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