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Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors 1. aging

Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors 1. aging 2. biochemistry 3. genes 4. hormones. Exogenous factors 1. viruses (HPV, HBV, HTLV) 2. DNA reactive carcinogens a.   lifestyle 1.       food – heterocyclic amines, aflatoxin

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Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors 1. aging

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  1. Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors 1. aging 2. biochemistry 3. genes 4. hormones

  2. Exogenous factors 1. viruses (HPV, HBV, HTLV) 2. DNA reactive carcinogens a.   lifestyle 1.       food – heterocyclic amines, aflatoxin 2.      water – arsenic (?) 3.       air – smoke 4.      solar radiation b.      occupation 1.       radiation 2.      chemicals 3.       minerals/asbestos 4.      metal dusts c.      iatrogenic 1.      topoII-inhibitors 2.      alkylating agents 3.       radiation d.     transplacental 1.       DES 2. TopoII-inhibitors

  3. What causes cancer? 3. promoters - estrogen 4. co-carcinogens – toxins/mitogens

  4. What suppresses cancer in humans?A. Exogenous 1. NSAID – COX2 2. tamoxifen/raloxifen – estrogen antagonists 3. vitamin A analogs – retinoidsB. Endogenous 1.      DNA repair – p53 as guardian of the genome 2.      immunity 3.      angiostatin (?) 4. tissue microenvironment

  5. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

  6. Sites of alkylation of DNA

  7. DNA strand scission by topoII poisons

  8. Mechanisms of chemical carcinogenesis Steps and stages initiation promotion progression metaplasia/hyperplasia dysplasia neoplasia/anaplasia

  9. Initiation and promotion of murine epidermal carcinogenesis

  10. Initiation – permanent heritable alteration Uptake Metabolic activation Adduction Fixation

  11. Consider two prototypic lung carcinogens benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) MetabolismDNA damageDNA repair

  12. benzo[a]pyrene Metabolism by Cytochrome p450 and Epoxide hydratase benzo[a]pyrene diolepoxide DNA adduct of BP

  13. And NNK

  14. Liver regeneration after two-thirds partial hepatic resection

  15. Initiation of hepatocarcinogenesis with BPDE

  16. Initiation of hepatocarcinogenesis with DMN-OAc

  17. Initiation of hepatocarcinogenesis

  18. Evolution of DNA damage

  19. Pathways of DNA repair O6-alkylguanine DNA alkyltransferase suicide protein transfers methyl group Base excision repair glycosylase, AP endonuclease, DNA polymerase, ligase Nucleotide excision repair transcription-coupled and global Cross-link repair Fanconi’s anemia genes and BRCA2 Double-strand break repair Homologous recombination and non-homologous end- joining Heteroduplex and mismatch repair Post-replication repair; translesion synthesis by pol eta, zeta, iota or kappa

  20. DECATENATION

  21. Familial cancer syndromes Ataxia telangiectasia - cell cycle checkpoint function, DNA repair. ATM, NBS1, MRE-11 Fanconi’s anemia - DNA repair. BRCA2 and 5 other genes HNPCC - mismatch repair, hMSH2, hMLH1, PMS2, hMSH6 Xeroderma pigmentosum - nucleotide excision repair and post-replication repair. 8 XP genes Familial breast cancer I - S and G2 checkpoint responses. BRCA1 Li-Fraumeni syndrome – cell cycle checkpoint function and DNA repair. P53, Chk2 Bloom’s syndrome, Werner syndrome, Rothmund-Thompson syndrome – chromosomal instability. Blm, Wrn, RecQ

  22. Promotion – reversible to a point Stimulates proliferation of initiated cells Inhibits apoptosis of initiated cells Progression – increments of cellular dysfunction Malignant progression enhanced by genetic instability

  23. Initiation and promotion of murine epidermal carcinogenesis

  24. Phenobarbital promotes hepatocarcinogenesis Plus phenobarbital Minus phenobarbital

  25. Expression of TGF-alpha in GSTP+ foci TGF-alpha GSTP

  26. Phenobarbital and TGF-alpha enhance clonal expansion by initiated hepatocytes

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