Carcinogenesis is a multistep process that involves genetic damage and alterations. Environmental and hereditary factors can cause initiation through DNA damage from chemicals, viruses, or radiation. This is followed by a latent stage and promotion as more DNA changes accumulate, eventually resulting in malignant transformation and tumor formation. Cancer develops through the sequential acquisition of multiple genetic defects over time.

1. "I think of life itself now as a wonderful play that I've written for myself... and so my purpose is to have the utmost fun playing my part…!" Shirley MacLaine, Actress and Author

2. Revision slides first …..

6. Etiology of Cancer Dr Ejaz Waris

7. Non-lethal Genetic damage lies at the center of carcinogenesis. Loss/damage to suppressor genes, Duplication of promotor genes Loss/damage to Apoptosis genes Loss/damage of DNA repair genes.

8. Carcinogenesis:

9. We owe, Sir Percival Pott the knowledge of carcinogenesis. Pott, related the increased incidence of scrotal cancer in chimney sweeps. On his findings, Danish Chimney Sweeps Guild ruled that it’s members must bathe daily . No public health measure since that time, has so successfully controlled a form of cancer……!!!

10. Etiology of Neoplasia Environmental causes: (Carcinogens) Chemicals Viruses Radiation Hereditary causes- Genetic defects.

11. Point to be noted ! In males bronchogenic carcinoma and in females breast carcinoma are at the top !

12. Preneoplastic conditions Cirrhosis of liver Atypical hyperplasia of endometrium Leukoplakia Inflammatory bowel disease Adenomatous colonic polyps

13. CHEMICAL CARCINOGESIS

14. IT’S A MULTISTEP PROCESS CHEMICAL CARCINOGENESIS CONSISTS OF TWO PROCESSES: INITIATION PROMOTION

15. Chemical Carcinogenesis: Initiators- Cause irreversible damage to DNA,but at maximum they can cause severe dysplasia. eg.Benzopyrene Promoters – itself cannot induce cancer,they propagate or enhance the effects of initiators Alcohol,smoking (co-carcinogens) Thus resulting in Malignant transformation: Visible tumor formation – further DNA damage.

17. Chemical Carcinogenesis: Direct Acting Carcinogens: Alkylating Agents: Cyclophosphamide Indirect acting / Procarcinogenes (needs activation) Polycyclinc hydrocarbons – Benzopyrene Aromatic amines, dyes - Benzidine Natural products: Aflatoxin Others: Vinyl chloride, turpentine etc.

18. Known Chemical carcinogens A- Asbestos - Lung, mesothelioma. GI tract (esophagus, stomach, large intestine) b- Arsenic - Lung, skin, hemangiosarcoma c- Beryllium - Lung d- Cadmium - prostate e. Benzene - Leukemia

19. f. Chromium- Lung g. Ethylene oxide  Leukemia h. Nickel  .. Nose, Lung i. Radon  .. Lungs j. Vinyl chloride  Angiosarcoma k.Aflatoxins – HCC l-Nitrates – Gastric carcinoma M.Aniline Dyes,B-naphthylamine – TCC of bladder

20. Lets see mode of action of any one of the chemical carcinogens ! The carcinogenicity of most aromatic amines and azo dyes is exerted mainly in the liver, where the "ultimate carcinogen" is formed by the action of the cytochrome P-450 oxygenase systems.

21. After absorption,azodyes like b naphthylamine is hydroxylated into an active form, then detoxified by conjugation with glucuronic acid. When excreted in the urine, the nontoxic conjugate is split by the urinary enzyme glucuronidase to release the electrophilic reactant again, thus inducing bladder cancer. Regrettably, humans are one of the few species to possess urinary glucuronidase.

22. Viral Oncogenesis: Insertion of viral nucleic acids  mutation Alterations in Oncogenes, cancer suppressor genes and genes regulating DNA repair resulting in up-regulation of cell division  Carcinogenesis.

23. Oncogenic DNA Viruses Human Papilloma Virus Cervical neoplasia – warts, papilloma, ca cervix Epstein-Barr virus – Burkitts Lymphoma, Nasopharyngeal ca,Hodgkin’s disease,B cell lymphoma Hepatitis B & C virus Hepatocellular carcinoma.

24. Oncogenic DNA Viruses Kaposi Sarcoma Hepes Virus Causes Kaposi Sarcoma

25. Oncogenic RNA viruses Human T-Cell Leukemia Virus

26. Radiation Carcinogenesis: Ionizing radiation  dysjunction  random fusion  mutation. X Ray workers – Leukemia Radio-isotopes – Thyroid carcinoma Atomic explosion – Skin cancer, Leukemia Mutations Neoplasia

28. Molecular Basis of Neoplasia: Proto-oncogene Oncogene V-Onc Other Heredity Radiation Chemical

29. Remember - Multi-step Process Tumor initiation and progression results from stepwise accumulation of DNA mutations. Several characters of malignant neoplasm are the result of multiple genetic defects. Initial steps reversible(e.g. dysplasia), but final Malignant transformation is irreversible. “Hit & Run”

30. Tumor Progression

31. Multi-step Theory Stage of initiation Latent stage Stage of promotion Stage of malignant transformation

32. Summary DNA damage - loss of control over cell division. Radiation, Chemicals & Viral infections are some known causes of cancers. Cancer evolves in multiple steps by sequentially acquiring different DNA damages. Initiation, Latent stage, Promotion and Malignant transformation are recognizable stages in carcinogenesis. Each character of malignancy depends on unique DNA alteration.

33. It is easy to kill cancer cells, but the challenge is keeping the patient alive at the same time…..!

34. Do not fear mistakes… fear only the absence of constructive and corrective responses to those mistakes…