1. Biology of Cancer Weeks 1 Introduction and 2 RTKs Dr. Michael Chorney Susquehanna Medicine and Health Science Magnet February 17 th -28 th, 2014

2. Learning Objectives Describe what is meant by ‘cancer being a somatic genetic disease.’ The transition from a normal cell to a malignant, transformed cell is complex and multistep-explain what this means. The Rous retrovirus set the stage for many decades of cancer research- explain in what way. Hanahan and Weinberg have published on the ‘hallmarks’ of cancer-put these into your own words and convey what they refer to. Discuss the pathways leading to the uncontrolled growth of a cancer cell with the end point being increases in cyclins and crossing of the restriction point.

3. Hallmarks-Things that cancer cells need to circumvent, or phenotypic features they adopt (modified by Dr. Chorney 1.Activation of the Receptor Tyrosine Kinases 2.Uncontrolled, constitutive expression of important signal transduction molecules (H-Ras, Akt, and others) 3.Shutdown of Rb and crossing of the restriction point (cyclins and their kinases increased) 4.Inactivation of p53 activity and avoidance of apoptosis 5.Turn-on of telomerase 6.Reliance on glycolysis even in the presence of oxygen 7.Formation of new blood vessels, i.e. angiogenesis 8.Avoidance of the immune system 9.Exploitation of inflammation (reactive oxygen species, or ROS) 10.Avoidance of growth suppression effectors and pathways

4. Know the following: Cancer vs. a benign tumor Malignant transformation Anchorage dependence and contact inhibition Oncogene, proto-oncogene Src, transduction, RSV Hyperplasia, dysplasia, metaplasia, anaplasia, dedifferentiation Loss of heterozygosity, LOH Tumor suppressor gene Retinoblastoma protein p53 Kinase (phosphorylation) Carcinoma Epithelial-mesenchymal transition Metastasis Papilloma virus Carcinogenesis Immortalization (e.g. HeLa cell)

5. Spectral karyotype analysis, multicolor FISH

6. Pancreatic cancer

7. Chronic Myelogenous Leukemia and the Philadelphioa Chromosome

8. Amplified chromosome regions Cancer results from a combination of point mutations, amplifications/deletions, insertional mutagenesis, aneuploidy, Translocation(s), and epigenetic modifications

9. The wildtype proto-oncogene versus the mutant oncogene derived from a bladder cancer

10. Ras is activated by GTP It functions as a KINASE

11. RTK Monomers

12. RTK homodimers formed following binding of the specific growth factor

13. Constitutive (always on) expression of the receptor due to a genetic change

14. The Src protein activated to perform its own phosphorylation SH=Src homology domains, i.e. kinase domains

15. In fruit flies, the RTK acts on a downstream Protein Called Sos Src homology domains

16. Phosphotyrosines in the cytoplasmic tail of two RTKs and the proteins that bind Adapter proteins

17. The detailed cascade (pathway) of a human RTK Grb2 and Shc possess SH2 domains that bind Phosphotyrosine, the cascade terminates at Ras

18. Ras’s three pathways

19. Phosphotidyl inositol-ATK pathway

20. PIP3 activate AKT

21. AKT inactivates GSK

22. AKT downstream effect