Familial Colon Cancer as a model of carcinogenesis

Question 1

FAP

Answer 1

autosomal dominant disease caused by a germline mutation in one of the APC gene
–accelerated tumor INITIATION

Question 2

HNPCC

Answer 2

familial form of colon cancer in which a defect in mismatch repair accelerates tumor PROGRESSION

Question 3

adenoma to carcinoma sequence

Answer 3

normal–inact of APC–>dysplasia –mutation of KRAS–>adenoma –CIN defect, 18q loss DCC, DPC4, inact of p53 (17p loss)–>carcinoma

Question 4

Axin

Answer 4

death protein

binds protein complex (APC, TSG) –>complex binds, phos, and ubiq B-catenin (TF binding protein)

Question 5

Wnt signaling

Answer 5

translocate Axin away from protein complex via Fz and LRP5/6–> b-catenin isnt degraded and is translocated to nucleus–>binds TCF/LEF–>associates with and activates wnts downstream signaling

if there is no wnt (no APC defect), can’t do this

Question 6

B-catenin in nucleus

Answer 6

makes cells progress from G1–>G1/S in cell cycle

anchors cadherin to actin in adherens junctions–securely attach adjoining cells and also play a role in anchoring the cell to basement membrane

Question 7

no B-catenin in nucleus

Answer 7

apoptosis

Question 8

ApC regulates aixin…

Answer 8

independently of b-catenin

Question 9

bottom line, where should b-catenin be

Answer 9

stem/progenitor cells! not in non-proliferative cells

Question 10

APC truncated mutation

Answer 10

increase in free B catenin–abnormal cell division and differentiation–>dysplasia

also cant bind MTs as well, effecting cytoskeletal and mitotic cell functions

Question 11

mutation in CRC patients

Answer 11

FAP- 1 allele germine truncation

sporadic polyps- single acquired mutation

Question 12

cells differentiate as

Answer 12

reach surface of crypt

Question 13

what determines the cell type that stem cells become

Answer 13

notch-wnt interactions and lateral inhibition

differentiated cells lose Wnt activation

processes have strict spatial relationships in crypt–>APC mutations mess up these dynamics

Question 14

NSAIDs

Answer 14

shown to decrease and slow formation of polyps in patients with FAP

inhibit free B catenin–>inhibits cell proliferation–>permits cell deat through apoptosis

Question 15

prostaglandins

Answer 15

experimental animals with increased PG levels develop colon cancer

FAP patients show decreased levels of PG dehydrogenase in glands compared to normal ones

Question 16

COX2 inhibitor c

Answer 16

celecoxib–reduce adenomas

Question 17

food that targets intermediates in wnt/b catenin signaling pathway

Answer 17

retinoids, curry, bbq sauce, honey mustard

Question 18

B cat vs apc

Answer 18

apc- tumor suppressor gene

b cat- protooncogene