16 CARCINOGENESIS.pptx

Cancer

1. CARCINOGENESIS Surg Capt Ritu Mehta

2. Carcinogenesis P rocess by which a normal cell is transformed into a malignant cell

3. Molecular hallmark of cancer Self sufficiency in growth signals Insensitivity to inhibitory signals Altered cellular metabolism Evasion of apoptosis Sustained angiogenesis Ability to evade and metastasize Ability to evade host immune response

4. Proto- oncogenes - Normal cellular genes whose products promote cell proliferation Oncogene Mutated or overexpressed version of proto-oncogene Function autonomously No dependence on normal growth promoting signals Oncoproteins Proteins encoded by oncogenes

5. Types Chemical Carcinogenesis (a) Direct acting carcinogens (b) Indirect acting carcinogens Radiational Carcinogenesis (a) UV Rays (b) Ionizing Radiation Microbial Carcinogenesis (a) Viral (c) Fungal (b) Bacterial (d) Parasitic

6. Chemical Carcinogenesis

7. Types of chemical carcinogenesis Initiators P romotors

8. Chemical Carcinogenesis

9. Initiator Initiation- results from exposure of cells to a sufficient dose of carcinogenic agent It becomes altered cells which is potentially capable of giving rise to a tumor Not sufficient for tumor formation Causes permanent DNA damage

10. Promotor Promotor should act after initiator Don't affect DNA and are reversible Tumor don’t occur when promoting agents are applied before initiating agents

11. INITIATOR CARCINOGEN 1. Induction of Mutation 2. Single dose 3 . Sudden response 4 . Irreversible 5. Acts first 6 . Effective alone 7 . Direct and indirect carcinogens PROMOTOR CARCINOGEN 1. Non Mutagenic 2. Repeated dose 3 . Gradual response 4 . May be reversible 5 . Acts afterwards 6 . Not effective alone 7 . P horbol esters, P henol, P henobarbitone , Hormones, Misc.

12. Types of initiator Direct acting agents - require no metabolic conversion to become carcinogenic Indirecting acting ag ents- chemicals that require the metabolic conversion to ultimate carcinogen before they become active

13. Direct Initiators

14. Indirect Initiators

15. Polycyclic Aromatic Hydrocarbons Present in fossil fuels Present in smoked meats and fish- produced during broiling and grilling meats Benzo [alpha] pyrene – formed during high temperature combustion of tobacco in cigarettes and causes Lung Cancer Aromatic Amines and Azo Dyes Used in Aniline dye and rubber industries

16. What does carcinogens do? Causes mutation through out genome Damage to oncogenes and tumor suppressor genes Carcinogens interact with particular DNA sequences

17. The commonly mutated oncogenes and tumor suppressor are RAS and p53

18. FACTORS AFFECTING CHEMICAL CARCINOGENESIS Two most important ones are Metabolism of carcinogens Molecular targets of carcinogens

19. METABOLISM Most indirect carcinogens metabolised by cyt P-450 dependent monooxygenases .

20. Molecular Targets Because of their chemical structure some carcinogens cause mutations in particular DNA sequence K/A Hotspots e.g. Aflatoxin B1 related HCC shows specific mutation in p53 gene while non aflatoxin HCC shows no mutation of p53.

21. OCCUPATIONAL CANCERS Agent and its typical use 1.) Arsenic - alloys 2.) Asbestos- floor tile underlaying 3.) Benzene - paint, printing 4.) Cadmium - batteries 5.) Nickel - batteries 6.) Chromium - paint, pigments 7.) PVC - adhesive for plastic Human Cancers caused by it Lung & skin CA Lung, esophageal, gastric, colon CA &Mesothelioma AML Prostate CA Lung CA Lung CA Hepatic angiosarcoma

22. Radiation carcinogenesis It is in the form of UV rays of sunlight or as ionizing electromagnetic and particulate radiation is mutagenic

23. Radiational Carcinogenesis Ultraviolet Rays Ionising Radiation

24. Marie Curie and Irene ?

25. UV Radiation

26. Factors determining the Risk of cancer Type of UV rays exposure UV-C:- Highest risk but screened by Ozone UV-B:- Causes cutaneous cancers The intensity of exposure Non Melanomatous skin cancers –Risk is * to total cumulative exposure to UV rad i.e. lifetime sun exposure Melanomas- Intense excessive exposure as in sun bathing Quantity of Melanin in skin Fair skinned /Dark skinned Inherited disorders of NER mechanism Xeroderma Pigmentosum

27. UV Radiation induced Cancers 1. Squamous Cell Ca 2. Basal cell CA 3. Malignant Melanoma

28. Mechanism of Carcinogenesis

29. Formation of pyrimidine molecules Chemical reaction leading to cross linking of pyrimidine bases Distortion of DNA helix Distorted DNA repair Repeated sun exposure causes activation of error prone non templated DNA repair mechanism- mutations in the cell

30. Ionizing Radiation Electromagnetic Radiation (a) X Rays (b) Gamma Rays (c) Radiofrequency radiation Particulate Radiation (a) Alpha Particles (b) Beta Particles (c) Protons (d) Neutrons

31. Sources of Ionising Radiation NATURAL Cosmic Rays - sun Terrestrial Radiation - Uranium, Thorium, Radon Inhalation - Radon gas, Thoron gas Ingestion - Red meat, Carrot, White Potato, Banana, Brazil Nuts ARTIFICIAL Medical - X Rays, Nuclear Medicine, CT Scans Industrial - Smoke detectors, Nuclear and Density Gauges Nuclear sources - Nuclear power plants, Yellow cake

32. Order of Occurrence of Radiation induced cancers Most frequent Leukemia Thyroid cancers Intermediate frequency Ca Breast Ca Lung Salivary gland Tumors Least frequent Skin cancers Bone tumors GIT cancers

33. Microbial Carcinogenesis

34. Microbial Carcinogenesis 1. Viral RNA Viruses ( i ) Human T Cell Lymphotropic Virus-1 (ii) HCV DNA Viruses ( i ) HPV (ii) EBV (iii) HBV (iv) Merkel Cell Polyoma Virus (v) Kaposi Sarcoma Virus (HHV-8)

35. 2. Bacterial H . pylori 2. Parasitic Schistosoma haematobium 3. Fungal Aspergillus flavus

36. Viral Oncogenesis

37. Human T Cell Lymphotropic Virus-1 Ss RNA Retrovirus Only retrovirus causing human cancers In 3%-5% of infected individuals- Adult T Cell Leukemia/Lymphoma ( ATLL ) 15-20 Million remain infected world wide Endemic in : Japan, Caribbean, South America & Africa Sporadic elsewhere Long latency of 40-60 years after infection Has CD4+ tropism

38. HTLV-1 Routes of Transmission (Transfer of T cells) Sexual route Blood Products Breast Feeding Mechanism for oncogenesis HTLV-1 genome has- gag, pol, env , tax, HBZ genes Tax- Essential for viral replication HBZ- Alters the transcription of host genes

39. HEPATITIS C VIRUS SS RNA virus Leads to cell mediated immune reactions Hepatocellular injury HCC

40. Human Papilloma Virus DNA Virus Atleast 70 Types described Low risk HPVs: 1,2,4,6,7 & 11 (a) Benign squamous papillomas (Warts) High Risk HPVs : 16, 18, 31 & 33 (a) Ca Cervix (b) SCC anogenital region (c) Head and neck cancers ( tonsillar mucosa) Sexually Transmitted

41. HPV Carcinogenesis

42. HPV Carcinogenesis

43. EBV Burkitt Lymphoma (African Form) B cell Lymphomas in Immuno suppressed (HIV/Post organ Transplant immunosuppresssion ) Hodgkin’s Lymphoma Nasopharyngeal Ca Gastric Carcinoma T cell Lymphoma NK Cell Lymphoma

44. Oncogenesis by EBV Surface glycoproteins of EBV attach to CD21 Oncogenesis is by 3 genes- LMP-1, EBNA-2, vIL-10 LMP-1:- An oncogene acting like CD40 Activates BCL-2 , preventing apoptosis EBNA-2: Activates Cyclin -D vIL-10:- Suppresses activation of T-Cells

45. Burkitt Lymphoma B Cell Lymphoma Endemic form Central Africa, New Guinea ( Most common childhood tumor) > 90% A frican tumors carry EBV genome 100% patients have elevated antibody titres against EBV capsid Ags Serum Ab titres are correlated with risk of tumor Sporadic form 15-20 % only show EBV genome The Exact mechanism involved is unknown t (8;14)

46. EBV positive B Cell Lymphomas in Immunosuppressed Immunosuppressed HIV Post organ/BM transplant immunosuppression Arises at multiple sites: Gut, CNS etc Consistently Express- LMP1 & EBNA 2 Lack MYC translocations

47. Nasopharyngeal Carcinoma Endemic form Southern China Parts of Africa 100% of NPCs contain EBV genome Abs against EBV elevated Ig A antibodies appear before the tumor in endemic areas Express LMP-1, EBNA 2 & PDL-1

48. Hepatitis B Virus 70%-85% HCCs are attributable to HBV & HCV infections Exact Mode of oncogenesis not fully known But seems to be immunologically mediated .

49. Chronic viral infection Plethora of GF, Cytokines, Chemokines Compensatory proliferation of hepatocytes & Release of ROS- genotoxic and mutagenic HCC HBX gene of HBV activates transcription factors

50. Merkel cell Polyomavirus Merkel Cell Carcinoma (Skin cancer) Kaposi Sarcoma Virus (HHV 8) - Kaposi Sarcoma Primary effusion lymphoma Multicentric Castleman’s disease - lymphoproliferative disorder.

51. Helicobacter Pylori First Bacteria classified as a carcinogen Implicated in Gastric Adenocarcinoma Gastric Lymphoma ( MALToma ) Gastric Ca occurs in 3% of infected individuals

52. Oncogenesis mechanism same as HBV- Chronic inflammation increased epithelial cell proliferation ROS Mutagenic Cag A gene - penetrates gastric epithelial cells

53. H Pylori: Gastric Lymphoma B cell Origin Location- Stomach They resemble the Payer’s patches origin: MALToma H Pylori reactive T-Cell mediated stimulation of B Cells Initially Curable But later not amenable Later becomes T cell independent Lymphoma

54. PARASITIC Schistoma haematobium -SCC of urinary bladder

55. FUNGAL Aspergillus flavus - Grows in stored grains - Liberates Aflatoxin - Causes HCC

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