1. Neoplasia lecture 7
Dr Heyam Awad
FRCPath

2. Continuation of insensitivity to growth inhibitors

3. 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

4. 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

5. 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????

6. 100% of pancreatic 83% of colon at least one component of is TGF b pathway is mutated

7. 100% of pancreatic 83% of colon at least one component of is TGF b pathway is mutated

8. 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.

9. Contact inhibition

10. 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.

11. NF2 gene’s protein product is neurofibromin 2=merlin facilitates contact inhibition
Homozygotic loss of NF2 causes neural tumors ( neurofibromatosis syndrome)

12. 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

13. SO: Beta catenin stimulates growth by two ways:
Inhibits contact inhibition by binding to E cadherin and stimulating TWIST and SLUG transcription regulators that decrease cadherin expression
Stimulates growth by increasing transcription of growth promoting genes like cyclin D1 and MYC

14. APC suppresses growth by being part of a complex that destructs the beta catenin.

15. 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

16. Quiescent cells not exposed to WNT
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

17. WNT pathway

18. 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

19. FAP syndrome: colon full of adenomas!

20. Third hallmark: limitless replicative potential
Normal cells: limited capacity to duplicate ( usually doublings)
After these doublings cells lose capacity to replicate and become senescent
This is because of progressive shortening of telomeres

21. 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

22. 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

23. 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.

25. Adenoma- carcinoma sequence in colon cancer… note that telomerase are acquired late in the process