology Of Cancer ............................. 11

Cancer Development .......................... 19

Cancer Treatment ............................... 31

References: ......................................... 57

1
 History Of Cancer
o Cancer In The Sixteenth To Eighteenth Centuries

During the Renaissance, beginning in the 15th century, scientists developed greater
understanding of the human body. Scientists like Galileo and Newton began to use the
scientific method, which later was used to study disease. Autopsies, done by Harvey
(1628), led to an understanding of the circulation of blood through the heart and body
that had until then been a mystery.

In 1761, Giovanni Morgagni of Padua was the first to do something which has be-
come routine today – he did autopsies to relate the patient’s illness to pathologic find-
ings after death. This laid the foundation for scientific oncology, the study of cancer.

The famous Scottish surgeon John Hunter (1728-1793) suggested that some can-
cers 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 clas-
sic cancer operations such as the radical mastectomy were developed.

o Cancer In The Nineteenth Century

The 19th century saw the birth of scientific oncology with use of the modern micro-
scope in studying diseased tissues. Rudolf Virchow, often called the founder of cellular
pathology, provided the scientific basis for the modern pathologic study of cancer. As
Morgagni had linked autopsy findings seen with the unaided eye with the clinical
course of illness, so Virchow correlated microscopic pathology to illness.

This method not only allowed a better understanding of the damage cancer had
done, but also aided the development of cancer surgery. Body tissues removed by the
surgeon could now be examined and a precise diagnosis could be made. The

2
pathologist could also tell the surgeon whether the operation had completely removed
the cancer.

o Early Theories About Cancer Causes

From the earliest times, physicians have puzzled over the causes of cancer. Ancient
Egyptians blamed cancers on the gods.

1) Humoral Theory

Hippocrates believed that the body

had 4 humors (body fluids): blood,
phlegm, yellow bile, and black bile.
When the humors were balanced, a
person was healthy. The belief was
that too much or too little of any of the
humors caused disease. An excess of
black bile 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 1,300
years. During this period, the study of
the body, including autopsies, was
prohibited for religious reasons, which
limited progress of medical knowledge.

2) Lymph Theory

Among theories that replaced the humoral theory of cancer was the formation of
cancer by another body fluid, lymph. Life was believed to consist of continuous and
appropriate movement of the fluid parts of the body through the solid parts. Of all the
3
fluids, the most important were blood and lymph. Stahl and Hoffman theorized that
cancer was composed of fermenting and degenerating lymph, varying in density, acidi-
ty, and alkalinity. The lymph theory gained rapid support. John Hunter, the Scottish
surgeon from the 1700s, agreed that tumors grow from lymph constantly thrown out by
the blood.

3) Blastema Theory

In 1838, German pathologist Johannes Muller demonstrated that cancer is made up

of cells and not lymph, but he believed that cancer cells did not come from normal
cells. Muller proposed that cancer cells developed from budding elements (blastema)
between normal tissues. His student, Rudolph Virchow (1821-1902), the famous Ger-
man pathologist, determined that all cells, including cancer cells, are derived from oth-
er cells.

4) Chronic Irritation Theory

Virchow proposed that chronic irritation was the cause of cancer, but he believed in-
correctly that cancers “spread like a liquid.” In the 1860s, German surgeon, Karl
Thiersch, showed that cancers metastasize through the spread of malignant cells and
not through some unidentified fluid.

5) Trauma Theory

Despite advances in the understanding of cancer, from the late 1800s until the
1920s, trauma was thought by some to cause cancer. This belief was maintained de-
spite the failure of injury to cause cancer in experimental animals.

6) Infectious Disease Theory

Zacutus Lusitani (1575-1642) and Nicholas Tulp (1593-1674), 2 doctors in Holland,

concluded at almost the same time that cancer was contagious. They made this con-
clusion based on their experiences with breast cancer in members of the same house-
4
hold. Lusitani and Tulp publicized the contagion theory in 1649 and 1652, respectively.
They proposed that cancer patients should be isolated, preferably outside of cities and
towns, in order to prevent the spread of cancer.

Throughout 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 be-
cause people feared cancer would spread throughout the city. Although human cancer,
itself, is not contagious, we now know that certain viruses, bacteria, and parasites can
increase a person’s risk of developing cancer.

o Development Of Modern Knowledge About Cancer Causes

1) Viral And Chemical Carcinogens

In 1915, Katsusaburo Yamagiwa and Koichi Ichikawa at Tokyo University, induced

cancer in lab animals for the first time by applying coal tar to rabbit skin. More than 150
years had passed since clinician John Hill of London recognized tobacco as a carcino-
gen (a substance known or believed to cause cancer in humans). Many more years
passed before tobacco was “rediscovered” as the most destructive source of chemical
carcinogens known to man.

Today we recognize and avoid many specific substances that cause cancer: coal
tars and their derivatives (like benzene), some hydrocarbons, aniline (a substance
used to make dyes), asbestos, and many others. Ionizing radiation from a variety of
sources, including the sun, is also known to cause cancer. To ensure the public’s safe-
ty, the government has set safety standards for many substances, including benzene,
asbestos, hydrocarbons in the air, arsenicin drinking water, and radiation.

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 sar-
coma virus. He was awarded the Nobel Prize for that work in 1968. Several viruses are
now linked to cancer in humans, for example:

 Long-standing infection with the hepatitis B or C viruses can lead to cancer of the
liver.

5
  One of the herpes viruses, the Epstein-Barr virus, causes infectious mononucle-
osis and has been linked to non-Hodgkin lymphomas and nasopharyngeal can-
cer.
 People with human immunodeficiency virus (HIV) have greater increased risk of
developing several cancers, especially Kaposi sarcoma and non-Hodgkin lym-
phoma.
 Human papilloma viruses (HPVs) have been linked to many cancers, especially
those of the cervix, vulva, vagina, anus, and penis. Some head and neck cancers
(mostly the tongue and tonsils) are linked to the high-risk types of HPV, too. To-
day there are vaccines to help prevent HPV infection.
As of 2014, the World Health Organization’s International Agency for Research on
Cancer (IARC) has identified more than 100 chemical, physical, and biological carcin-
ogens. Many of these associations were recognized long before scientists understood
much about how cancer develops. Today, research is discovering new carcinogens,
explaining how they cause cancer, and providing insight into ways to prevent cancer.

By the middle of the 20th century, scientists had the instruments they needed to
work on some of the complex problems of chemistry and biology that remained un-
solved. 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. Af-
ter 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 vi-
ruses, and that sometimes cancer seemed to run in families. But as the understanding
of DNA and genes increased, they learned that it was the damage to DNA by chemi-
cals and radiation, or the introduction of new DNA sequences by viruses that often led
to the development of cancer. It became possible to pinpoint the exact site of the dam-
age on a specific gene.

Scientists discovered that sometimes defective genes are inherited, and sometimes
these inherited genes are defective at the points where certain chemicals also tend to
cause damage. In other words, most of the things that caused cancer (carcinogens)
6
caused genetic damage (mutations) that looked a lot like the mutations that could be
inherited and could result in the same types of cancer if more mutations were intro-
duced.

No matter which way the first mutation started (inborn or spontaneous), the cells
that grew from the mutated cells led to groups of abnormal cells (called clones, or du-
plicates of the abnormal cell). The mutant clones evolved to even more malignant
clones over time, and the cancer progressed by more and more genetic damage and
mutations. The big difference between normal tissues and cancer is that normal cells
with damaged DNA die, while cancer cells with damaged DNA do not. The discovery of
this critical difference answered many questions that had troubled scientists for many
years.

2) Oncogenes AND TUMOR SUPPRESSOR GENES

During the 1970s, scientists discovered 2 particularly important families of genes re-
lated to cancer: oncogenes and tumor suppressor genes.

Oncogenes: These genes cause cells to grow out of control and become cancer
cells. They are formed by changes or mutations of certain normal genes of the cell
called proto-oncogenes. Proto-oncogenes are the genes that normally control how of-
ten a cell divides and the degree to which it differentiates (or specializes in a specific
function in the body).

Tumor suppressor genes: These are normal genes that slow down cell division, re-
pair DNA errors, 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 com-
pared 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 some-

7
thing goes wrong with the gene, for example if a mutation causes it to stop working,
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 those that, when inherited, can
lead to cancer. For example, the 1990s discovery of 2 genes that cause some breast
cancers, BRCA1 and BRCA2, is a step forward because these genes can be used to
identify people who have a higher risk of developing breast cancer.

Other genes have been discovered that are linked to cancers that run in families,
such as cancers of the colon, rectum, kidney, ovary, thyroid, pancreas, and skin mela-
noma. Familial cancer is not nearly as common as spontaneous cancer (cancer that is
caused by DNA damage that starts during a person’s lifetime). Cancer linked to heredi-
ty is less than 15% of all cancers. Still, it’s important to understand these cancers be-
cause with continued research in genetics we may be able to identify more people at
very high risk.

Once researchers recognized the importance of specific genetic changes in cancer,

they soon began working to develop targeted therapies (drugs or substances that inter-
fere with specific molecules) to overcome the effects of these changes in tumor sup-
pressor genes and oncogenes.

o History Of Cancer Screening And Early Detection

Screening refers to tests and exams used to find a disease, such as cancer, in peo-
ple who do not have any symptoms. The first screening test to be widely used for can-
cer was the Pap test. The test was developed by George Papanicolaou as a research
method in understanding the menstrual cycle. Papanicolaou soon recognized its poten-
tial for finding cervical cancer early and presented his findings in 1923. At first, most
doctors were skeptical, and it was not until the American Cancer Society (ACS) pro-
moted the test during the early 1960s that this test became 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.

8
 Current American Cancer Society guidelines include methods for early detection of
cancers of the cervix, breast, colon and rectum, endometrium, lung, and prostate, as
well as a cancer-related check-up which, depending on a person’s age and gender,
might include exams for cancers of the thyroid, mouth, skin, lymph nodes, testes,
and ovaries.

o Cancer In The Twenty-First Century

The growth in our knowledge of cancer biology has led to remarkable progress in
cancer prevention, early detection, and treatment. Scientists have learned more about
cancer in the last 2 decades than had been learned in all the centuries preceding. This
doesn’t 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
we know that there’s still a lot more to learn.

Cancer research is advancing on so many fronts that it’s hard to choose the ones to
highlight, but here are a few examples:

More targeted therapies: As more is learned about the molecular biology of cancer,
researchers will have more targets for their new drugs. Along with more monoclonal
antibodies and small signaling pathway inhibitors, researchers are developing new
9
classes of molecules such as antisense oligodeoxynucleotides and small interfering
RNA (siRNA). Research is being done to develop targeted drugs that are aimed at pro-
teins produced by specific gene mutations in cancer cells, too.

Immunotherapy: Drugs aimed at specific immune checkpoints are being developed

to help the immune system better kill cancer cells.

More on cancer genetics: Researchers are looking for gene mutations that cause
some patients to respond better to certain drugs.

Nanotechnology: New technology for producing materials that form extremely tiny
particles is leading to very promising imaging tests that can more accurately show the
location of tumors. It also is aiding the development of new ways to deliver drugs more
specifically and effectively to cancer cells.

Robotic surgery: This term refers to manipulation of surgical instruments remotely

by robot 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 uses in surgical oncology. As mechanical and computer technology improve,
some researchers expect future systems will be able to remove tumors more complete-
ly and with less surgical trauma.

Expression profiling and proteomics: Expression profiling lets scientists determine

relative output of hundreds or even thousands of molecules (including the proteins
made by RNA, DNA, or even a cell or tissue) at one time. Knowing what proteins are
present in cells can tell scientists a lot about how the cell is behaving. In 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 good at finding

early cancers. But researchers are hopeful that comparing the relative ing large

amounts of certain proteins and less of others can provide accurate, useful information

about cancer treatment and its outcomes. Proteins (and other types of molecules) are
10
even found in exhaled breath, which is now being tested to find out if it can show early

signs of lung cancer. This is an exciting area of research and early results inlung and

colorectal cancer studies have been promising.

Etiology Of Cancer
 A term for diseases in which abnormal cells divide without control and can invade

nearby tissues.

 Cancer cells can also spread to other parts of the body through the blood and

lymph systems.

 Cancer arises from the transformation of normal cells into tumour cells in a multi-

stage process that generally progresses from a pre-cancerous lesion to a malig-

nant tumour.

o Cases Of Cancer:

1) Physical carcinogens

2) chemical carcinogens

3) biological carcinogens

4) genetic changes

5) Lifestyle

11
 6) Hormones

o Genetic:

-Although there are over 50 identifiable hereditary forms of cancer, less than 0.3%

of the population are carriers of a cancer-related genetic mutation and these make up

less than 3–10% of all cancer cases. The vast majority of cancers are non-hereditary

("sporadic cancers"). Hereditary cancers are primarily caused by an inherited genetic

defect.family cancer syndrome is a genetic disorder in which inherited genetic muta-

tions in one or more genes predisposes the affected individuals

To the development of cancers and may

also cause the early onset

of these cancers.

Many of these syndromes

are caused by mutations in

tumor suppressor genes that

regulate cell growth. Other

common mutations alter the

function of DNA repair genes,

oncogenes and genes in-

volved in the production of

12
blood vessels. Certain inherited mutations in the genes BRCA1 and BRCA2 with a

more than 75% risk of breast cancer and ovarian cancer. Some of the inherited genetic

disorders that can cause colorectal cancer include familial adenomatous polyposis and

hereditary non-polyposis colon cancer.

o Chemicals:

Exposure to particular substances have been linked to specific types of cancer.

These substances are called carcinogens Tobacco smoke, for example, causes

90% of lung cancer. It also causes cancer in the larynx, head, neck, stomach, blad-

der, kidney, esophagus and pancreas. Tobacco smoke contains over fifty known car-

cinogens, including nitrosamines and polycyclic aromatic hydrocarbons.

Tobacco is responsible for about one in five cancer deaths worldwide and about one

in three in the developed world.

Lung cancer death rates in the United States have mirrored smoking patterns, with

increases in smoking followed by dramatic increases in lung cancer death rates and,

more recently, decreases in

smoking rates since the 1950s followed

by decreases in lung cancer death rates in men since 1990.

13
 In Western Europe, 10% of cancers in males and 3% of cancers in females are at-

tributed to alcohol exposure, especially liver and digestive tract cancers. Cancer from

work-related substance exposures may cause between 2 and 20% of cases, causing

at least 200,000 deaths. Cancers such as lung cancer and mesothelioma can come

from inhaling tobacco smoke or asbestos fibers, or leukemia from exposure to ben-

zene.

o Physical Agents:

Usually, physical carcinogens must

get inside the body (such as through in-

halation) and require years of exposure

to produce cance.

Some substances cause cancer pri-

marily through their physical, rather than chemical, effects. A prominent example of this

is prolonged exposure to asbestos, naturally occurring mineral fibers that are a major

cause of mesothelioma (cancer of the serous membrane) usually the serous mem-

brane surrounding the lungs

-Generally, it is believed that cancer arises, or

14
 a pre-existing cancer is encouraged, during the process of healing, rather than di-

rectly by the trauma. However, repeated injuries to the same tissues might promote

excessive cell proliferation, which could then increase the odds of a cancerous

o Radiation:

Up to 10% of invasive cancers are

related to radiation exposure, includ-

ing both non-ionizing radiation and

ionizing radiation.

1- delete parts of the DNA se-

quence

2- tumor suppressor genes were

damaged by the radiation

-Even if the radiation particle does

not strike the DNA directly, it triggers

responses from cells that indirectly increase the likelihood of mutations

o Lifestyle:

Many different lifestyle factors contribute to increasing cancer risk.

15
  Alcohol

Alcohol is an example of a chemical carcinogen. The World Health Organization has

classified alcohol as a Group 1 carcinogen. In Western Europe 10% of cancers in

males and 3% of cancers in females are attributed to alcohol. Worldwide, 3.6% of all

cancer cases and 3.5% of cancer deaths are attributable to alcohol.[36] In particular,

alcohol use has been shown to increase the risk of developing cancers of the mouth,

esophagus, pharynx, larynx, stomach, liver, ovaries, and colon. The main mechanism

of cancer development involves increased exposure to acetaldehyde, a carcinogen

and breakdown product of ethanol. Other mechanisms have been proposed, including

alcohol-related nutritional deficiencies, changes in DNA methylation, and induction of

oxidative stress in tissues.

Chronic damage due to alcohol consumption can lead to liver cirrhosis

Chronic damage due to alcohol consumption can lead to liver cirrhosis

 Obesity:
16
 In the United States, excess body weight is associated with the development of

many types of cancer and is a factor in 14–20% of all cancer deaths. Every year, near-

ly 85,000 new cancer diagnoses in the United States are related to obesity.

There is an associated between obesity and colon cancer, post-menopausal breast

cancer, endometrial cancer, kidney cancer, and esophageal cancer. Obesity has also

been linked with the development of liver cancer.

The current understanding regarding the mechanism of cancer development in obe-

sity relates to abnormal levels of metabolic proteins (including insulin-like growth fac-

tors) and sex hormones (estrogens, androgens and progestogens). Adipose tissue al-

so creates an

inflammatory environment which may contribute to the development of cancers

 Hormones:

Some hormones play a role in the development of cancer by promoting cell prolifer-

ation. Insulin-like growth factors and their binding proteins play a key role in cancer cell

growth.

Hormones are important agents in sex-related cancers such as cancer of the breast,

endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer.

Women who take hormone replacement therapy have a higher risk of developing

cancers associated with those hormones

17
  Breast Cancer

Infection and Inflamation: Worldwide, approximately 18% of cancer cases are relat-

ed to infectious diseases. This proportion varies in different regions of the world from a

high of 25% in Africa to less than 10% in the developed world. Viruses are the usual

infectious agents that cause cancer but bacteria and parasites also contribute. Infec-

tious organisms that increase the risk of cancer are frequently a source of DNA dam-

age or genomic instability.

Viral infection is a major

risk factor for cervical

and liver cancer. A virus

that can cause cancer is

called an oncovirus. These

include human papilloma-

virus (cervical carcinoma)

Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas),

hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and Human T-cell leu-

kemia virus-1 (T-cell leukemias).

Certain bacterial infections also increase the risk of cancer, as seen in Helicobacter

pylori-induced gastric carcinoma.

18
 The mechanism by which H. pylori causes cancer may involve chronic inflammation

or the direct action of some of the bacteria's virulence factors.Certain parasitic infec-

tions can also increase the presence of carcinogenic compounds in the body, leading

to the development of cancers Kaposi's sarcoma on the skin of an AIDS patient

 Inflammation:

There is evidence that inflammation itself plays an important role in the development

and progression of cancer. Chronic inflammation can lead to DNA damage over time

and the accumulation of random genetic alterations in cancer cells.Inflammation can

contribute to proliferation, survival, angiogensis and migration of cancer cells by influ-

encing tumor microenvironment.

Individuals with inflammatory bowel disease are at increased risk of developing col-

orectal cancers.

Cancer Development
o Introduction:

Simply put, cancer is the result of unregulated cell division. Cancer cells divide

when they are not supposed to, don't stop dividing when they are supposed to and

don't die when they should. In the worst cases, the cancer cells leave the area in which

they arose and travel to other parts of the body.

19
 Cancer cells do not look or act like the normal cells from which they originate. It is

reasonable, then, to ask 'Why do cancer cells behave so badly?'. It turns out the the

answers lie in the genes of the affected cells. In cancer cells, changes to key genes

cause the cells to act abnormally. The changes are often the result of changes to the

DNA (mutations) in the cells. Because there are many different things that are capable

of causing mutation, there are an equally large number of causes of cancer.

The development of cancer takes place in a multi-step process. As the cells become

more abnormal, they gain new capabilities, such as the ability to release growth factors

and digestive enzymes. The cells continue to divide, impacting nearby normal cells, of-

ten reducing the function of the affected organ. Even abnormal cancer cells die some-

time and a tumor that is large enough to feel can take years to reach that size. Alt-

hough not all cancers share exactly the same steps, there are some general features

that are shared in the development of many types of cancer. Further information on the

topics on this page can also be found in most introductory Biology textbooks, we rec-

ommend Campbell Biology, 11th edition.

o Below is a list of topics covered in this section:

• Cancer Initiation, Promotion and Progression

• Stages of Tumor Development

• Cancer Stem Cells

- The Search for Cancer Stem Cells

20
 - Cancer Stem Cells and Treatment

• Section Summary

o Cancer Initiation,

Promotion, and

Progression:

In the eighteenth century, London

physician Percival Pott made the first

link between cancer and environ-

mental agents when he noted a high

incidence of scrotal cancer among

chimney sweeps. He hypothesized

that it was caused by exposure to

coals and tars. Out of this observa-

tion grew the two-stage model of

cancer development by 1) initiators

and 2) promoters. In the years since

Pott's observations a wide range of

chemicals, radiation sources, viruses

and bacteria have been implicated in

the development of cancer.

21
 The initial experimental studies of carcinogenesis were conducted in animals.

Chemicals able to react with DNA and non-reactive compounds were both tested for

their ability to cause cancer. The model used was mouse skin carcinogenesis. In this

system researchers painted test chemicals on the skin and observed the growth of tu-

mors. Researchers found that application of a DNA reactive substance only resulted in

tumor formation when the animals were further treated with another non-reactive sub-

stance. A compound that reacts with DNA and somehow changes the genetic makeup

of the cell is called a mutagen. The mutagens that predispose cells to develop tumors

are called initiators and the non-reactive compounds that stimulate tumor development

are called promoters. Approximately 70% of known mutagens are also carcinogens--

cancer-causing compounds. A compound that acts as both an initiator and a promoter

is referred to as a 'complete carcinogen' because tumor development can occur with-

out the application of another compound.

Initiation

Initiation is the first step in the two-stage model of cancer development. Initiators, if

not already reactive with DNA, are altered (frequently they are made electrophilic) via

drug-metabolizing enzymes in the body and are then able to cause changes in DNA

(mutations). Since many initiators must be metabolized before becoming active, initia-

tors are often specific to particular tissue types or species. The effects of initiators are

irreversible; once a particular cell has been affected by an initiator it is susceptible to

promotion until its death. Since initiation is the result of permanent genetic change, any
22
daughter cells produced from the division of the mutated cell will also carry the muta-

tion. In studies of mouse skin carcinogenesis, a linear relationship has been observed

between the dose of initiator and the quantity of tumors that can be produced, thus any

exposure to the initiator increases risk and this risk increases indefinitely with higher

levels of exposure.

Promotion

Once a cell has been mutated by an initiator, it is susceptible to the effects of pro-

moters. These compounds promote the proliferation of the cell, giving rise to a large

number of daughter cells containing the mutation created by the initiator. Promoters

have no effect when the organism in question has not been previously treated with an

initiator.

Unlike initiators, promoters do not covalently bind to DNA or macromolecules within

the cell. Many bind to receptors on the cell surface in order to affect intracellular path-

ways that lead to increased cell proliferation. There are two general categories of pro-

moters: specific promoters that interact with receptors on or in target cells of defined

tissues and nonspecific promoters that alter gene expression without the presence of a

known receptor. Promoters are often specific for a particular tissue or species due to

their interaction with receptors that are present in different amounts in different tissue

types.
23
 While the risk of tumor growth with promoter application is dose-dependent, there is

both a threshold and a maximum effect of promoters. Very low doses of promoters will

not lead to tumor development and extremely high doses will not produce more risk

than moderate levels of exposure.

Progression

In mice, repeated promoter applications on initiator-exposed skin produces benign

papillomas. Most of these papillomas regress after treatment is stopped, but some

progress to cancer. The frequency of progression suggests that the papillomas that

progress to cancer have acquired an additional, spontaneous, mutation. The term

progression, coined by Leslie Foulds, refers to the stepwise transformation of a benign

tumor to a neoplasm and to malignancy. Progression is associated with a karyotypic

change since virtually all tumors that advance are aneuploid (have the wrong number

of chromosomes). This karyotypic change is coupled with an increased growth rate, in-

vasiveness, metastasis and an alteration in biochemistry and morphology.

o Stages Of Tumor Development:

The growth of a tumor from a single genetically altered cell is a stepwise progres-

sion. The process described below is applicable for a solid tumor such as a carcinoma

or a sarcomaA malignant cancer that originates in bone, muscle or connective tissues..

Blood cell tumors go through a similar process but since the cells float freely, they are

not limited to one location in the body.

24
 Hyperplasia- The altered cell divides in an uncontrolled manner leading to an ex-

cess of cells in that region of the tissue. The cells have a normal appearance but there

are too many of them!

Dysplasia- Addi-

tional genetic changes

in the hyperplastic

cells lead to increas-

ingly abnormal growth.

The cells and the the

tissue no longer look

normal. The cells and

the tissue may become

disorganized.

Carcinoma in situ-

Additional changes

make the cells and tis-

sues appear even

more abnormal. The

cells are now spread

over a larger area and

25
the region of the tissue involved primarily contains altered cells. The cells often 're-

gress' or become more primitive in their capabilities. An example would be a liver cell

that no longer makes liver-specific proteins. Cells of this type are said to be de-

differentiated or anaplastic. A key facet of in situ growths is that the cells are contained

within the initial location and have not yet crossed the basal lamina to invade other tis-

sues. Cancers of this type are often totally curable by surgery since the abnormal cells

are all in one location.

Tumors of this type have not yet invaded neighboring tissue. Based on information

about patients with similar growths and microscopic examination, these growths are of-

ten considered to have the potential to become invasive and are treated as malignant

growths.

Cancer (Malignant tumors)- These tumors have the ability to invade surrounding

tissues and/or spread (metastasize) to areas outside the local tissue. These metastatic

tumors are the most dangerous and account for a large percentage of cancer deaths.

The next few sections will go into some detail on the changes and capabilities that al-

low cancer cells to form large tumors and to metastasize to other parts of the body.

Some tumors do not progress to the point where they invade distant tissues. Such

tumors are said to be benign. Because they do not spread beyond their initial location,

they are not considered to be cancerous. Benign tumors are less often lethal than ma-

lignant tumors, but they can still cause serious health problems. Large benign tumors

26
can put pressure on organs and cause other problems. In the case of brain tumors, the

limited space within the skull means that a large growth in the brain cavity can be fatal.

o Cancer Stem Cells

What is a stem cell?

A stem cell is a special cell type that has both the ability to reproduce exact copies

of itself (also called self-renewal) and the ability to change (differentiate) into one of the

many specialized cell types in the body. Examples of specialized cells that arise from

stem cells include nerves, muscles and the cells lining our digestive system.

In most parts of the body, stem cells are not very active. In some locations, includ-

ing the gastrointestinal tract, stem cells divide and differentiate constantly to replace

cells that are shed or die. Stem cells also play a role in healing damaged tissue.

Below is a video of the process by which stem cells can accomplish both self-

renewal and differentiation. The process is called "asymmetric cell division," and it as-

sures that stem cells are always available when needed.

What is a cancer stem cell?

Cancer stem cells (CSCs) are thought to arise from normal stem cells. Sometimes,

genetic changes or mutations damage normal stem cells, preventing them functioning

properly. If this improper function includes uncontrolled reproduction, then the normal

stem cell has the ability to form a tumor; it is now a cancer stem cell .
27
 The existence of CSCs was predicted decades ago, but recent research has identi-

fied cancer stem cells in multiple cancer types, prompting extensive research in this

field

Where do cancer stem cells come from?

In theory, CSCs could be formed in more than one way. Mutations could occur in a

differentiated cell (i.e. a skin cell) causing the cell to go backwards or 'devolve' into a

cell with some stem cell abilities. Cancer stem cells could also be formed by the muta-

tion of a normal stem cell that causes it to become cancerous. Cancer stem cells have

been created in research laboratories from skin cells10 The researchers used a virus

to activate specific pathways and give the target cell stem cell-like qualities. The re-

search proves that a normal cell can become a stem cell with the right set of mutations.

The probability of any particular cell developing a set of mutations that leads to can-

cer is relatively low. The cells types that are affected by the majority of cancers, epithe-

lial cells, have short lives and are even less likely to accumulate all the mutations they

need. Normal stem cells, which are long-lived, are more likely to be around long

enough to accumulate the necessary mutations and are a good possible source of

cancer stem cells

What is the difference between the cancer stem cell hypothesis of the origin

of cancer and traditional views on the origin of cancer?

28
 The cancer stem cell hypothesis suggests that only a small portion of cells are ca-

pable of becoming cancerous. In other words, only a small population of cells in a tu-

mor is responsible for the continuous, uncontrolled growth seen in cancer.

The traditional views on the origin of cancer predict that any cell is able to acquire

mutations that lead to uncontrolled reproduction. Likewise, all of the cells in a tumor

would be predicted to be able to divide endlessly.

o Cancer Development Summary

 Introduction

 All of our cells have similar structures and share a majority of their functions.

 Cancers may be categorized into five basic types based on the cell of origin:

- Carcinoma - epithelial cells

- Sarcoma - muscle, bone, cartilage, fat, or connective tissue

- Leukemia - blood cells or their precursors

- Lymphoma - bone marrow derived cells; cancer affects the lymphatic system

- Myeloma - specific blood cells; B lymphocytes (B-cells)

 Stages Of Tumor Progression

 Tumors typically progress is a stepwise fashion:

- Hyperplasia - cells divide too much but appear normal

- Dysplasia - the tumor cells and tissue appear abnormal

29
- Carcinoma in situ - tumor contains primarily altered cells and is growing larger; it

has not left the site of origin

- Malignant Cancer - tumor has begun to invade nearby or distant tissues

 Benign tumors remain in their initial location and do not invade other tissues.

 Initiators And Promoters

- Initiation is the first step in the two-stage model of cancer development.

- Initiators cause irreversible changes (mutations) to DNA that increase cancer

risk.

- Promotion is the second step in the two-stage model of cancer development.

- Once a cell has been mutated by an initiator, it is susceptible to the effects of

promoters.

- Promoters increase the proliferation of cells and there are two main types:

 Specific - interact with receptors on or in particular target cells.

 Nonspecific - alter gene expression without the presence of a known receptor

 Carcinogens

- Substances which can cause cancer are known as carcinogens.

- The process of cancer development is called carcinogenesis.

- Certain carcinogenic chemicals are associated with an increased risk of specific

cancers due to chronic exposure.

- One of the most potent carcinogens in humans is benzo[a]pyrene, a compound

found in cigarette smoke.

30
  Viruses And Bacteria

- Certain viruses and bacteria have also been associated with the initiation and

promotion of tumor growth.

- Some viruses cause cancer directly by affecting cell division while other viruses

cause cancer by causing chronic inflammation or reducing immune system func-

tion.

 Chronic Inflammation

- Chronic inflammation is an important factor in tumor development.

- Inflammation can lead to altered behavior of cells, stimulation of blood vessel

growth (angiogenesis) and tissue remodeling.

- Markers of inflammation correlate with a worse prognosis for cancer patients.

Cancer Treatment

Anti-Cancer Strategies

31
 Gleeve Ire Erbitux (ab) Avastin
c ssa (ab)

sa

Some current and prospective modalities of cancer chemotherapy

Category Function Examples

Antimetabolites Interfere with intermediary metabolism of Methotrexate, 5-fluorouracil
proliferating cells
Monoclonal anti- Target cancer cells that express specific Herceptin (Genentech),
bodies antigen Zevalin (IDEC Pharmaceu-
ticals/Schering-Plough)
Mitosis inhibitors Target microtubules and associated proteins Taxol
required in cell division
Steroid hormones Block steroid- and hormone-dependent Tamoxifen, flutamide
growth of certain tumours
Alkylating/cross- Damage DNA and result in death of grow- Endoxan, cisplatin, cyclophos-
linking agents ing cells phamide
Signal-transduction Modulate communication between cells Gleevec (Novartis), Tarceva
agents (OSI), Iressa (AstraZeneca),
LY900003 (ISIS 3521) (Eli Lilly)
Angiogenesis inhib- Block blood-vessel formation to tumour Avastin (Genentech)
itors
Histone- Affect transcription of genes SAHA (Aton Pharma)
deacetylase inhibi-
tors
Telomerase inhibi- Affect telomere maintenance required for BIBR1532 (Boehringer Ingel-
tors tumour growth heim)
Antitumour antibiot- Bind DNA to prevent DNA and/or RNA Etoposide, doxorubicin
ics synthesis

32
Phases of the Cell Cycle

G1 phase (gap 1): Cell grows in size and prepares to copy its DNA in response to various growth factors

Sphase(synthesis):Replicationof DNA, copying of the chromosome

G2 phase (gap 2): Preparation for cell division. Check copied DNA and repair damaged copies.

Mphase(mitosis):Formationofthe mitotic spindle, and separation into two individual cells (cell division).

Control of Cell Cycle Progression by CDKs

Progression through the cell cycle is controlled by cyclin-dependent kinases (CDKs).

33
 Binding of cyclin with its associated kinase triggers to move the cell cycle to another

phase

inhibitory proteins are present that can modify the effect of cyclins. These include

p15 and p16, that block activity of the cyclin D-CDK complex. Another regulator is

p21, that is controlled by the tumor suppressor proteinp53.

over-active cyclins or CDKs have been associated with many tumors. Excessive

production of cyclins or CDKs or insufficient production of CDK inhibitors leads to dis-

ruption of the normal regulation of the cell cycle.

34
DrugsdirectlyinteractingwithDNA Intercalating agents

Mechanism of action

 Contain planar aromatic or heteroaromatic ring systems

 Planar systems slip between the layers of nucleic acid pairs and disrupt the shape of thehelix
 Preference is often shown for the minor or major groove
 Intercalation prevents replication and transcription
 Intercalation inhibits topoisomerase II (an enzyme that relieves the strain in the DNA helix by temporarily cleaving the DNA chain
and crossing an intact strand through the broken strand.

Intercalating agents

35
Dactinomycin

(Extra binding to sugar phosphate backbone by cyclic peptide)

Doxorubicin (Adriamycin)

(Extra binding to sugar phosphate backbone by NH3)

36
Intercalating reagents (II)

During replication, supercoiled DNA is unwound by the helicase. The thereby created tension is removed by the

topoisomeraseII,thatcutsandrejoins the DNA strands.

When doxorubicin is bound to the DNA it stabilizes the DNA-topoII complex at the point where the enzyme is

covalently bound

37
NaturalProductsinCancerTherapy: Bleomycins

 intercalate via the bithiazole moiety

 the N-atoms of the primary amines, pyrimidine ring and imidazole ring chelate Fe, which is involved in the formation of superoxide
radicals, which subsequently act to cut DNA between purine and pyrimidine nucleotides

38
Drugs directly interacting with DNA

Alkylating agents

 Contain highly electrophilicgroups

 Form covalent bonds to nucleophilic groups in DNA
 Attack N-1 and N-3 of adenine and N-3 of cytosine, and in particular N-7 of guanine bases
 Prevent replication andtranscription
 Useful as anti-tumouragents
 Toxic side effects (e.g. alkylation of proteins)

Intrastrand cross linking Interstrand cross linking

39
Mechanism of action ofChlormethine

•Chlormethine Aziridine ion

• Crosslinked DNA

40
 too reactive to survive oral route, putting an aromatic moiety instead of the Me group lowers reactivity (and moreover, mimics the
amino acid Phe)

41
Alkylating Drugs: Mitomycin C

Converted to alkylating agent in the body

Mitomycin C

Reduction

Alkylating
agent

42
Crosslinked
DNA
Nitrosoureas

 Lomustine and carmustine are lipid-soluble and can cross the blood-brain barrier
 The drugs decompose to form alkylating and carbamoylating

 the formed isocyanate reacts with lysine NH3 groups thereby inactivating DNA repair enzymes
 the alkylating agent reacts first with O-6 of guanine followed with N-3 of cytosine ofthe
other strand

43
Pt-Alkylating agents

 Binds to DNA in regions rich in guanine units

 Intrastrand links rather than interstrand
 Inhibits transcription
 In solution the Cl- ligands are exchanged against water to result in positively charged ligands that bind to the DNA (to N-7 or O-6 of
adjacent guanine groups)
 Results in localized unwinding of the DNA

44
Antimetabolites

 inhibit the synthesis of DNA or nucleotide building blocks

 Dihydrofolate reductase inhibitors

45
 source of one-C unit for methylations of deox-
yuridinemonophosphate (dUMP) to form deoxythymi-
dinemonophosphate (dTMP)

46
Antimetabolites

 Thymidylate synthase inhibitors

 5-Fluorouracil acts as an suicide inhibitor

47
Antimetabolites

 Inhibitors of ribonucleotide reductase

 enzyme converts ribonucleotide diphosphates into desoxyribonucleotide diphosphates, inhibitedby Hydroxycarbamide

 adenosine deaminase inhibitors, e.g. Pentostatin

48
 Pentostatin

49
Antimetabolites:

Purine antagonists DNA polymerase inhibitors

Hormone-based Anti-CancerTherapies

 steroid hormones bind to nuclear receptors and act as transcription factors

 if the cancer requires a specific hormone, a hormone resulting in the opposite effect can be administered
 Used: glucocorticoides (hormones involved in the biosynthesis of glucose, e.g. prednisolone), oestrogens, progestins (e.g.
50
medroxyprogesterone acetate), analogues of the luteinizing hormone-releasing hormones (LHRH)

51
Drugs acting on structural proteins

• mitosis is a ordered series of events in which identical copies of the genome are moved to discrete locations within the dividing
cell
• The mitotic spindle isvery important forthat event. The filaments in the mitotic spindle are formed from microtubule
• microtubule are cytoskeletal elements present in all eukaryotic cells.

• they are composed of α- and β-subunits

• both, formation (polymerization) and destruction (depolymerization) of microtubules are important for proper execution of cell di-
vision
• drugsinterferingwithmicrotubulepolymerization/depolymerizationinterferewith mitosis , cause cell-cycle arrest and trigger apop-
tosis

52
Drugs acting on structural proteins

Inhibitors of tubulin polymerization

• vinca alkaloids from the Madagascar periwinkle plant

• can be substrate for the P-glycoprotein efflux pump

53
Drugs acting on structural proteins

Inhibitors of tubulin depolymerization

Epothilone
Taxol

• Taxol is harvested from the bark of the yew trees

• binds to the β-subunit of tubulin and accelerates polymerization
• the resultant microtubules are stabilized, inhibiting depolymerization
• cell cycle is halted at the G2/M stage
• prepared semi-synthetically from a compound from yee needles
• cannot be taken orally
• causes multidrug resistance (substrate for p-glycoprotein)
• ephothilones are bacterial metabolites. They are not substrate for P-GP

54
Farnesyltransferase inhibitors

• The RAS signaling protein is involved in cancer. Mutations in RAS are found in 30% of cancer cells. Mutant RAS is constitutively ac-
tive.
• RASsignalingrequireslinkingRAStotheinnermembraneleaflet.Thisis done by adding a carbon chain by the farnesyl transferase.

55
Design of Farnesyltransferase inhibitors

• substratehasCys-aa-Xarchitecture (a=V,L,I; X=M,E,S)

• masking of C-terminal free acid

• removal of susceptibility to peptide
• bond cleavageby proteases •both carboxyl acid and thiol
• masked as prodrugs

56
 .

References:
• National Institutes of Health
• International Agency for Research on Cancer
• "Cancer Fact sheet N°297". World Health Organization
• "National Institute for Occupational Safety and Health- Occu-
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• Stewart B (2014). World Cancer Report 2014. World Health
Organization
• American Society of Clinical Oncology. Clinical Cancer Advanc-
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www.cancer.net/patient/ASCO%20Resources/Research%20an
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• American Society of Clinical Oncology. Clinical Cancer Advanc-

es 2010: ASCO’s Annual Report on Progress Against Cancer.
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www.cancer.net/patient/Publications%20and%20Resources/Cli
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• American Society of Clinical Oncology. Clinical Cancer Advanc-

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Accessed at
www.cancer.net/patient/Publications%20and%20Resources/Cli
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