Familial Colon Cancer as a model of carcinogenesis Flashcards Preview

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Flashcards in Familial Colon Cancer as a model of carcinogenesis Deck (18):
1

FAP

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

2

HNPCC

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

3

adenoma to carcinoma sequence

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

4

Axin

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

5

Wnt signaling

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

6

B-catenin in nucleus

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

7

no B-catenin in nucleus

apoptosis

8

ApC regulates aixin...

independently of b-catenin

9

bottom line, where should b-catenin be

stem/progenitor cells! not in non-proliferative cells

10

APC truncated mutation

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

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

11

mutation in CRC patients

FAP- 1 allele germine truncation
sporadic polyps- single acquired mutation

12

cells differentiate as

reach surface of crypt

13

what determines the cell type that stem cells become

notch-wnt interactions and lateral inhibition

differentiated cells lose Wnt activation

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

14

NSAIDs

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

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

15

prostaglandins

experimental animals with increased PG levels develop colon cancer

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

16

COX2 inhibitor c

celecoxib--reduce adenomas

17

food that targets intermediates in wnt/b catenin signaling pathway

retinoids, curry, bbq sauce, honey mustard

18

B cat vs apc

apc- tumor suppressor gene
b cat- protooncogene