2. Colon cancer: the second leading cause of cancer deaths in the U.S. Polyps, the first stage In tumor development http://www.clevelandclinic.org/registries/inherited/fap.htm

4. Familial adenomatous polyposis (FAP) = inherited predisposition to colon cancer

5. Cancer cells proliferate without differentiating, a property of our body’s normal stem cells

7. Normal cells are “contact-inhibited” and stop growing when they reach confluence Tumor cells are no longer “contact inhibited”

8. Cancer cells have alterations in cell adhesion and the cytoskeleton Normal “Transformed”

9. Normal Dysplasia Carcinoma in situ Malignant carcinoma Cancer develops through gradual changes in cell morphology and properties

10. Benign tumor Break through basal lamina Invade capillary Adhere to capillary wall Escape capillary Form metastasis Metastasis: the movement of tumor cells to new sites via the blood vessels or lymphatic system

12. Some normal cells like those of the neural crest have similar properties but end by differentiating at their new sites

13. The forces of Natural Selection drive the multistep process ECB Fig. 21-44

14. A single mutation is NOT enough!

15. Cancer cells accumulate chromosomal abnormalities

16. What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation

17. What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation Tumor suppressor genes Mutational inactivation of proteins that normally inhibit cell proliferation

18. Cells instruct one another via cell-cell signals

19. Signal transduction moves information from the cell surface to the nucleus & other cellular targets

20. Signal transduction occurs in a series of steps

21. Cell-cell signals can regulate cell proliferation

22. Cancer often results from alterations in proteins in signal transduction pathways

23. Cancer often results from alterations in proteins in signal transduction pathways

24. Src in its normal context Normal skin cell tightly adherent to ECM Wounding->platelet recruitment-> cell migration and proliferation

25. Many viral oncogenes are kinases including receptor tyrosine kinases

26. Activating mutations in RTKs take several forms but all lead to ligand-independent dimerization and thus activation

27. Double minute chromosomes Tandem duplications Gene amplification is also a common mechanism of inappropriate gene activation in human tumors

28. RTK signaling ultimately leads to activation of a transcription factor Gilbert Fig. 6.15

29. Elements of the ras signal transduction pathway are often activated in cancers

30. Remember this?

31. The vul mutations helped define the RTK-Ras pathway

32. We are making progress: The modern drug Gleevec stops certain cancers by blocking the kinase activity of protein tyrosine kinases Gleevec works for chronic myeloid leukemia

33. Lipid bilayer Outside the cell Inside the cell Steel White-spotting Tyrosine kinase domain In response to binding of Steel factor, kinase is activated and target proteins are phosphorylated P (aka c-kit) Gleevec also works for the cancers caused by activation of White-spotting=(c-kit)

34. What types of genes are mutated in cancers? Two broad categories Oncogenes Mutational activation of proteins that normally Promote cell proliferation Tumor suppressor genes Mutational inactivation of proteins that normally inhibit cell proliferation

35. E2F DP DO NOT transcribe gene required for DNA replication Rb Rb puts the brakes on cell proliferation

36. E2F DP Transcribe gene required for DNA replication P P Rb phosphorylation frees E2F/DP to turn on genes required for proliferation

37. Retinal tumor in patient that inherited a mutant copy of Rb

38. Even though its caused by a loss-of-function mutation Retinoblastoma is inherited in a dominant fashion What’s up with that?

41. Mechanisms to inactivate the second Rb allele

43. One strategy for isolating oncogenes