Dr S owmya U thaiah Assistant professor Dept of Pathology

1. Etiology and pathogenesis of neoplasia, premalignant lesions, physical, chemical & microbial carcinogens DrSowmyaUthaiah Assistant professor Dept of Pathology

2. Epidemiology of cancer • 12.7 million new cancer cases worldwide, leading to 7.6 million deaths (21,000 deaths per day) • Geographic variation in the incidence of specific cancers- differences in exposure to environmental carcinogens • Men - prostate, lung, and colon/rectum. • Women - cancers of the breast, lung, and colon/rectum

5. Race – • Disparity in cancer mortality rates between white and black americans • African americans – largest decline in cancer mortality during the past decade • Hispanics living in the united states - lower frequency of the most common tumors seen in the white non-hispanic population but a higher incidence of tumors of the stomach, liver, uterine cervix, gallbladder & leukemias.

6. Environmental Factors • Both genetic and environmental factors • Environmental influences appear to be the dominant risk factors

7. Wide geographic variation in the incidence of specific forms of cancer • most common tumor of men in the United States and developed world - prostate cancer • developing world- cancers of the liver, stomach, esophagus, bladder, lung, oropharynx, and the immune system • breast cancer - higher in women in developed countries than in developing world

8. Environmental factors affecting cancer risk are the following: • Infectious agents • 15% of all -directly or indirectly by infectious agents • three times higher in the developing world than in the developed world • Human papilloma virus (HPV)- sexual contact- cervical carcinoma and head and neck cancers

9. 2. Smoking • Cigarette smoking- most important environmental factor contributing to premature death in the United States • Lung cancer deaths (90%) • Cancer of the mouth • Pharynx • Larynx • Esophagus • Pancreas • Bladder

10. 3. Diet • wide geographic variation in the incidences of colorectal carcinoma, prostate carcinoma, and breast carcinoma 4. Obesity • weight is strongly associated with cancer risk • obese U.S. population have 52% (men) to 62% (women) higher death rates from cancer • approx14% of cancer deaths in men and 20% in women can be attributed to obesity.

11. 5. Reproductive history • Lifelong cumulative exposure to estrogen stimulation, particularly if unopposed by progesterone • risk of cancers of the breast and endometrium - tissues responsive to these hormones • timing and number of pregnancies a woman has during her lifetime - differences in breast cancer incidence

12. 6. Environmental carcinogens • Ultraviolet [UV] rays, smog • Drinking well water (eg: Arsenic, particularly in Bangladesh) • Medications (eg: Methotrexate) • Work - asbestos • Grilled meat, high-fat diet, alcohol “IT APPEARS THAT ALMOST EVERYTHING ONE DOES TO EARN A LIVELIHOOD OR FOR PLEASURE IS FATTENING, IMMORAL, ILLEGAL, OR, EVEN WORSE, CARCINOGENIC!”

14. Age • Most carcinomas occur in the later years of life (>55 years) • Cancer related death : women aged 40 to 79 and men aged 60 to 79 • Accumulation of somatic mutations over the years • Decline in immune competence with ageing • Cancer accounts for slightly more than 10% of all deaths in children younger than age 15 in the united states - acute leukemia and distinctive neoplasms of the central nervous system • Common neoplasms of infancy and childhood - so-called small round blue cell tumors such as neuroblastoma, wilms tumor, retinoblastoma, acute leukemias, and rhabdomyosarcomas.

15. Acquired Predisposing Conditions 1. Chronic inflammation 2. Precursor lesions 3. Immunodeficiency states

16. Chronic inflammation and cancer • First proposed by virchow in 1863 • Tissue injury----- compensatory proliferation of cells -----repair the damage----- increase the pool of tissue stem cells----- susceptible to transformation. • Activated immune cells-----reactive oxygen & inflammatory mediators----- directly genotoxic----- genomic damage • Chronic epithelial injury----- metaplasia Eg: Helicobacter pylori gastritis – gastric cancer

18. Precursor lesions and cancer • Precursor lesions can be defined as localized morphologic changes that are associated with a high risk of cancer • Barrett esophagus - gastric and colonic metaplasia of the esophageal mucosa in gastric reflux • Squamous metaplasia • Bronchial mucosa - smoking • Bladder mucosa - schistosomiasisinfection • Colonic metaplasia of the stomach – pernicious anemia and chronic atrophic gastritis

19. Leukoplakia - thickening of squamous epithelium in oral cavity, penis or vulva ---squamous cell carcinoma. • Endometrial hyperplasia----non inflammatory hyperplasias- sustained estrogenic stimulation of the endometrium--- endometrial carcinoma • Colonic villous adenoma – colon carcinoma

20. Immunodeficiency states and cancer • T-cell immunity deficient individuals- cancers- oncogenic viruses. – - lymphomas - carcinomas - sarcomas - sarcoma-like proliferations

21. Physical, chemical and microbiological carcinogenesis DrSowmya B U Assistant professor Dept of Pathology

22. Physical carcinogens- Radiation Carcinogenesis 1.UV rays of sunlight • 2.Ionizing electromagnetic 3.Particulate radiation

23. Ultraviolet Rays • Derived from the sun • Fair-skinned individuals • Squamous cell carcinoma • Basal cell carcinoma • Melanoma of the skin Factors affecting • type of UV rays • the intensity of exposure • quantity of the light-absorbing “protective mantle” of melanin in the skin

24. Non-melanoma skin cancers - total cumulative exposure to UV radiation • Melanomas - intense intermittent exposure – eg: sunbathing • UVB - induction of cutaneous cancers • UVC - potent mutagen but filtered out by the ozone layer

25. energy in a photon of UV light is absorbed by DNA Carcinogenicity of UVB light • Formation of pyrimidine dimers in DNA Chemical reaction leads to covalent crosslinking of pyrimidine bases, particularly adjacent thymidine residues in the same strand of DNA distorts the DNA helix prevents proper pairing of the dimer with bases in the opposite DNA strand

26. Pyrimidine dimers are repaired by the nucleotide excision repair pathway • Excessive sun exposure---- capacity of the nucleotide excision repair pathway is overwhelmed --- error-prone nontemplated DNA-repair mechanisms----survival of the cell at the cost of genomic mutations ----- lead to cancer

27. Ionizing Radiation • Electromagnetic (x-rays, γ rays) and particulate (α particles, β particles, protons, neutrons) • X-rays - skin cancers • Miners of radioactive elements in central Europe and the Rocky Mountain region of United States- 10 fold increase lung cancers • Hiroshima and Nagasaki- leukemias, carcinomas of the breast, colon, thyroid, and lung • Computerized tomography (CT scans)- children • 2-3 scans - 3 fold higher risk of leukemia • 5-10 scans - 10 fold higher risk of brain tumors

28. Ionizing radiation induced cancers • Myeloid leukemias – MC • Cancer of the thyroid (young) • Cancers of the breast, lungs, and salivary glands • Skin, bone, gastrointestinal tract – rare “practically any cell can be transformed into a cancer cell by sufficient exposure to radiant energy”

29. Chemical carcinogenesis

30. Carcinogens

31. Major Chemical Carcinogens • Direct-Acting Carcinogens • Alkylating Agents • Anticancer drugs (cyclophosphamide , chlorambucil, nitrosoureas) • β-Propiolactone, Dimethyl sulfate, Diepoxybutane • Acylating Agents • 1-Acetyl-imidazole, Dimethylcarbamyl chloride • Procarcinogens That Require Metabolic Activation • Polycyclic and Heterocyclic Aromatic Hydrocarbons • Benz(a)anthracene, Benzo(a)pyrene, Dibenz(a,h)anthracene, • 3-Methylcholanthrene, 7,12-Dimethylbenz(a)anthracene • Aromatic Amines, Amides, Azo Dyes • 2-Naphthylamine (β-naphthylamine), Benzidine, 2-Acetylaminofluorene, Dimethylaminoazobenzene (butter yellow) • Natural Plant and Microbial Products • Aflatoxin B, Griseofulvin, Cycasin, Safrole, Betel nuts • Others • Nitrosamine and amides, Vinyl chloride, nickel, chromium, Insecticides, fungicides, Polychlorinated biphenyls

32. Carcinogenic chemicals Direct acting alkylating agents • Activation dependent, weak carcinogens • Used as anticancer drugs • Induce lymphoid neoplasms, leukemia etc., • Powerful immunosuppressive agents • Ex: Cyclophosphamide Busulfan • Interact with DNA and damage

33. Carcinogenic chemicalsPolycyclic aromatic hydrocarbons • Source: combustion of smoke, smoked meat, animal fat processing , broiled meat, smoked fish • Induce lung and bladder cancer • Most potent carcinogens known • Require metabolic activation • Skin paint- skin cancer • Subcutaneous injection-sarcoma

34. Carcinogenic chemicalsAromatic amines & azo dyes • Source: food coloring agents Eg: Butter yellow, Scarlet red • Beta naphthylamine– rubber industry- bladder cancer.

35. Carcinogenic chemicalsNaturally occurring carcinogens • Source; moldy grains, peanuts, rice-aspergillusflavus- aflatoxin B1. • Potent hepatocarcinogen • Correlates with increased incidence in china/ Africa.

36. Carcinogenic chemicalsNitrosamines and amides • Source: Nitrostable amines and nitrates used as food preservative- bacteria convert them to nitrites • Induce gastric cancers

37. Carcinogenic chemicals miscellaneous agents

38. Initiation • Induction of mutation in genome of cells • Initiated cells are not transformed cells • They have no growth autonomy/unique phenotypic #. • In contrast to normal cells, can give rise to tumors when appropriately stimulated by promoting agents

39. Promotion of carcinogenesis • Process of tumor induction in a previously initiated cell by chemicals. • The effect of promoters is short lived and reversible. • They do not affect DNA. • Non tumorigenic by themselves. Eg: Phenols, artificial sweeteners • No sudden change • Need sufficient time and dose • Changes reversible • Enhance the effect of carcinogens • Acts through growth factor pathway

40. Promotion of carcinogenesis • Tumor promotion steps- multiple steps • Proliferation of preneoplastic cells • Malignant conversion • Tumor progression (depends on cells & stroma) • Involved in clonal expansion and aberrant differentiation of initiated cells • The effect of promoters are pleiotropic • Induction of cell proliferation is a sine qua none phenomenon of promoters • They act via signal transduction pathways eg. protein kinase C • Activation of PKC - series of phosphorylations- cell proliferation and differentiation

42. Chemical Carcinogen - Mechanism • Reactive electrophiles • Electron deficient substances • Binds with electron rich portions of cells (DNA) • Target molecules • DNA – mutation - carcinogenesis • Initiated cell Unrepaired DNA damage One cycle of proliferation Irreversible damage Vulnerable to promotion

43. Concept of initiation and promotion sequence • Initiation - exposure of cells to sufficient dose of carcinogen • Potential to induce tumor • Initiation alone is insufficient • Permanent DNA damage- mutation. • Rapid and irreversible • Promoters can induce tumor in an initiated cell, by themselves are not tumorigenic • The cellular changes resulting from application of promoters do not affect DNA directly and are reversible.

44. Property of direct acting & ultimate carcinogens • Require no metabolic conversion • Highly reactive electrophiles (electron deficient) react with nucleophilic ( electron rich) sites in the cell. • Non enzymatic reactions- covalent adducts b/n carcinogen & nucleotide DNA. • Electron rich sites in cell; DNA, RNA,proteins

45. Indirect – acting carcinogens- Metabolic action of carcinogens • Most carcinogens need activation to form ultimate carcinogens • Other metabolic pathways detoxify (eg: cytochrome P-450- dependent mono-oxygenases) • Carcinogenic potency a) inherent reactivity of electrophilic derivative b) balance b/n metabolic activation and inactivation. • Carcinogenesis is regulated in part by polymorphism in the genes that encode the genes • Age, sex and nutritional status determine the internal dose of toxicants

46. Molecular targets of chemical carcinogens • Mutations affecting oncogenes,tumor suppressor genes and genes that regulate apoptosis and genes involved in DNA repair • DNA is the primary target • No single or unique alteration @ with initiation • Each class of carcinogen produces limited pattern of DNA damage • Each carcinogen produces molecular ‘fingerprint’ that links specific chemical with their mutational effect.

47. Initiated cell • Unrepaired DNA alterations are essential first step in initiating tumor • Damaged DNA template must replicate to be inheritable and permanent • Quiescent cells may never be affected by carcinogens, unless mitogenicallystimulated • Concurrent exposure to viruses, parasites, hormones induce proliferation

48. Tests for Chemical Carcinogenecity • Experimental induction • Animals: Initiator……Promoter • Tests for mutagenicity (Ames Test) • In vitro test • Ability of potential carcinogens to induce mutations in selected strains of salmonella typhimurium

49. Microbiological carcinogenesis

50. Microbiological Carcinogens • Oncogenic Viruses • DNA • Human Papilloma Virus Papilloma, Ca. of cervix, skin • EB virus Lymphoma, Nasopharyngeal carcinoma • HHV 8 Kaposi sarcoma, B cell lymphoma • Hepatitis B Hepatocellular carcinoma • Pox virus Molluscumcontagiosum, Papilloma • RNA • HTLV 1 Adult T cell Leukemia/Lymphoma • HTLV 2 T cell variant of Hairy cell leukemia • Hepatitis C Hepatocellular carcinoma • Oncogenic Bacteria • H. pylori Gastric lymphoma, Adenocarcinoma