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

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

3. 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

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

5. 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

10. 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)

11. Sites of alkylation of DNA

12. DNA strand scission by topoII poisons

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

14. Initiation and promotion of murine epidermal carcinogenesis

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

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

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

18. And NNK

19. Liver regeneration after two-thirds partial hepatic resection

20. Initiation of hepatocarcinogenesis with BPDE

21. Initiation of hepatocarcinogenesis with DMN-OAc

22. Initiation of hepatocarcinogenesis

23. Evolution of DNA damage

25. 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

27. DECATENATION

34. 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

39. 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

40. Initiation and promotion of murine epidermal carcinogenesis

41. Phenobarbital promotes hepatocarcinogenesis Plus phenobarbital Minus phenobarbital

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

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