carcinogenesis -origin of cancer, pathogenesis, mutation.pptx

carcinogenesis

1. ADVANCES IN CANCER DIAGNOSIS DEPARTMENT OF PATHOLOGY

2. PATHOPHYSIOLOGY OF CANCER DEPARTMENT OF PATHOLOGY CHAFB

3. Neoplasia : Neo + Plasia  New + Growth. Willis definition: “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissue and persists in the same manner after cessation of the stimuli which evoked the change” “Cell division without control” Irreversible DNA damage, resulting in autonomous growth of abnormal cells *

4. HALL MARKS OF CANCER

5. Genetic Basis of Cancer Tumor growth promoting genes (Oncogenes) Tumor-suppressor genes Genes regulating apoptosis Genes regulating DNA repair

6. Normal cell DNA Damage Mutations in genome Alterations of genes governing apoptosis Expression of altered gene products and loss of regulatory gene products Inactivation of tumor suppressor genes Activation of proto-oncogenes DNA damaging agents Chemicals Radiation viruses Inherited mutations in genes affecting cell growth or apoptosis Failure of DNA repair Successful DNA repair CANCER Clonal expansion, additional mutations and heterogeneity Genetic basis of cancer

7. © 2005 Elsevier

8. Genetic Basis of Cancer Tumor growth promoting genes (Oncogenes ) Proto-oncogenes : genes that permit normal cell growth Oncogenes: Activation of proto-oncogenes by point mutation ,amplification or dysregulation  Oncogenes

9. Levels of activation of Oncogene products in the cell 1 . Growth factor 2 . Growth factor receptor 3. Signal transduction proteins 4. Nuclear regulatory proteins 5.Cell cycle regulators NUCLEUS CELL

10. S.No Category Protooncogene Mechanism Associated human cancer 1. Growth factors Platelet derived growth factor sis Overexpression Astrocytoma Osteosarcoma Fibroblast growth factor hst-1 Overexpression Stomach Int-2 Amplification Bladder, breast, melanoma 2. Growth factor receptors Epidermal Growth Factor erb-B1 Overexpression Sq cell ca lung erb-B2 Amplification Breast, ovary, lung, stomach erb-B3 Overexpression Breast CSF-1 fms Point mutation Leukemia ret Point mutation Multiple endocrine neoplasia Classes of oncogenes, mode of activation and association with human cancers

11. Genetic Basis of C ancer Tumor-suppressor genes

12. S. No Gene Function Tumors due to somatic mutations Tumors due to Inherited mutations 1. TGF-ß receptor E-cadherin Growth inhibition Cell adhesion Colon Stomach, breast Unknown Familial gastric cancer 2. NF-1 Inhibition of ras signaling Schwannoma NF I and sarcomas 3. NF-2 Unknown Schwannoma and meningioma NF II, acoustic schwannomas, meningioma 4. APC Inhibition of ras signaling Stomach, colon, pancreas, melanoma Familial adenomatous polyposis coli, colonic cancer 5. Rb Regulation of cell cycle Retinoblastoma, osteosarcoma, breast, colon, lung Retinoblastoma, osteosarcoma Tumor Suppressor genes in human cancer

13. Genetic Basis of Cancer Genes regulating apoptosis Apoptosis: Programmed cell death a normal physiological phenomenon in the body. Imbalance of agonists and antagonists leads to uncontrolled cell proliferation

14. Proapoptotic Antiapoptotic bax, bclxS bad bid bcl2, bclxL p53 C-myc

15. Genetic Basis of Cancer Genes regulating DNA repair

16. Normal cell DNA Damage Mutations in genome Alterations of genes governing apoptosis Expression of altered gene products and loss of regulatory gene products Inactivation of tumor suppressor genes Activation of proto-oncogenes DNA damaging agents Chemicals Radiation viruses Inherited mutations in genes affecting cell growth or apoptosis Failure of DNA repair Successful DNA repair CANCER Clonal expansion, additional mutations and heterogeneity Genetic basis of cancer

17. Genes regulating DNA repair Also called mismatch repair genes eg in hereditary non- polyposis coli (HNPCC) where accumulation of DNA defects leads to higher risk of Ca colon

18. Tumor growth Proliferation vs cell death Proportion of cells in the cell cycle

19. Tumor angiogenesis Angiogenic factors Antiangiogenic factors vascular endothelial growth factor VEGF, basic fibroblast growth factor bFGF angiostatin, endostatin and vasculostatin

20. The M etastatic Cascade Sequential steps involved in the hematogenous spread of a tumor