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

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.

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

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)

Spectral karyotype analysis, multicolor FISH

Pancreatic cancer

Chronic Myelogenous Leukemia and the Philadelphioa Chromosome

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

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

Ras is activated by GTP It functions as a KINASE

RTK Monomers

RTK homodimers formed following binding of the specific growth factor

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

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

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

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

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

Ras’s three pathways

Phosphotidyl inositol-ATK pathway

PIP3 activate AKT

AKT inactivates GSK

AKT downstream effect