Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors 1. aging
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Mechanisms of carcinogenesis What causes cancer in humans? Endogenous factors
1. aging2. biochemistry3. genes4. hormones
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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
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3. promoters - estrogen
4. co-carcinogens – toxins/mitogens
What causes cancer?
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What suppresses cancer in humans?
A. Exogenous1. NSAID – COX22. tamoxifen/raloxifen – estrogen antagonists3. vitamin A analogs – retinoids
B. Endogenous
1. DNA repair – p53 as guardian of the genome2. immunity3. angiostatin (?)4. tissue microenvironment
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2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)
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Sites of alkylation of
DNA
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DNA strand
scission by topoII
poisons
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Mechanisms of chemical carcinogenesis Steps and stages
initiationpromotionprogression
metaplasia/hyperplasiadysplasianeoplasia/anaplasia
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Initiation and promotion of murine epidermal carcinogenesis
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Initiation – permanent heritable alteration
UptakeMetabolic activationAdductionFixation
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Consider two prototypic lung carcinogens
benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK)
MetabolismDNA damage
DNA repair
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benzo[a]pyrene
benzo[a]pyrene diolepoxide
DNA adduct of BP
Metabolism by Cytochrome p450 and Epoxide hydratase
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And NNK
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Liver regeneration after two-thirds partial hepatic resection
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Initiation of hepatocarcinogenesis with BPDE
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Initiation of hepatocarcinogenesis with DMN-OAc
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Initiation of hepatocarcinogenesis
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Evolution of DNA damage
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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
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DECATENATION
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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
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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
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Initiation and promotion of murine epidermal carcinogenesis
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Phenobarbital promotes hepatocarcinogenesis
Plus phenobarbital
Minus phenobarbital
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Expression of TGF-alpha in GSTP+ foci
GSTP
TGF-alpha
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Phenobarbital and TGF-alpha enhance clonal expansion by initiated hepatocytes
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