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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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Agents Causing Neoplasm
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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Agents Causing Neoplasm
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
Carcinogenesis
Agents Causing Neoplasm
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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
Carcinogenesis
Agents Causing Neoplasm
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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
Carcinogenesis
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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