Etiology and Pathogenesis of Cancer

1. Etiology and Pathogenesis of Cancer By: Santoshi Naik Assistant Professor Yenepoya Pharmacy College and Research Centre

2. Etiology and Pathogenesis of Cancer Carcinogenesis/ Oncogenesis/ Tumorigenesis means mechanism of induction of tumours (pathogenesis of cancer); agents which can induce tumours are called carcinogens(etiologyof cancer)

3. Etiology and Pathogenesis of Cancer

4. Molecular pathogenesis of Cancer (genetic mechanisms of Cancer)

5. Molecular pathogenesis of Cancer (genetic mechanisms of Cancer)

6. Cell growth of normal as well as abnormal types is under genetic control. • In cancer, there are either genetic abnormalities in the cell, or there are normal genes with abnormal expression. • The abnormalities in genetic composition may be from inherited or induced mutations (induced by etiologic carcinogenic agents namely: chemicals, viruses, radiation). • The mutated cells transmit their characters to the next progeny of cells and result in cancer.

7. GENETIC REGULATORS OF MITOSIS

8. Genetic regulators of normal cell mitosis • Proto-oncogenes - are growth-promoting genes i.e. they encode for cell proliferation pathway. • Anti-oncogenes - are growth inhibiting or growth suppressor genes. • Apoptosisregulatory genes -control the programmed cell death. • DNA repair genes – regulatethe repair of DNA damage that has occurred during mitosis and also control the damage to proto-oncogenes and antioncogenes.

9. Genetic regulators of cancer cell mitosis In cancer, the transformed cells are produced by abnormal cell growth due to genetic damage to these normal controlling genes. • Activation of growth-promoting oncogenes - causing transformation of cell (protooncogene to oncogene) • Inactivation of anti-oncogenes -permitting the cellular proliferation of transformed cells. • Abnormal apoptosis regulatory genes - which may act as oncogenes or anti-oncogenes. • Failure of DNA repair genes and thus inability to repair the DNA damage resulting in mutations.

10. Chemical Carcinogens & Chemical carcinogenesis

11. CHEMICAL CARCINOGENS

12. INITIATOR CARCINOGENS These are the carcinogens which initiate the process of carcinogenesis

13. Direct acting carcinogens These chemical carcinogens do not require metabolic activation a) Alkylating agents • Anti-cancer drugs (e.g. cyclophosphamide, chlorambucil, melphalan, nitrosoureaetc), β-propiolactoneand epoxides. b) Acylatingagents • Examples - Acetyl imidazole and dimethyl carbamyl chloride.

14. Indirect acting carcinogens These are chemical substances which require prior metabolic activation before becoming potent ‘ultimate’ carcinogens a) Polycyclic aromatic hydrocarbons Examples:anthracenes, benzapyrene and methylcholanthrene • Smoking and lung cancer: There is 20 times higher incidence of lung cancer in smokers.

15. Skin cancer: Direct contact of polycyclic aromatic hydrocarbon compounds with skin - skin cancer eg. Kangri cancer in Kashmir natives. • Tobacco and betel nut chewing and cancer oral cavity: Cancer of the oral cavity is more common in people chewing tobacco and betel nuts.

16. Indirect acting carcinogens b) Aromatic amines and azo-dyes Examples: • β-naphthylamine - bladder cancer, especially dye and rubber industry workers. • Benzidine-bladder cancer. • Azo-dyesused for colouring foods – (e.g. yellow colour for butter, scarlet red for cherries) -hepatocellular carcinoma. c) Naturally-occurring products Derived from plant and microbial sources are aflatoxin B1, actinomycin D, mitomycin C, safrole and betel nuts.

17. d) Miscellaneous: Examples • Nitrosamines and nitrosamides- gastric carcinoma by nitrosylation of food preservatives. • Asbestos in bronchogenic carcinoma especially in smokers. • Metalslike nickel, lead, cobalt, chromium etc in industrial workers - lung cancer • Insecticides and fungicides

18. PROMOTER CARCINOGENS • Promoters are chemical substances which lack the intrinsic carcinogenic potential but their application helps the initiated cell to proliferate further to cancer cell. • Examples: • Phorbol esters – TPA (tetradecanoylphorbol acetate) • Hormones – excessive production of oestrogen • Miscellaneous – dietary fat , cigratte smoke.

19. Chemical carcinogenesis

20. Stages of Chemical Carcinogenesis • Initiation of Cracinogenesis: • Initiation is the first stage in carcinogenesis induced by initiator chemical carcinogens. • The change can be produced by a single dose of the initiating agent for a short time or largerdose for longer duration.

21. Iniation steps

22. 2) Promotion of Carcinogenesis • Promotion is the next sequential stage in the chemical carcinogenesis. • Examples of Promoters - phorbolesters, phenols, hormones, artificial sweeteners and drugs like phenobarbital. • Persistent and sustained exposure of the cell to initiator alone without application of promoter may result in cancer. But the vice versa does not hold true.

23. 3) Progessionof Carcinogenesis • Progression of cancer is the stage when mutated proliferated cell shows phenotypic features of malignancy. • Such phenotypic features appear only when the initiated cell starts to proliferate rapidly and in the process acquires more and more mutations.

24. PHYSICAL CARCINOGENESIS

25. PHYSICAL CARCINOGENESISPhysical agents in carcinogenesis are divided into 2 groups

26. 1) Radiation Carcinogenesis • Ultraviolet (UV) light and ionising radiation are forms of radiation carcinogens which can induce cancer in experimental animals and cause some forms of human cancers. • A property common between the two forms of radiation carcinogens is the appearance of mutations followed by a long period of latency after initial exposure, often 10-20 years or even later. • Radiation carcinogenesis, have sequential stages of initiation, promotion and progression in their evolution.

27. a) Ultraviolet light • Sources of UV Light – sunlight, UV lamps and welder’s arcs. • In humans, excessive exposure to UV rays can cause various forms of skin cancers—squamous cell carcinoma, basal cell carcinoma and malignant melanoma. • Epidemiological evidence - high incidence of skincancers in fair-skinned Europeans, inhabitants of Australia and New Zealand living close to the equator who receive more sunlight, and in farmers and outdoor workers.

28. Welder’s Arc

29. Mechanism of UV light Carcinogenesis • Causes of UV radiation- induction of mutation in oncogenes (RAS gene) and antioncogenes (p53 gene), inhibition of cell division, inactivation of enzymes and sometimes causing cell death. • The most important biochemical effect of UV radiation is the formation of pyrimidine dimers in DNA. Such UV-induced DNA damage in normal individuals is repaired, while in the persons who are excessively exposed to sunlight such damage remain unrepaired.

31. b) Ionising radiation • Ionising radiation like X-rays, α-, β- and γ-rays, radioactive isotopes, protons and neutrons can cause cancer in animals and in humans. • Radiation-induced cancers – leukaemias, cancer of skin, breast, ovary, uterus, lung, myeloma, and salivary glands.

32. Examples: • Higher incidence of radiation dermatitis and subsequent malignant tumours of the skin in X-ray workers and radiotherapists without safety measures. • Japanese atom bomb survivors of the twin cities of Hiroshima and Nagasaki after World War II have increased frequency of malignant tumours.

33. Neoplastic (left) and non-neoplastic complications (right) of ionising radiations

34. Mechanism of Ionising radiations • Radiation damages the DNA of the cell by one of the 2 possible mechanisms: a) It may directly alter the cellular DNA. b) It may dislodge ions from water and other molecules of the cell and result in formation of highly reactive free radicals that may bring about the damage. • Damage to the DNA resulting in mutagenesis is the most important action of ionising radiation. It may cause chromosomal breakage, translocation, or point mutation.

35. 2) Non Radiation Carcinogenesis Examples: • Stones in the gallbladder, • Stones in the urinary tract, • Healed scars following burns or trauma, • Implants of inert materials such as plastic, glass etc.

36. BIOLOGIC CARCINOGENESIS

37. Biologic Carcinogenesis • Biologic agents are involved in the development of carcinogenesis. • Most commonly –Viruses • Other egs. of biologic agents – parasites, fungus, bacteria. • Parasites: Schistosoma haematobiuminfection of the urinarybladder -squamous cell carcinoma of the urinary bladder. • Fungus: Aspergillus flavusgrows in stored grains – hepatocellular carcinoma. • Bacetria:Helicobacter pylori causes peptic ulcer, prolonged infection leads to gastric carcinoma.

38. Viral Carcinogenesis • The role of viruses in the causation of cancer is more significant. Therefore, biologic carcinogenesisis largely referred as viral carcinogenesis. Routes of transmission of oncogenic viruses

39. TYPES OF ONCOGENIC VIRUSES RNA oncogenic viruses are also called as Retroviruses

40. PRIMARY VIRAL INFECTIONS • Infection last for few days to few weeks • Produces clinical manifestations • Cleared by body’s immune system • PERSISTENCE OF VIRAL INFECTION OR LATENT INFECTION • Viruses acquire mutations & resist immune attack by the host orinduces immunosuppression in the host such as HIV.

41. Examples of oncogenic viruses • Hepatitis B virus: Hepatocellular carcinoma • Human papilloma virus: Cervical cancer, skin cancer.