Download Neoplasia lecture 7

Neoplasia lecture 7
Dr Heyam Awad
FRCPath
Continuation of insensitivity to growth
inhibitors
TGF beta pathway
• TGF beta is a potent inhibitor of cell proliferation
• TGF beta binds to receptors..
• Receptors activated .. Transmit signal through SMAD proteins
• transcription activation of CDKIS. This results in Growth suppression
• It also causes Repression of MYC CDK2, CDK4 that encode cyclin A and
E
• Mutations affecting TGF beta signaling causes cancer
• These mutations involve TGF beta receptor or SMAD molecules that
transduce antiproliferative signals from the receptor to the nucleus
• Mutation affecting type 2 receptor seen in colon, stomach and
endometrial cancer
• SMAD4 mutated in pancreatic cancer
• In some cancers mutations in TGF B happen downstream of signaling
pathway.
• These mutations change other properties of TGF beta
• Causes Immune system suppression or promotion of angiogenesis so:
facilitate tumor progression
• so Can prevent or promote tumor growth????
• 100% of pancreatic 83% of colon at least one component of is TGF b
pathway is mutated
• 100% of pancreatic 83% of colon at least one component of is TGF b
pathway is mutated
Contact inhibition
• Normally cells proliferate in organized fashion. Monolayers are
formed and contact between adjacent cells inhibits further growth.
• This process is called contact inhibition.
• In cancer cells: contact inhibition is lost so cells pile upon each other.
Contact inhibition
• Contact inhibition is mediated by cadherin molecules.
• E cadherin’s function is facilitated by NF2 protein
• If E cadherin is lost: no contact inhibition….. Cells proliferate in
uncontrolled fashion.
• NF2 gene’s protein product is neurofibromin 2=merlin facilitates
contact inhibition
• Homozygotic loss of NF2 causes neural tumors ( neurofibromatosis
syndrome)
APC ( adenomatous polyposis coli) gene
• APC gene is tumor suppressor gene
• Suppresses growth by regulating intracellular beta catenin levels
• Functions of beta catenin: binds and inhibits E cadherin
•
to nucleus.. Activate cell proliferation
• SO: Beta catenin stimulates growth by two ways:
1. Inhibits contact inhibition by binding to E cadherin and stimulating
TWIST and SLUG transcription regulators that decrease cadherin
expression
2. Stimulates growth by increasing transcription of growth promoting
genes like cyclin D1 and MYC
• APC suppresses growth by being part of a complex that destructs the
beta catenin.
• Beta catenin is an important component of WNT signaling
• WNT is a soluble factor that induces cell proliferation by binding to a
receptor and transmit signals that prevent degradation of beta
catenin
• Now beta catenin to nucleus .. Transcription activator in conjunction
with another molecule TcF
• Quiescent cells not exposed to WNT .. Cytoplasmic b catenin is
degraded by destruction complex ( of which APC is a main
component)
• APC is an important component of these destruction complexes
• Loss of APC .. B catenin not degraded and WNT pathway activated
without the WNT
• This leads to transcription of growth promoting genes cyclin D1 ,MYC
and transcription regulators: TWIST AND SLUG that repress e cadherin
and thus reduce contact inhibition
WNT pathway
APC adenomatous polyposis coli
• APC syndrome: one allel lost in germ line.. Patients have polyps
(adenomatous polyps= adenoma).. Hundreds of adenomas
• 100% risk of malignancy
• Some polyps acquire another hit.. Malignant
• 70-80% of sporadic colon cancers have APC mutation
• Colonic cancers with normal APC have mutated b catenin making
them undegradable by. APC
FAP syndrome: colon full of adenomas!
Third hallmark: limitless replicative potential
• Normal cells: limited capacity to duplicate ( usually 60 -70 doublings)
• After these doublings cells lose capacity to replicate and become
senescent
• This is because of progressive shortening of telomeres
• Cells avoid senescence by activating telomerase.
• Telomere length is maintained in all cancer cells.. Mainly by
upregulation of telomerase but also by other mechanisms like DNA
recombinations
• If cells have short telomere and no telomerase… then shortened
telomeres fuse and cells divide causing more DNA breaks ( this
happens of course if the cell cycle checkpoints are disabled)
• This bridging, fusion, breakage cycle continues and ends in mitotic
catastrophe unless the cell acquires telomerase activation
• The presence of a time window during which cells have short
telomeres, disabled checkpoints and low telomerase activity is
beneficial to tumor cells because it causes genetic instability that
allows the accumulation of mutations.
• This happens during progression of colonic adenomas to colonic
carcinomas.
Adenoma- carcinoma sequence in colon cancer…
note that telomerase are acquired late in the
process