Post on 25-Sep-2015
description
Carcinogenesis Overview
Neoplasia DefinitionsHypotheses of the Origin of NeoplasiaAgents Causing Neoplasia*
Carcinogenesis - Overview
Neoplasia is an abnormality of cell growth and multiplication characterised byAt cellular level Excessive cellular proliferationUncoordinated growthTissue infiltrationAt molecular level Disorder of growth regulatory genesDevelops in a multistep fashion*
Carcinogenesis Overview
Hypotheses of the Origin of NeoplasiaOncogenes and Tumor Suppresor Genes
Viral Oncogene Hypothesis
Epigenetic Hypothesis
Failure of Immune Surveillance
Agents Causing Neoplasia*
Carcinogenesis
Hypotheses of the Origin of Neoplasia
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Monoclonal
Initial neoplastic change affects a single cell
Subclones may evolve from initial clone due to further genetic changes
Eg. B-cell lymphoma, plasma-cell myeloma
Field origin
Carcinogen acts on large number of cells producing field of potentially neoplastic cells
Neoplasm arises from one or more of these cells, each from a separate clonal precursor
Polyclonal, multiple discrete, or multifocal neoplasms
Eg. Breast, urothelial, liver, colon
Carcinogenesis
Hypotheses of the Origin of Neoplasia
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Carcinogenesis
Hypotheses of the Origin of Neoplasia
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Increase in promoter factors or decrease in suppressor factors result in uncontrolled cell growth
See figure on relationships of cellular oncogenes and suppressor genes to normal growth and neoplasia
NORMAL CELL
Growth factor
Growth factor receptor
Signal transduction
Activation of transcription
cytoplasm
nucleus
Carcinogenesis
Hypotheses of the Origin of Neoplasia
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Mechanisms of activation & inactivation
Mutation
Translocation
Insertion of oncogenic virus to adjacent site
Amplification
Introduction of viral oncogene
Derepression
How does proto-oncogene get activated?
Relationship between gene products of proto oncogene
Growth factors eg IGF
Growth factor receptors
Eg erb-2, ret
Signal transducing factors
Eg cytoplasmic kinases
DNA binding proteins concerned with transcription
cell cycle proteins eg cyclin D
NEOPLASTIC CELLS
Increased
In growth factor
Increased
In growth factor
receptors
Increased in signal transduction
Increase in activation of transcription
Carcinogenesis
Hypotheses of the Origin of Neoplasia
*
See figure on RNA Virus oncogenesis
Carcinogenesis
Hypotheses of the Origin of Neoplasia
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Carcinogenesis
Hypotheses of the Origin of Neoplasia
*
Supporting evidence
Higher incidence of neoplasia in the immunodeficient and immunosuppressed
Cancer is disease of elderly
Challenges to hypothesis
Immunodeficient and immunosuppressed individuals develop mainly lymphomas
Thymectomised patients show no increase in neoplasia
Immune response to tumors are ineffective at time of clinical expression
See diagram on immune response to cancer
Carcinogenesis Overview
Neoplasia DefinitionsHypotheses of the Origin of NeoplasiaAgents Causing NeoplasiaChemical OncogensisRadiation OncogenesisViral OncogenesisNutritional OncogenesisHormonal OncogenesisGenetic Oncogenesis*
Carcinogenesis
Agents Causing Neoplasm
*
Carcinogenesis
Agents Causing Neoplasm
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Major chemical carcinogens
Polycyclic hydrocarbons
Aromatic amines
Aflatoxins
Nitrosamines
Cancer chemotherapeutic agents
Asbestos
Heavy metals
Vinyl chloride
See table on major chemical carcinogens and their cancers
Carcinogenesis
Agents Causing Neoplasm
*
Potency
Varies with carcinogen
Expressed in amount that must be given to induce cancer on a regular basis (Eg. Saccharin 10g/kg/d, aflatoxin 10-6 g/kg/d)
Carcinogenesis
Agents Causing Neoplasm
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X-rays, radioisotopes and nuclear power plants account for
Carcinogenesis
Agents Causing Neoplasm
*
Carcinogenesis
Agents Causing Neoplasm
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Carcinogenesis
Agents Causing Neoplasm
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Radium is metabolised and incorporated into bone like calcium
Thorium used in diagnostic radiology (1930-1955)
Carcinogenesis
Agents Causing Neoplasm
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Hiroshima, Nagasaki (atomic blasts) population 0showed increased incidence of leukemia, CA breast, CA lung, CA thyroid
Marshall islands (atmospheric testing of nuclear devide containing radioactive iodine) increased thyroid CA
Chernobyl, 1986 radioactive iodine
Carcinogenesis
Agents Causing Neoplasm
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RNA Virus
Introduction of DNA provirus containing oncogene (v-onc)
Insertion of DNA provirus adjacent to cellular oncogene (c-onc)
DNA Virus
Inactivation of tumor-suppressor gene proteins
Enhancement of oncogene action
Carcinogenesis
Agents Causing Neoplasm
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Carcinogenesis
Agents Causing Neoplasm
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Carcinogenesis
Agents Causing Neoplasm
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Estrogen
Granulosa cell tumor and recurrent ovulatory failure result in increased risk of endometrial CA
endometrial hyperplasia dysplasia neoplasia
Minimal increase in risk of breast CA with high-dose estrogen OCP
Diethylstilbestrol (DES)
Female children exposed to DES in utero high risk of vaginal clear-cell CA
Steroid hormones
OCP and anabolic steroids associated with liver cell adenoma, carcnoma
Carcinogenesis
Agents Causing Neoplasm
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Carcinogenesis
Agents Causing Neoplasm
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Dominant gene codes for activation factor
Recessive absence of tumor suppresor genes lead to failure in production of tumor suppressing factor
See table on tumor suppressor genes.
Carcinogenesis
Agents Causing Neoplasm
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Retinoblastoma inherited abnormality of one Rb1 gene is followed by mutation of counterpart Rb1 gene. Therefore the inheritance appears to be dominant. However it is the loss of expression of both Rb1 tumor suppressor genes that result in neoplasia hence the expression of a recessive change.
Wilms tumor deletion of part of WT-1 tumor suppressor gene by a mechanism similar to retinoblastoma.
Carcinogenesis
Agents Causing Neoplasm
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Breast CA 1st degree female relatives of premenopausal women with breast CA have 5X higher risk. The risk is higher when the relative has bilateral breast CA.
Colon CA occurs in families both as a complication of inherited familial polyposis coli and independently.
1/4th colon cancer patients demonstrate abnormalities of MSH2 gene which encodes a DNA housekeeper protein
Carcinogenesis
Agents Causing Neoplasm
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Syndromes characterised by increased chromosomal fragility and associated with higher risk of neoplasia are such as xeroderma pigmentosum, Blooms syndrome, Fanconis syndrome, and ataxia-telangiectasia. There are frequent DNA abnormalities.
Syndromes of immunodeficiency predispose to neoplasia due to a failure of immune surveillance. The neoplasia is not inherited, but susceptibility is.
conclusion
Pathogenesis of cancer is complexit is a genetic disease- either acquired genetic abnormality or inherited genetic abnormalityIt arises when several mutations accumulate within genomeconclusion
Added insults from the environmental exposures to carcinogens : chemicals, radiation, virusesGrowth autonomy from activation of growth factors or by suppression of tumour suppressor genesPathogenesis
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