Lecture #21 | Colon Cancer: Stem Cells and Telomerase

Mutations needed for development of colon cancer

1. APC mutation

2. RAS mutation: Common in large ones

3. SMAD4 mutation: Common in malignant tumors but not polyps

4. p53 mutation: Leads to genetic instability for metastasis

Needs 6 mutations but only 4 genes involved

• 2 hit hypothesis

• Tumor repressors need 2 alleles to be non functional

APC role in the nucleus

Necessary for ensuring chromosomal stability during spindle formation → chromosomal segregation

• Mutations in APC lead to chromosomal instability which fuels cancer progression

APC/B-catenin in cell adhesion

• B-catenin anchors the cytoskeleton at cell-cell junctions

• B-catenin binds cytoplasmic domains of E-cadherins

• b-catenin binds either APC or E-cadherins

HNPCC: Hereditary nonpolyposis colon cancer

Mutations in mismatch repair pathway

• account its for 15% of colorectal cancer and more common that FAP

• Not as many polyps as in FAP

• but the adenomas that do develop acquire mutations at a rate 2-3x higher and have an accelerated progression to invasive carcinoma

Leads to Microsatellite instability → mutations at nt level in repetitive sequences

Aspirin and colon cancer

Possibly protective against colon cancer

• decrease number and size of polyps

• Act via PPARd

Mechanism of PPARd

Target gene of b-catenin

• high levels of PPAR are often found in colon cancer

• fatty acids are ligands for PPARd

• COX-2 leads to the synthesis of PPARd ligands like prostaglandins

  • more PGE→ more and bigger polyps

• Aspirin inhibits cox-2 and PPARd expression and decreases Bcl2 expression → no more growth

role of fiber in colon cancer n

Increases production of sodium butyrate by gut microbes and blocks HDAC activity which leads to histone acetylation and increased transcription which increases differentiation

• means that we are cycling through the cells at a a higher rate → non damaged cells are not replicating

stem cells

self renewing cells that give rise to different cell types

• much more susceptible to be cancerous

• telomerase is key to stem cell longevity

• cancer cells have lots of telomerase activity

  • critical for infinite lifespan requirement of cancer cells

telomeres

complex structures at the end of chromosomes that prevent the ends to end fusing with one another

• like shoeless tips

• telomerase: protein + DNA primer

telomeres in normal cells

without, each successive round of replication the telomeres get shorter and shorter

• explains limited lifespan of normal cells

• cells can replicate as long as there are telomeres

How do stable telomeres allow for continues cell proliferation

telemoerase activity is required in highly proliferate cells

• expression of catalytic subunit telomerase (htert) is increased in a vast majority of cancers

Inactive hTERT

Shortened telomeres→ cell senescence →aging → limited cell life

Active hTERT

Stable telomeres → cell survival → cancer

Since stem cells have active hTERT, they are one step closer to cancer