Cancer

Uglyar T.Y.

What is cancer?
Caner is defined as the continuous uncontrolled
growth of cells.
A tumor is a any abnormal proliferation of cells.
Benign tumors stays confined to its original
location
Malignant tumors are capable of invading
surrounding tissue or invading the entire body
Tumors are classified as to their cell type
Tumors can arise from any cell type in the body

What Is Cancer?
Cancer a large group of diseases characterized
by the uncontrolled growth and spread of
abnormal cells
Neoplasm new growth of tissue that serves no
physiological function
Tumor clumping of neoplasmic cells
Malignant - cancerous
Benign - noncancerous
Biopsy microscopic examination of cell
development

Cancer is an umbrella term covering a plethora of

conditions characterized by unscheduled and
uncontrolled cellular proliferation.

Almost any mammalian organ and cell type can succumb to oncogenic
transformation, giving rise to a bewildering array of clinical outcomes.
The causes of cancer are many and varied, and include genetic
predisposition, environmental influences, infectious agents and ageing.
These transform normal cells into cancerous ones by derailing a wide
spectrum of regulatory and downstream effector pathways. It is just
this complexity that has hampered the development of effective and
specific cancer therapies.
Any attempt to provide a comprehensive overview of cancer-related
knowledge would be futile therefore the next two lectures will
focus on topics undergoing particularly rapid progress.

Cancer continued; three cancer types

Carcinomas; constitute 90% of cancers, are
cancers of epithelial cells
Sarcomas; are rare and consist of tumors of
connective tissues (connective tissue,
muscle, bone etc.)
Leukemias and lymphomas; constitute 8%
of tumors. Sometimes referred to as liquid
tumors. Leukemias arise from blood
forming cells and lymphomas arise from
cells of the immune system (T and B cells).

What Causes Cancer?

External Factors chemicals, radiation,
viruses, and lifestyle
Internal Factors hormones, immune
conditions, and inherited mutations
Theories
Cellular change/mutation theories
Carcinogens
Oncogenes/ protooncogenes

Risks For Cancer

Lifetime risk the probability that an individual,
over the course of a lifetime, will develop cancer or
die from it
Relative risk measure of the strength of the
relationship between risk factors and a particular
cancer
Smoking 30% of all cancer deaths, 87% of lung
cancer deaths
Obesity 50% higher risk for breast cancer in
postmenopausal women, 40% higher risk in colon
cancer for men

Biological Factors
Some cancers such as breast, stomach,
colon, prostate, uterus, ovaries and lung
appear to run in families
Hodgkins disease and certain leukemia's
show similar patterns
University of Utah research suggests that a
gene for breast cancer exists
A rare form of eye cancer appears to be
transmitted genetically from mother to child

Reproductive And Hormonal

Risks For Cancer
Pregnancy and oral contraceptives increase
a womans chances of breast cancer
Late menarche, early menopause, early
first childbirth, having many children have
been shown to reduce risk of breast cancer

Social And Psychological Factors

Stress has been implicated in increased
susceptibility to several types of cancers
Sleep disturbances, diet, or a combination
of factors may weaken the bodys immune
system

Chemicals In Foods
Sodium nitrate when ingested forms a
potential carcinogen, nitrosamine
Sodium nitrate is still used because it is
effective in preventing botulism
Pesticide and herbicide residues

Viral Factors
Herpes-related viruses may be involved in the
development of leukemia, Hodgkins disease,
cervical cancer, and Burkitts lymphoma
Epstein-Barr virus, associated with
mononucleosis, may contribute to cancer
Human papillomavirus (HPV), virus that causes
genital warts, has been linked to cervical cancer
Helicobacter pylori causes ulcers which are a
major factor in the development of stomach
cancer

Medical Factors
Some medical treatments actually increase a
persons risk for cancer
Diethylstilbestrol (DES) used 1940 to 1960 to
control bleeding during pregnancy, the
daughters of mothers that used DES were found
to have an increased risk for cancers of the
reproductive organs
Estrogen supplementation
Chemotherapy used to treat one form of cancer
may increase risk for another type of cancer

Properties of cancer cells

Normal cells show

contact inhibition

Cancer cells lack

contact inhibition

Properties of cancer cells

They keep growing
And growing
And growing
And growing

Cancer: Benign
Benign: localized and of
small size
Cells that closely resemble,
and may function, like
normal cells
May be delineated by a
fibrous (Basal lamina)
capsule
Become problems due to
sheer bulk or due to
secretions (e.g. hormones)

Cancer : Malignant

Malignant tumors: high rate of division, properties may vary compared

to cells of origin. Most malignant cells become metastatic
Invade surrounding tissue and establishment of secondary areas of
growth: Metastasis

Metastasis
Carcinoma: derived from endoderm or ectoderm

Oncology
Biology of abnormal cancer cells
They have continuous or inappropriate, usually
faster growth or larger growth patterns
They have no specific morphology and often do
not resemble their parent cells = anaplastic
They do not respond to signals for apoptosis =
programmed cell death

Apoptosis
Apoptosis is a tightly regulated form of cell death,
also called the programmed cell death.
Morphologically, it is characterized by chromatin
condensation and cell shrinkage in the early stage.
Then the nucleus and cytoplasm fragment, forming
membrane-bound apoptotic bodies which can be
engulfed by phagocytes. In contrast, cells undergo
another form of cell death, necrosis, swell and
rupture. The released intracellular contents can
damage surrounding cells and often cause
inflammation.

p53 in apoptosis

Following DNA damage, e.g. by radiation, p53 levels rise, and

proliferating cells arrest in G1. This allows time for DNA repair
prior to the next round of replication. This arrest is mediated by
stimulation of expression of p21CIP1, the cyclin kinase inhibitor.
Very high p53 levels, or susceptible cell types, e.g. lymphocytes,
are triggered to undergo apoptosis. Bcl-2 acts between p53 and the
caspase:

The role of caspase

During apoptosis, the cell is killed by a class of proteases
called caspases. More than 10 caspases have been
identified. Some of them (e.g., caspase 8 and 10) are
involved in the initiation of apoptosis, others (caspase 3,
6, and 7) execute the death order by destroying
essential proteins in the cell. The apoptotic process can
be summarized as follows:
1. Activation of initiating caspases by specific signals
2. Activation of executing caspases by the initiating
caspases which can cleave inactive caspases at specific
sites.
3. Degradation of essential cellular proteins by the
executing caspases with their protease activity.

Capsase activation
Comparison between active and inactive forms of
caspases. Newly produced caspases are inactive.
Specifically cleaved caspases will dimerize and
become active.

P53 can bind to DNA!

Stabilized by Zn2+.

DNA

p53

What does p53 do?

Suppresses tumors in response to DNA
by inducing cell cycle arrest or apoptosis

How can you inhibit gene

expression?

How is p53 Activated?

1) Regulation of p53 by MDM2
P53 tumor suppressor protein can be stabilized and
activated by two separate mechanisms in
response to DNA-damage-induced
phosphorylation.
2) p53 nuclear export is inhibited, to ensure that it is
activated in response to DNA damage.

The discovery of p53

Studies of SV40-transformed cells show that a 55kDa protein is coprecipitated with the large-T antigen
(Chang et al. 1979; Kress et al. 1979; Lane and
Crawford 1979; Linzer and Levine 1979; Melero et al.
1979). This association was shown to be the result of
an in vivo association between the two proteins
(Lane and Crawford 1979). It was then postulated that
this protein could be encoded by the cellular
genome. (It should be kept in mind that no middle-T
was found for SV40 and that the molecular weight of
this protein was similar to that of polyoma middle-T
antigen). Linzer and Levine (Linzer and Levine 1979)
found that the 54-kDa protein was overexpressed in a
wide variety of murine SV40 transformed cells, but
also in uninfected embryonic carcinoma cells. A
partial peptide map from this 54-kDa protein was
identical among the different cell lines, but was
clearly different from the peptide map of SV40 large-T
antigen (Kress et al. 1979; Linzer and Levine 1979). It
was then postulated that SV40 infection or
transformation of mouse cells stimulates the
synthesis or stability of a cellular 54-kDa protein.

Oncology
Cancer grading and staging
Cancer is graded upon the resemblance to normal cells
= G
(The higher the number, the worse the grade of cancer) i.e. G1,
G2, G3, G4

Staging is based upon

the presence of a primary tumor = T
involvement in lymph nodes = N
and appearance of metastasis = M
Numbers of the stage range from
x = none to 3 or 4 for each letter

Is this a high grade or low grade

cancer?

1. High
2. Low

Oncology
Types of cancer cells are named for their site of
origin:
Adenocarcinoma
Carcinoma in situ (CIS)
Squamous
Basal cell
Astrocytomas
Melanomas
Sarcomas
Lymphomas

Oncology

Symptoms of Cancer
Cachexia weight loss,unexplained
Anorexia
Anemia
Impaired immune response
Pain when the cancer is large enough to
compress nerves or organs
Lymphadema when the tumor blocks lymph or
circulatory flow
Motor or sensory deficits

Oncology
Cancer statistics
Lung cancer has annual
new cases (incidence)
of 173,770 people
per year: 93,110 males and
80,660 females
Annual mortality: 160,440 per year
consisting of 92,000 males and
68,510 females

Oncology
Cancer statistics
28% of all cancer deaths are due to lung cancer
This is the leading cause of cancer death in
both men and women
There are more deaths from lung cancer than
prostate, breast, and colorectal cancers
combined

Oncology

Cancer statistics
Risks for lung cancer:
Smoking (75-80% of cases)
Occupational exposure
Nutrition/Diet
Genetic factors

Oncology
Cancer statistics
Prostate cancer is number two cause of cancer in
men
Breast Cancer is number two cause of cancer in
women
Most common non-malignant or non-fatal cancer
is non-melanoma type skin cancers

Oncology

Lab tests for cancer

Ultrasounds to determine size
CT scan with contrast the golden standard
Genetic markers BRCA 1 and BRCA 2
Tumor markers:
CEA general carcinogenic antigen
PSA prostate antigen
CA-125 ovarian
CA-25,27 breast
HER 2 NEU breast tissue needed

Oncology

Lab tests for cancer

Liver function tests
CBC with diff
Renal function tests
PET scan looks for metastasis using a
radioactive glucose solution
PT, PTT, Fibrinogen, Fibrin levels

Oncology
Lab tests for cancer
Pathology slide of tumor:
(Should be kept for a period of years)
Determines type of tumor
Source of tumor
Aggression of tumor whether fast growing,
differentiated, or non-differentiated
Used to determine tumor growth factors and
susceptibility to certain chemotherapies

Cancer treatment.
By Dr.Huda abd-alkarim.
Assistant prof.& consultant oncologist.

Modalities of treatment:
1-local therapy:
-surgery.
-radiation therapy.

2-systemic treatment:

chemotherapy.
Hormonal therapy.
Monoclonal antibodies.
Radioactive material.

3-supportive care.
4-non-conventional therapy.

Surgery:
Surgery was the first modality used
successfully in the treatment of cancer.
It is the only curative therapy for many
common solid tumors.
The most important determinant of a
successful surgical therapy are the absence
of distant metastases and no local
infiltration.

Cont:
Microscopic invasion of surrounding normal
tissue will necessitate multiple frozen section.
Resection or sampling of regional lymph node is
usually indicated.
Surgery may be used for palliation in patients for
whom cure is not possible.
Has significant role in cancer prevention.
E.g familial polyposis coli.

Surgery for prevention:

Patients with conditions that predispose
them to certain cancers or with genetic traits
Associated with cancer can have normal life
span with prophylactic surgery.
-colectomy .
-oophorectomy.
-thyroidectomy.
-removal of premalignant skin lesion .

Radiation therapy:

Radiation therapy:
Radiation therapy: is a local modality used in the
treatment of cancer .
Success depend in the difference in the radio
sensitivity between the tumor and normal tissue.
It involves the administration of ionizing radiation
in the form of x-ray or gamma rays to the tumor
site.
Method of delivery: External beam(teletherapy).
Internal beam therapy(Brachytherapy).

Cont:
Radiation therapy is planned and performed
by a team of nurses, dosimetrists,physician
and radiation oncologist.
A course of radiation therapy is preceded by
a simulation session in which low-energy
beam are used to produce radiograghic
images that indicate the exact beam
location.

Cont:
Radiation therapy is usually delivered in
fractionated doses such as 180 to 300 cGy per
day,five times a week for a total course of 5-8
weeks.
Radiation therapy with curative intent is the main
treatment in limited stage Hodgkins disease,some
NHL,limited stage ca prostate,gynecologic
tumors&CNS tumor .
Also can use in palliative &emergency setting.

Complication of radiation:
There is two types of toxicity ,acute and long term
toxicity.
Systemic symptoms such as Fatigue,local skin
reaction,GI toxicity,oropharyngeal
mucositis&xerostomia.myelosuppression.
Long-term sequelae:may occur many months or years
after radiation therapy.
Radiation therapy is known to be
mutagenic,carcinogenic,and teratogen,and having
increased risk of developing both secondary leukemia
and solid tumor.

Nuclear medicine

Radionuclides:
For decades have been used systemically to treat
malignant disorders.
They are administer by specialists in nuclear
medicine or radiation oncologist.
Radioactive iodine:in the from of 131I is effective
therapy for well differentiated thyroid ca
Strontium-89. Is used for the treatment of body
metastasis.it is an alkaline earth element in the
same family as calcium

Chemotherapy:

Chemotherapy:
Systemic chemotherapy is the main
treatment available for disseminated
malignant diseases.
Progress in chemotherapy resulted in cure
for several tumors.
Chemotherapy usually require multiple
cycles.

Classification of cytotoxic drug:

Cytotoxic agent can be roughly categorized
based on their activity in relation to the cell
cycle.
c y to to x ic d ru g
p h a s e n o n s p e c ific .

p h a s e sp e c ific

Cont :
What is the difference between phase specific &
phase non specific?..
Phase non-specific:
The drugs generally have a linear dose-response
curve( the drug administration ,the the fraction of
cell killed).

Phase specific:
Above a certain dosage level,further increase in drug
doesnt result in more cell killing.but you can play with
duration of infusion.

What are the chemotherapeutic

agent?..

Chemotherapeutic agents:

Alkylating agents:
Antimetabolites:
Antitumor antibiotic:
Plant alkaloids:
Other agents
Hormonal agent:
Immunotherapy:

Complication of Chemotherapy:
Every chemotherapeutic will have some
deleterious side effect on normal tissue .
E.G; Myelosuppression,nausea&vomiting,
Stomatitis,and alopecia are the most
frequently observed side effects.

Criteria used to describe response

are:
Complete response (complete remission)is the
disappearance of all detectable malignant disease.
Partial response:is decrease by more than 50% in the
sum of the products of the perpendicular diameters of all
measurable lesions.
Stable disease:no increase in size of any lesion nor the
appearance of any new lesions.
Progressive disease:means an increase by at least 25% in
the sum of the products of the perpendicular diameters of
measurable lesion or the appearance of new lesions.

Endocrine therapy:

Endocrine therapy:
Many hormonal antitumor agents are functional agonist or

antagonist of the steroid hormone family.

Adrenocorticoids:
Antiandrogen:
Estrogen:
Antiestrogen:
Progestins
Aromatase inhibitor:
Gonadotropin-releasing hormone agonists:
Somatostatin analogues:

Adrenocorticosteroid:
Are frequently used in combination regimen for
the treatment of lymphocytic leukemia and
lymphoma.
They function by binding to glucocorticoidspecific receptors present in lymphoid cells and
initiate programmed cell death
They most commonly used agent are
prednisone,methylprednisone,dexamethosone.

Antiandrogens:
Flutamide :
Effectively blocks the binding of androgen to
its receptor in the periphral tissue .
It is used in the treatment of disseminated
prostate ca

Biological therapy:

Biologic therapy:
Immunotherapy:
Cytokines
Cellular therapy.
Tumor vaccine:

Hematopoietic growth factors.

Oncology
The waves of the future:
Stem Cell Research
Oncogene therapy now that cancer cells are
being genetically tagged, we can tell which growth
factors are present, and which enzymes turn off
the gene. Soon all gene markers will have a pill
that matches the enzyme, i.e. IRESSA is a
tyramine kinase inhibitor, and stops the tumors
growth that use tyramine kinase

Oncology
Stem Cell Induction there are new drugs out
for stem cell induction to immunosuppress the
patient, even in deadly cancers, i.e. Multiple
Myeloma. Recently, the combination of
lenalidomide(Revalamid), bortezomib
(Velcade) and dexamethasone produced a
98% response rate in patients

Oncology
The waves of the future:
Cancer vaccines
Oncology is the science of cancer and
treatment of all cancer patients. It is one of
the most demanding and rewarding fields in
medicine.
The future is open for a cure.

Oncology