Carcinogenesis I

Question 1

Phenotype of malignant cancer cells?

Answer 1

1. ) Unresponsive to normal signals for proliferation control
2. ) De-differentiated
3. ) Invasive (outgrowth into neighboring normal tissues)
4. ) Metastatic (shedding cells into circulatory system)
5. ) Clonal in origin (derived from ONE cell)

Question 2

Molecular basis of cancer

Answer 2

1. ) Altered morphology (round up, little cytoplasm)
2. ) Loss of contact inhibition
3. ) Anchorage independent (agar experiments)
4. ) Ability to proliferate independently
5. ) Decreased requirement for mitogenic GF (insensitive)
6. ) Increased use of glucose (ferment glucose to lactic acid, decreased need for O2)
7. ) Evade apoptosis

-Need cellular hereditary changes for neoplastic transformation

Question 3

LOH examples

Answer 3

LOH- loss of a tumor suppressor gene. Retinoblastoma and APC gene in FAP (familial adenomatous polyposis)

Question 4

Autosomal Dominant Cancers

Answer 4

FAP-APC, RB gene, BRCA1 and BRCA2, Wilms tumor.

Question 5

Autosomal Recessive

Answer 5

Xeroderma pigmentosa, Ataxia-telangiectasia (AT gene), Bloom’s syndrome, fanconi’s

Question 6

RB gene

Answer 6

Tumor suppressor. Knudson theory. Bilateral tumors. RB inhibits the cell cycle (G1–> S). Add GF, produce cyclin, this stimulates CDK, this phosphorylates RB and inhibits it so cell cycle proceeds. In cancer no RB, cell divides constitutively w/o GF.
Also have RB issues in many other cancers (small cell lung cancer, breast tumors).
Tumor cells are homozygous for mutant RB. Hallmark of tumor suppressor gene.
was initially detected with PCR/southern blot. 13q14.

Question 7

Viruses and RB

Answer 7

Many viruses target RB. SV40 and HPV produce a T antigen or E7 protein that inactivate RB, get proliferation.

Question 8

HeLa cells

Answer 8

Cervical carcinoma. Express HPV E7 and E6 (E6 inhibits p53 a tumor suppressor). Block E7 and E6? cells go back to normal.

Question 9

Rb and mice

Answer 9

In mice inactivated Rb leads to pituitary tumors b/c in humans Rb is only active one in the retina (other Rb homologues cannot compensate), in mice the homologues compensate in retina.. but not in pituitary.

Question 10

Rb homologues

Answer 10

pRb, p107, p130. Can duplicate fx of Rb. they bind E2F transcription factors and prevent them from fx. Lose Rb and it releases E2F, which goes and allows trx of genes of proliferation.
Gives tissue specificity.

Question 11

LOH mechanisms

Answer 11

Mutation, mitotic recombo, chromosome loss, environmental factors.