Section 12   Etiology and Oncogenesis of Tumors

Section 12 Etiology and Oncogenesis of Tumors PowerPoint PPT Presentation

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Acquired (environmental) DNA damaging agents:ChemicalsRadiationviruses. . Normal cell. . . DNA Damage. . Mutations in the genome of somatic cells. . . . Activation of growth- promoting oncogenes. Alterations of genes that regulate apoptosis. Inactivation of cancer suppressor genes. . . . Expressi

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Section 12 Etiology and Oncogenesis of Tumors

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1. Section 12 Etiology and Oncogenesis of Tumors

3. 1. Molecular Basis of Tumor Nonlethal genetic damage lies at the core of carcinogenesis Four classes of regulatory genes, protooncogene, cancer suppressor gene, regulated apoptosis gene, and DNA repair gene, are the principal targets of genetic damage. Carcinogenesis is a multistep process at both the phenotypic and genetic levels.

4. (1) Oncogenes and cancer ? Protein products of oncogenes a. Growth factors b. Growth factors receptors c. Signal transducing proteins d. Nuclear transcription proteins e. Cyclones and cyclic-dependent kinases

5. ? Activation of oncogenes a. Point mutations b. Chromosome rearrangements Translocations Inversions C. amplification

9. Table Selected oncogenes their mode of activation and associated human tumors

13. ?????????????????????? ?????? ???? ???? ?????? ????: PDGF-Ŗ? sis ???? ????????? FGF HST-1 ???? ?? INT-2 ?? ???????????? TGF-a TGF-a ???? ?????????? HGF HGF ???? ???? ??????: EGF???? erb-B1(ECFR) ???? ????????? erb-B2 ?? ??????? CSF-1?? FMS ??? ??? ???????? RET ??? ????????2A?B, ????????? PDGF?? PDGF-R ???? ????? ??????? KIT ??? ??????????????? ??????: GTP???? K-RAS ??? ????????? H-RAS ??? ?????? N-RAS ??? ??????????????? ???????? ABL ?? ??????????????????? RAS???? BRAF ??? ???? WNT???? Ŗ-catenin ??? ???? ?????????? ?????: ?????? C-MYC ?? ?????? N-MYC ?? ???????????? L-MYC ?? ????? ???????: ????? Cyclin D ?? ?????? ?? ??????? Cyclin E ???? ??? ??????? CDK4 ?????? ?????????????? (??Robbin Pathologic Basis of Disease,2005)

14. (2) Cancer suppressor genes ? Molecules that regulated nuclear transcription and cell cycle Rb gene: 13q14, G1 ◊ S P53 gene: 17p13.1, related to 50% of human tumors BRCA- l gene: 17q12-21, BRCA-2 gene: 13q12-13

15. ? Molecules that regulated signal transduction NF-1 gene: 17q11.2 APC gene: 5q21

16. ? Cell surface receptors SMAD2 gene: SMAD4 gene: DCC gene: 18q21

17. ? Other tumor suppressor genes NF- 2 gene VHL gene: 3p PTEN gene: 10q23, WT- 1 gene: 11p13

19. Selected tumor- suppressor genes involved in human neoplasms

22. (3) Genes that regulate apoptosis Inhibit apoptosis: bc1- 2 gene (18q21), bc1-Xl Favor apoptosis: bax, bad, bc1-xS

24. (4) Genes that regulate DNA repair Humans literally swim in a sea of environmental carcinogens. Although exposure to naturally occurring DNA- damaging agents, such as ionizing radiation, sunlight, and dietary carcinogens, is common, cancer is a relatively rare outcome of such encounters.

25. This happy state of affairs results from the ability of normal cells to repair DNA damages and thus prevent mutations in genes that regulate cell growth and apoptosis. In addition to possible DNA damage from environmental agents, the DNA of normal dividing cells is also susceptible to alterations resulting from errors that occur spontaneously during DNA replication. Such mistakes, if not repaired promptly, can also push the cells along the slippery sloe of neoplastic transformation.

26. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Those born with such inherited mutations of DNA repair proteins are at a greatly increased risk of developing cancer. Several examples are discussed next.

27. (5) Telomere and tumor telomerase activity increased in majority of human tumors.

29. (6) Molecular Basis of Multistep Carcinogenesis

30. 2. Carcinogenic agents A large number of agents cause genetic damage and inchece neoplastic transformation of cells (1) Chemical carcinogens Chemical carcinogenesis is also a multistep process.

31. ? Inition of carcinogensis Chemical carcinogens are diverse in structure, but they fall into one of two categories: a. Direct-acting chemical carcinogenes b. Indirect-acting chemical carcinogens (procarcinogenes), Which require metabolic conversion in vivo to produce. Ultimate carcinogens capable of transforming cells.

32. Both of them are highly reactive electrophiles that can react with nucleophilic (electron-rich) sites in the cells. These reactions are nonenzymatic and result in the formation of covalent adducts between the chemical carcinogen and nucleotide in DNA.

33. The carcinogenic potency of a chemical is determined not only by the inherent reactivity of its electrophilic derivative, but also by the balance between metabolic activation and inactivation reactions. If initiation occurs, carcinogen-altered cells could be heritable.

34. ? Promotion of carcinogenesis Promoters earn induce tumors in initiated cells, but they are nontumorigenic by them selves. Prompters render cells susceptible to additional mutations by causing cellular proliferation.

36. Major Chemical carcinogens ? Direct acing alkylating agents(???) a. In general they are weak carcinogens. But they are important because many of them are anticancer drugs. b. e. g. Cyclophosphamide(????), Chlorambucil, busulfan, melphalan. c. Induce: lymphoid neoplasms, leukemia

37. ? Polycyclic aromatic hydrocarbons (????) a. The most potent carcinogens. b. Require metabolic activation c. Can induce tumors in a wide variety of tissues and species.

38. ? Aromatic amines(???) and azo dyes a. Mainly in liver b. Can induce hepatocellular carcinomas and bladder cancer

39. ? Naturally occurring carcinogens Aflatixi(?????)B1 and HBV related to hepatocellular carcinoma ? Nitrosamine(???) and amides Related to gastric carcinoma

40. ? Miscellaneous agents a. Asbestos associated with increased incidence of bronchogenic carcinomas, mesotheliomas, gastrointestinal cancers b. Chromium, nickel, and other metals, when volatilized and inhaled, have caused lung cancer c. Arsenic associated with skin cancer

41. ? Promoters of chemical carcinogenesis a. Hormones: e. g. estrogens as promotes of liver tamers, postmenopausal endometrial carcinoma b. Bile salts: high levels of dietary fat associated with increased risk of colon cancer that may be related to more bile acids.

42. (2) Radiation carcinogenesis ? UV light is clearly implicated in causation of skin cancers; Ionizing radiations, atomic bomb have produced a variety of forms of malignant neoplastic, especially in leukemia lymphoma, thyroid cancers ? Radiation may inhibited cell division, inactive enzymes, induce mutations.

43. (3) Viral carcinogens ? RNA oncogenic viruses a. Acute transforming viruses Which containing viral oncogene (src, abl, myb) may directly trans form human oncogenes b. Slow transforming viruses Which not containing viral oncogene may insert the sites that nearby human oncogene and make them overdressed now only human fell leukemia virus type 1 (HTLV-1) is firmly implicated in the causation of human caner

44. ? DNA oncogenic viruses Transforming DNA viruses form stable association with the host cell genome and are important for cell transformation.

45. a. Human papillomavirus (HPV) HPV-1, 2, 4, 7 can cause benign squamous papillomas in human; HPV-16, 18 are found in approximately 85% of severe squamous dysplasias, carcinoma in situ, and invasine squamous cell can cars. E6, E7 proteins of HPV-16, 18 E6 protein can degrade the P53 gene product ; E7 protein may bind to the underphosphorylated form of the tumor- suppressor protein PRb.

46. b. Epstein-Barr virus (EBV) EBV has been implicated in pathogenesis of four human Tumors: Burkitt lymphoma, B-cell lymphoma, Hodgken disease and nasopharyngeal carcinoma. c. Hepatitis Ŗ virus (HBV) Epidemiologic studies strongly suggest a close association between HBV infection and the occurrence of liver cancer.

47. 3. Influence factors of oncogenesis and development (1) Heredity factors ? Autosomal dominant inherited cancer syndromes Familial retinoblastoma Familial adenomatous polyps of the colon Multiple endocrine neoplasia syndromes Neurofibromatosis types 1 and 2 Von Hipped- Lindace syndrome(cerebellar hemengioblastomas, retinal angiomas, epididymal tumors)

48. ? Familial cancers Breast cancer, ovarian cancer Colon cancer other than familial adenomatous polyps They are associated with specific marker phenotype. Some of them may be linked to the inheritance of mutant genes.

49. ? Autosomal recessive syndromes of defective DNA repair gene xeroderma pigmentosum: ?????? ???????,?????,???? Ataxia-telangiectasia:?????????,?????,??? Bloom syndrome:????????????,?????????????,?????? 15q26.1. ?????,???? Fanconi anemia:????????????????????,???????

50. (2) Host defense against tumors- Tumor immunity ? Tumor antigen a. Tumor- specific antigen (TSA) b. Tumor- associated antigen (TAA)

51. Embryonic antigens: e. g. AFP, CEA Differentiation antigens: CD10 Tissue-specific antigens: e. g. tyrosinase Antigens resulting from mutations: e. g. mutatead P53, K-ras, CDK4 Overexpressed antigens: e. g, c-erbB2 protein Viral antigens: e. g. E7

52. ? Antitumor effector mechanisms Both cell-mediated and humoral immunity can have antitumor activity. a. Major immune antitumor cells: Cytotoxic T lymphocytes Natural killer cells Macrophages

53. b. Immunosurveillance The tumor cells have developed mechanisms to escape from the immune system in hosts. Selective outgrowth of antigen-negative variants Loss or reduced expression of histocompatibility antigens Lack of costimulation Immunosuppression Apoptosis of cytotoxic T cells.

54. (3) The Others ? Endocrine ? Sex ? Age ? Ethnic ? Geography

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