familial colon cancer - model of carcinogenesis - lecture notes - julia Flashcards Preview

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Flashcards in familial colon cancer - model of carcinogenesis - lecture notes - julia Deck (21)
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1
Q

what does normal colon look like histologically?

A
  • straight tubular structures with no lateral branching and a structured pattern of epithelial growth, differentiation and death
  • tubular structures lined by cells
  • some inflammatory cells around (not abnormal)
  • number of crypts should be uniform
  • cells turn over every 3-4 days
2
Q

what does tubular adenoma look like histologically?

A
  • benign colon polyp
  • lack of organization to crypts
3
Q

what does dysplasia look like histologically?

A
  • cells crowded and there’s some loss of cell polarity with nuceli present at the cell surface
  • loss of cytoplasmic differentiation (reduced mucin production)
  • nuclei are enlarged and the chromatin is dense and irregularly distributed
  • abnormal mitotic figures
  • colonic mucosa no longer a single layer - stratified
4
Q

what does adenocarcinoma look like histologically?

A
  • invading into muscularis propria
5
Q

what causes FAP? how does it relate to sporadic colon cancer?

A
  • genetic defect in adenomatous polyposis coli gene - has regulatory roles in colonic cells
  • over 80% of sporadic polyps share the genetic abnormality seen in patients with FAP
6
Q

what causes hereditary non-polyposis colonic cancer (HNPCC)?

A
  • familial form of colon cancer
  • due to defects in DNA mismatch repair (MMR)
  • results in accelerated tumor progression - accelerated growth and increased mutational events
7
Q

what does APC do?

A
  • regulates transcription and cell proliferation through its regulation of beta catenin
  • in abscense of Wnt ligand, beta-catenin is sequestered in a multiprotein degradation complex of axin, APC, CKI and GSK3beta
  • upon phosphorylation, beta catenin is ubiquitinated by b-TrCP-E3 ligase complex
  • B-catenin is degraded and there’s no transcription of Wnt genes
  • so APC involved in squestering beta catenin and therefore preventing wnt target genes from being transcribed
  • when wnt ligand binds, beta catenin released, activates TCF which results in wnt target genes being activated
8
Q

what does APC regulate? (4)

A
  1. the amount of beta catenin - free beta catenin in the nucleus can initiate cell division
  2. APC regulates microtubule assembly and has a role in cytoskeletal maintenance
  3. APC regulates AXIN independently of beta-catenin
  4. plays regulatory role in certain apoptosis pathways
9
Q

what is the role of beta catenin?

A
  • acts at progression of G1 and S into cell cycle
  • abscense of beta catenin in the process ultimately favors apoptosis
  • anchors cadherin to actin at adherens cell junctions - attach cells to each other and basement membrane
  • promotion of beta catenin promotes adherence and cell to cell connections
10
Q

where is beta catenin located in normal colonic cells? in cancerous or abnormal cells?

A
  • normally has membranous localization
  • most part of cell junctions
  • in polyp cells, gets more localized to the cytoplasm and nucleus - implies more wnt signaling
  • also free in cytoplasm in stem cells
11
Q

how is mutated APC in colon cancer functionally different from normal APC?

A
  • mutated = 1 allele has germ line trunctaion mutation
  • trunctated => protein that can’t bind to beta catenin - allows free beta catenin to accumulate in cells - beta catenin can’t bind actin => increased cell proliferation
  • may also not be able to bind microtubules => effected cytoskeletal and mitotic spindle cell functions
12
Q

what is the normal process of crypt development?

A
  • crypt ordered so that cell proliferation occurs toward the base of the crypt
  • cells migrate toward the surface and differentiate
  • eventually die and are shed into the lumen
  • occurs continously over 3-4 days
13
Q

what is the role of wnt and notch in development of colonic crypts?

A
  • together may play role in maintaining stem cell compartment
  • changes in notch associated with differentiating cells in transit amplifying compartments
  • differentiated cells lose wnt activation
  • processes have strict spacial relationships in the crypt
14
Q

what are the consequences of mutating APC? (5)

A
  1. altered interactions with microtubles/F-actin => decreased cell migration => inappropriate accumulation of cells
  2. altered interactions with beta-catenin => decreased differentiation => maintains stem cell or transit amplifying cell character
  3. changes interactions with beta-catenin and microtubules => changes proliferation levels => maintains stem cell or transit amplifying cell character, but faulty and less efficient mitosis
  4. changes in interactions with microtubules => decreased genetic stability => chromosomal aberrations
  5. changes in interactions with microtubules and beta catenin => decreased apoptosis => inappropriate survival of damaged cells
15
Q

what does normal crypt fission look like histologically?

A
  • crypts normally form through an orderly process of crypt fission
  • crypt numbers are normally held fairly constant
  • indented region on right = almost completed crypt fission
16
Q

how does mutated APC affect crypt fission? what will it look like histologically?

A
  • increased crypt fission
  • altered stem cell dynamics
  • abnormal crypt fission
  • enhanced unstable stem cell population
  • crypts will be incrased in number, longer in length, increased branching
  • cells more crowded, especially in the lower parts of the crypt
17
Q

what is going on in this picture?

A
  • top left corner has early adenomatous (dysplastic) crypt = begining of tubular adenoma
  • rest has aberrant crypt fission, hyperplastic crypts
  • due to both germline and acquired APC mutations
18
Q

what will catenin expression look like in early adenoma? how will this change in late adenoma

A
  • membranous, cytoplasmic and nuclear localization
  • illustrates increase in free beta-catenin in the cytoplasm and transcriptional activation by beta catenin in the nucleus
  • in late, will only be cytoplasmic and nuclear
  • as cells lose junctional integrity, concentration of membranous catenin (junction associated) markedly diminshes
  • d= early, f= late
19
Q

how can NSAIDs be used theraputically for patients with colon cancer?

A
  • have been found to prevent initiation of colon cancer/slow progression in pateints wtih FAP (and also with normal people)
  • ligand for PPAR delta is blocked by NSAIDS => inhibits cell prolifferation effect of free beta catenin, permits cell death through apoptosis
  • get reduction in polyps
20
Q

how are prostaglandins related to colon cancer?

A
  • elevated levels promote colon cancer
  • if you give animals a mutation that increases PG levels, you get worse polyp formation
  • 15-PGDH gene is often lost in FAP pateints
  • 15 PGDH catalyzes NAD+-linked oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and is the key enzyme responsible for the biological inactivation of these eicosanoids.
21
Q

what is celecoxib? how is it used?

A
  • cox-inhibitor - reduces adenoma burden in retained rectum of patients after colectomy
  • may reduce diminutive duodenal adenomas
  • effects prostaglandin levels - inhibits cox-2, which normally increases PG levels