CARCINOGENESI

S


Definition
The process of transformation from a normal
cell to a cancerous one

Synonym: neoplasia
Carcinogenesis
Neoplasia
Neoplasia is an abnormality of cell growth and
multiplication characterised by:
At cellular level
Excessive cellular proliferation
Uncoordinated growth
Tissue infiltration
At molecular level
Disorder of growth regulatory genes

Carcinogenesis
NORMAL CELL
growth factor
growth factor receptor
signal transduction
activation of
transcription
cytoplasm
nucleus
DNA
RNA
Carcinogenesis
NEOPLASTIC (malignant) CELLS
Increase
in growth
factors
Increase
in growth
factor
receptors
Increase in
signal
transduction
Increase in
activation of
transcription
- Disturbed processes of mitosis and protein synthesis
Carcinogenesis
Malignant cells
Continuous reproduction

Formation of abnormal proteins

ANAPLASIA:
loss of normal cell function (abnormal DNA transcription)
proliferation
movement of cells
invasion of nearby tissue
metastasis
Carcinogenesis
Caused by altered DNA and
altered cellular programs
which make new signals
Carcinogenesis
Hypotheses of the Origin of Neoplasia
Agents Causing Neoplasia
Chemical Oncogensis
Radiation Oncogenesis
Viral Oncogenesis
Nutritional Oncogenesis
Hormonal Oncogenesis
Genetic Oncogenesis
Hypotheses of the origin of neoplasia
two general types
Monoclonal
initial neoplastic change affects a single cell

Field origin
carcinogen acts on large number of cells producing field
of potentially neoplastic cells

Carcinogenesis
Regulatory genes
Proto-oncogenes (activated oncogenes) code for:
growth factors
receptors
signal-relay or transduction factors
ras - colon cancer
myc - lymphoma
bcr-abl - chronic myelogenous leukemia (Philladelphia chromosome)

Tumor suppressor genes - code for factors that down-
regulate the cell cycle, promote differentiation and supress oncogenes from
causing cancer
Rb-1 retinoblastoma gene
p53



Carcinogenesis
NEOPLASIA proto-oncogene is activated or tumor
suppressor gene is inactivated

normal growth oncogenesis

Activation of proto-oncogene:
point mutation
translocation
gene amplification

Also - Failure of Immune Surveillance theory : immune
system responds to neoantigens as to foreign antigens, but
neoplastic cells escape recognition and destruction -->
become clinical cancers

Carcinogenesis
Agents Causing Neoplasm
Carcinogens substances known to cause cancer or
produces an increase in incidence of cancer in
animals or humans
Cause of most cancers is unknown
Most cancers are probably multifactorial in origin
Known carcinogenic agents constitute a small
percentage of cases
Unidentified environmental agents probably play a role
in 95% of cancers
Carcinogenesis
Agents Causing Neoplasia
Environmental agents
Chemical Oncogensis
Radiation Oncogenesis
Viral Oncogenesis
Nutritional Oncogenesis
Hormonal Oncogenesis
Heredity
- Genetic Oncogenesis

Carcinogenesis
Agents Causing Neoplasm
1 - Chemical Carcinogenesis
Types
Proximate or direct-acting : act locally without
metabolic change
Indirect acting : carcinogenic only after being
metabolised into active compounds
(procarcinogen ultimate carcinogen)

Carcinogenesis
Agents Causing Neoplasm
Mode of carcinogenesis by chemical agents:
Inducing changes in DNA eg. Base alkylation, deletion,
breakage, cross-linkage
Epigenetic mechanisms
Synergistic action with viruses
Promoter for other carcinogens
Carcinogenesis
2 Radiation Oncogenesis
sunlight
X-rays
radioactive substances
nuclear fusion

Energy interacts with DNA causing its damage and mutation,
which leads to CANCER

E.g. - leukemia (radiologists, atomic bomb survivors)
- skin cancer UV radiation from the sun
Carcinogenesis
Agents Causing Neoplasm
3. Viruses (oncogenic viruses)
HTLV causes a form of leukemia in adults
Herpes VIII Kaposi sarcoma
Papilloma virus cervical carcinoma
Epstein-Barr virus Burkitt lymphoma

Two types RNA and DNA viruses
Carcinogenesis
Agents Causing Neoplasm

Agents Causing Neoplasm

4. Nutritional Oncogenesis
Some associations
Low-fiber diet and colonic CA
Fatty diet with breast ca
Betel leaves with oral ca
Protective agents ?antioxidant effect, awaiting
confirmation
Beta-carotene
Vitamin C, E


Carcinogenesis

Agents Causing Neoplasm

5 Hormonal Oncogenesis
Types
Induction of Neoplasms by Hormones
Dependence of Neoplasms on Hormones
Hormones inducing Neoplasms
Estrogen breast ca.
Neoplastic cells possess receptors for binding hormone
Loss of hormonal stimulation slow but does not halt growth
Examples
Prostate CA
Breast CA
Thyroid CA

Carcinogenesis
Agents Causing Neoplasia
Heredity
Transmission of some forms of cancer from parents to
offspring through defects in the DNA of the egg or sperm cells
E.g. Retinoblastoma tumor of the retina of the eye
Polyposis coli syndrome polyps that grow in the
colon and rectum
Other colon, breast and kidney cancers

Cause: loss of a segment of DNA or a change in the coding
sequence of DNA
Detection DNA sequencing, DNA probes

In many cases abnormalities in tumor suppressor genes
Carcinogenesis
Acquired environmental factors
chemicals ,radiation ,viruses
Changes in genome
of somatic cells
Activation of growth
promoting oncogenes
Inactivation of cancer
supressor genes
Expression all altered gene products
and loss of regular gene products
MALIGNANT NEOPLSM
Genetic factors
Host defense against tumors- Tumor immunity

Tumor antigen

a. Tumor- specific antigen (TSA)

b. Tumor- associated antigen (TAA)
Antitumor effector mechanisms
Both cell-mediated and humoral immunity can have
antitumor activity.

Cytotoxic T lymphocytes
Natural killer cells
Macrophages
or immune antitumor cells:

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