Biology of Cancer

Weeks 1 Introduction and 2 RTKsDr. Michael Chorney

Susquehanna Medicine and Health Science Magnet February 17th-28th, 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 iscomplex 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 cancercell with the end point being increases in cyclins and crossing of therestriction point.

Hallmarks-Things that cancer cells need to circumvent, or phenotypicfeatures they adopt (modified by Dr. Chorney

1. Activation of the Receptor Tyrosine Kinases2. 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 apoptosis5. Turn-on of telomerase6. Reliance on glycolysis even in the presence of oxygen7. Formation of new blood vessels, i.e. angiogenesis8. Avoidance of the immune system9. Exploitation of inflammation (reactive oxygen species, or ROS)10. Avoidance of growth suppression effectors and pathways

Know the following:

Cancer vs. a benign tumorMalignant transformationAnchorage dependence and contact inhibitionOncogene, proto-oncogeneSrc, transduction, RSVHyperplasia, dysplasia, metaplasia, anaplasia, dedifferentiationLoss of heterozygosity, LOHTumor suppressor geneRetinoblastoma proteinp53Kinase (phosphorylation)CarcinomaEpithelial-mesenchymal transitionMetastasisPapilloma virusCarcinogenesisImmortalization (e.g. HeLa cell)

Spectral karyotype analysis, multicolor FISH

Pancreatic cancer

Chronic Myelogenous Leukemia and the PhiladelphioaChromosome

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 ofthe 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 downstreamProteinCalled Sos

Src homology domains

Phosphotyrosines inthe cytoplasmic tail oftwo RTKs and the proteinsthat bind

Adapterproteins

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 inactivatesGSK

AKT downstream effect