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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