Carcinogenesis Last

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CARCINOGENESIS


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Definition

The process of transformation from a normal

cell to a cancerous one

Synonym: neoplasia

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Neoplasia

Neoplasia is an abnormality of cell growth andmultiplication characterised by:

At cellular level

Excessive cellular proliferation

Uncoordinated growth

Tissue infiltration

At molecular level

Disorder of growth regulatory genes

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NORMAL CELL growth factorgrowth factor receptor

signal transduction

activation oftranscription

cytoplasm

nucleusDNA

RNA

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NEOPLASTIC (malignant) CELLS

Increasein growthfactors

Increasein growthfactorre eptors

Increase insignaltransduction

Increase inactivation oftranscription

-Disturbed processes of mitosis and protein synthesis

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Carcinogenesis

Hypotheses of the Origin of Neoplasia Agents Causing Neoplasia

Chemical Oncogensis

Radiation Oncogenesis Viral Oncogenesis

Nutritional Oncogenesis

Hormonal Oncogenesis

Genetic Oncogenesis


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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

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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 fromcausing cancer

Rb-1retinoblastoma gene

p53

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NEOPLASIA

proto-oncogene is activatedor tumor

suppressor gene is inactivated

normal growthoncogenesis

Activation of proto-oncogene:

point mutation

translocation

gene amplification

Also - Failure of Immune Surveillance theory :immunesystem responds to neoantigens as to foreign antigens, butneoplastic cells escape recognition and destruction -->

become clinical cancers

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Agents Causing Neoplasm

Carcinogens

substances known to cause cancer or

produces an increase in incidence of cancer inanimals 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

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Agents Causing Neoplasia

Environmental agents

Chemical Oncogensis

Radiation Oncogenesis

Viral Oncogenesis

Nutritional Oncogenesis

Hormonal Oncogenesis

Heredity

- Genetic Oncogenesis

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1 - Chemical Carcinogenesis

Types

Proximate or direct-acting : act locally withoutmetabolic change

Indirect acting: carcinogenic only after being

metabolised into active compounds

(procarcinogenultimate carcinogen)

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Mode of carcinogenesis by chemical agents:

Inducing changes in DNAeg. Base alkylation, deletion,

breakage, cross-linkage

Epigenetic mechanisms

Synergistic action with viruses

Promoter for other carcinogens

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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 cancerUV radiation from the sun

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3. Viruses (oncogenic viruses)

HTLVcauses a form of leukemia in adults

Herpes VIIIKaposi sarcoma

Papilloma viruscervical carcinoma

Epstein-Barr virusBurkitt lymphoma

Two typesRNA and DNA viruses

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C i i


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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.Retinoblastomatumor of the retina of the eye

Polyposis coli syndromepolyps 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

DetectionDNA sequencing, DNA probes

In many casesabnormalities in tumor suppressor genes

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Acquired environmental factorschemicals ,radiation ,viruses

Changes in genomeof somatic cells

Activation of growthpromoting oncogenes

Inactivation of cancersupressor genes

Expression all altered gene productsand loss of regular gene products

MALIGNANTNEOPLSM

Genetic factor


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Host defense against tumors- Tumor immunity

Tumor antigen

a. Tumor- specific antigen (TSA)

b. Tumor- associated antigen (TAA)


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Antitumor effector mechanisms

Both cell-mediated and humoral immunity can haveantitumor activity.

Cytotoxic T lymphocytes

Natural killer cells

Macrophages

or immune antitumor cells:


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Thank you

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