Neoplasia Etiology and pathogenesis of cancer

1. Neoplasia-2 Etiology and pathogenesis of cancer S . Parasuraman Faculty of Pharmacy AIMST University

2. Cancer incidence World wide cancer related death – 20 % In US- cancer is second most common cause of death Most common cancer in developed countries are lung, breast, prostate and colorectal Most common cancer in developing countries are liver, cervical and oesophageal . Following life-style factor attributing cancer worldwide: tobacco use , alcohol abuse , obesity , physical inactivity, low fiber diet, unprotected sex , polluted air, indoor household smoke and contaminated injections.

3. Cancer incidence S.No Men Women Children (under 20) 1 Lung Breast Acute leukaemia 2 Prostate Lung CNS tumour 3 Colorectal Colorectal Bone sarcoma 4 Urinary bladder Endometrial Endocrine 5 Lymphoma Lymphoma Soft tissue sarcoma Five most common primary cancers in the world (descending order)

4. Epidemiologic factors Predisposing factors Familial and genetic factors Racial and geographic factors Environmental and cultural factors Age and gender Chronic non-neoplastic (pre-malignant) conditions Carcinoma in situ Benign tumour Miscellaneous conditions Role of hormones in cancer Oestrogen Contraceptive hormones Anabolic steroids Hormone-dependent tumor

5. Epidemiologic factors Predisposing factors Familial and genetic factors: Risk of developing first degree relatives of cancer patient is 3 times higher as compare to control Genetic cancer comprise not greater than 5 % of all cancer. E.g.: 49% of retinoblastoma are inheritance (missing of RB gene in chromosome 13), 100% of familial Polyposis coli develop cancer of the colon, neurofibromatosis or von Recklinghausen’s disease (50% inheritance), cancer of breast (2-6 times higher risk than normal; inherited breast cancer- 5-10%,; mutant genes- BRCA-1 and BRCA-2 .)

6. Epidemiologic factors Predisposing factors Racial and geographic factors White Europeans and Americans Lungs, breast and colon; Breast cancer common in Americans but uncommon in Japanese Black Africans Skin, penis, cervix and liver Japanese 5 times higher incidence of carcinoma of the stomach than the Americans South-East Asians Chinese - nasopharyngeal cancer Indians Higher incidence of carcinoma of the oral cavity and upper aerodigestive tract; female- carcinoma of uterine cervix, breast. Cancer of liver (HBV and HCV viral hepatitis)

7. Epidemiologic factors Predisposing factors Environmental and cultural factors Cigarette smock: cancer of oral cavity, pharynx, larynx, oesophagus , lungs, pancreas and urinary bladder Alcohol and tobacco together: risk of developing cancer of the upper aerodigestive track Cancer of cervix: age at first coitus, frequency of coitus, multiplicity of partners and parity Penile cancer: rare in the Jews and Muslims. Carcinogenic compound smegma plays a role in etiology of cancer Betel nut cancer: common in some part of India due to habitual of keeping the bolus of pann in particular place of mouth for a long time

8. Epidemiologic factors Predisposing factors Age and gender Age is most significant factor for cancer (two-third of all cancer occur above 65 yr of age) Cancer in advanced age may be due to alterations in the cells of host, longer exposure to the effect of carcinogen, or decreased ability of the host immunity Tumours in infancy and childhood: Neuroblastoma , nephroblastoma , rhabdomyosarcoma , Ewing’s sarcoma, teratoma and CNS tumours . Apart form malignant tumours , most tumours are common for men than in women except cancer of the breast Breast cancer: throughout the world common for women Lung cancer: common for men

9. Epidemiologic factors Chronic non-neoplastic (pre-malignant) conditions Carcinoma in situ Malignancy are present in epithelium without invasion across the basement membrane Common sites for carcinoma in situ are uterine cervix, Bowen’s disease of the skin, oral leukoplakia, intralobular and intraepithelial carcinoma of the breast Benign tumour Benign tumour not become malignant excepts multiple villous adenomas of the large intestine (adenocarcinoma), neurofibromatosis ( neurofibrosarcoma ) Miscellaneous conditions Patients of long standing ulcerative colitis  colorectal cancer Cirrhosis of liver  hepatocellular carcinoma Chronic bronchitis in heavy cigarette  cancer of bronchus Old burn scar ( Marjolin’s ulcer)  squamous cell carcinoma

10. Epidemiologic factors Role of hormones in cancer Hormone sensitive tissues developing tumour are the breast, endometrium, myometrium, vagina, thyroid, liver, prostate and testis. Oestrogen therapy increase the risk of developing endometrial carcinoma Oral contraceptives increase the risk of developing breast cancer Anabolic steroids increase the risk of developing benign and malignant tumours

11. Carcinogenesis

12. Causes/ pathogenesis of cancer Carcinogenesis/ oncogenesis or tumorigenesis : mechanism of induction of tumours Three major type of carcinogens Chemical carcinogenesis Mutagens Chemical carcinogenesis and their metabolism Physical carcinogenesis (radiation) Ultraviolet radiation, Asbestos Infectious Pathogens (Viral) Human T-cell leukemia viruses, DNA viruses, Human papillomaviruses Epstein-Barr virus, Hepatitis B virus

13. Chemical carcinogenesis/ mutagens Two-step/ multistep process Initiation : causes permanent DNA damage (Mutation) Promotion (Proliferation ) INITIATORS Direct acting compounds: Direct acting carcinogens are bind covalently to cellular macromolecules. E.g . nitrogen mustard, bis ( chloro -methyl) ether, benzyl chloride, Epoxides Indirect acting carcinogen ( Procarcinogens ): Require metabolic conversion to form ultimate active carcinogen. PROMOTERS Can cause cellular proliferation & induce tumors in initiated cells, e.g estrogen but they are non tumorigenic by themselves. Proliferation of a mutated cell may lead to accumulation of additional mutations.

14. Chemical carcinogenesis/ mutagens E.g. for indirect-acting chemical carcinogens ( procarcinogens ) Polycyclic aromatic hydrocarbons  cigarette smoke  lung cancer Aflatoxin B 1  Fungi Aspergillus flavus (contamination of veg. food, peanuts)  liver cancer (Africa and Asia regions) Aromatic amines and Azo dues  bladder (aniline dye) and liver tumors. Nitrosamines: Nitrosamines (nitrosamine, dimethyl nitrosamine) are potent carcinogen, produce kidney, liver tumor and gastrointestinal cancers. Metals: Ni 2+ , Pb 2+ , Cd 2+ , Co 2+ and Be 2+ .

15. Test for chemical carcinogenesis Experimental induction Rodents are used Chemical (investigational product) administration  promoting agents administration  after study period animals are autopsied and results obtained. Test for mutagenicity (AMES’ test ) Check the mutation ability of a chemical to induce mutation in the mutant strain of Salmonella typhimurium

16. Factors influencing chemical carcinogenesis Metabolism of carcinogens: Most of the chemical carcinogen required metabolic activation. If carcinogen augmenting the detoxification pathways, reduce incidence of cancer . Sex and hormonal status: Pregnancy is associated with a decreased incidence of cancers of the breast, endometrium and ovary. Women who are borne children at an early age are at a lesser risk than nulliparous woman for cancers of the breast, endometrium and ovary . Early menarche, late menopause and later age of first pregnancy all increase the risk of breast cancer. Diet: Low-protein diet reduce the hepatic activity and decreased sensitivity to hepatocarcinogens . Obesity is associated with an increased number of tumors.

17. Physical carcinogenesis

18. Physical carcinogenesis Radiation- Ultraviolet light Causes: mutation, inhibits cell division and cell death MOA: formation of pyrimidine dimer Main source of UV light is sunlight, UV lamp and welder’s arcs Penetration of UV light protected by melanin pigmentation of the skin. Sun light  white race  basal cell carcinoma, squamous carcinoma and malignantmelanoma Sun light  darker races  protected by melanin pigment, which absorbs UV radiation Lifetime risk of 1 rad of whole-body x-ray or gamma-ray radiation is one excess cancer death per 10,000 person

19. Physical carcinogenesis Radiation- Ionising radiation X-rays, α - , β - and γ -rays , radioactive isotopes , protons and neutrons can cause cancer Image form ‘Essential Pathology for Dental Students’ by Harsh Mohan and Sugandha Mohan, 4 th ed. India

20. Physical carcinogenesis Non-radiation Physical Carcinogenesis Asbestos: A fibrous amphibole; used for making fireproof articles I nhaling a sbestos can cause lung cancer Source of inhalation: mining and manufacturing of asbestos installation of asbestos insulation air in the vicinity of asbestos plants contaminated air in buildings undergoing repair or demolition clothing of asbestos workers

21. Infectious Pathogens Virus Viral infection is responsible for 20% of human cancer worldwide RNA retrovirus HTLV-I  T-cell leukemia/ lymphoma (endemic in Japan, Africa, the Caribbean basin and southeastern United States) Human papillomavirus (DNA)  squamous carcinoma of the cervix Hepatitis B and C viruses  primary hepatocellular carcinoma Epstein-Barr virus (EBV)  lymphoma and nasopharyngeal carcinoma Human herpesvirus 8  kaposi sarcoma

22. Infectious Pathogens Bacteria Helicobacter Pylori (Gastric lymphoma, Mucosal Associated Lymphoid Tumor (MALT) & Gastric carcinoma) Fungi aflatoxins produced by Aspergillus flavus - hepatocellular carcinoma Parasites Schistosoma and Clonorchis sinensis Cancer inheritance Cancer inheritance: Genetic basis. E.g., Breast cancer (associated genes are BRCA-1 and BRCA-2)

23. Thank you

24. Tobacco-Related Cancers Lung cancer estimates for 2013 (Source: Cancer Facts & Figures 2013 ): New cases of lung cancer: 228,190 Males: 118,080 Females: 110,110 Deaths from lung cancer: 159,480 Males: 87,260 Females: 72,220 Tobacco use also increases the risk for cancers of the mouth, lips, nasal cavity (nose) and sinuses, larynx (voice box), pharynx (throat), esophagus (swallowing tube), stomach, pancreas, kidney, bladder, uterus, cervix, colon/rectum, ovary (mucinous), and acute myeloid leukemia . Tobacco use is responsible for nearly 1 in 5 deaths in US Tobacco use accounts for at least 30% of all cancer deaths and 87% of lung cancer deaths Back

25. Cancer induced by alcohol abuse: Mouth cancer Pharyngeal cancer (upper throat) Oesophageal cancer (food pipe) Laryngeal cancer (voice box) Breast cancer Bowel cancer Liver cancer Back

26. Cancer induced by obesity: 49 % of endometrial cancers are caused by excess body fat. esophageal cancer pancreatic cancer kidney cancer gallbladder cancer cases breast cancer cases colorectal cancer cases Back

27. Cancer induced by unprotected sex : HPV is a virus that's transmitted through sexual contact -- genital or oral Back