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