Oncogenes
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Cancer is characterized by uncontrolled cell growth and spread. At the cellular level, cancer cells proliferate excessively, grow in an uncoordinated manner, and infiltrate surrounding tissues. This uncontrolled growth is caused by genetic disorders that affect genes regulating cell growth. Cancer cells lose control over growth and multiplication and do not self-destruct like normal cells. They crowd out healthy cells. Genetic changes can activate oncogenes or inactivate tumor suppressor genes, disrupting the normal balance between cell proliferation and cell death. A variety of genetic, environmental, and viral factors can cause these genetic changes and contribute to cancer development.
Oncogenes
- 1. What Is Cancer? •Cancer is a large group of diseases (over 200) characterized by uncontrolled growth and spread of abnormal cells.* *American Cancer Society, Cancer Facts and Figures 2005
- 2. •At cellular level • Excessive cellular proliferation • Uncoordinated growth • Tissue infiltration •At molecular level • Disorder of growth regulatory genes Carcino genesis
- 3. Normal Cells Vs. Cancer Cells • Cancer cells: • Lose control over growth and multiplication • Do not self-destruct when they become worn out or damaged • Crowd out healthy cells
- 4. NORMAL CELL growth factor growth factor receptor signal transduction activation of transcription cytoplasm nucleus DNA RNA Carcino genesis
- 5. NEOPLASTIC (malignant) CELLS Increase in growth factors Increase in growth factor receptors Increase in signal transduction Increase in activation of transcription - Disturbed processes of mitosis and protein synthesis Carcino genesis
- 6. Properties of cancer cells •1: self-sufficient in growth signals •2: insensitive to anti-growth signals •3: stimulate local angiogenesis •4: evade apoptosis
- 7. Classes of Genes Involved in the Development of Tumour • Non lethal genetic damage is the initiating event in carcinogenesis.There are principally four classes of genes which when affected by such changes , can result in the development of a tumour 1. Proto-oncogenes 2. Tumour suppressor gene 3. Genes involved in DNA repair 4. Genes involved in apoptosis
- 8. Oncogenes • Oncogene: “onco” (cancer) gene • 1989 Nobel Prize in Medicine or Physiology: The Discovery of the Cellular Origin of Retroviral Oncogenes • J. Michael Bishop (UCSF) • Harold Varmus (UCSF)
- 9. Oncogenes Cont’d • Proto-oncogenes: normal cellular genes usually involved in cell growth and/or cell division • Oncogenes: a proto-oncogene that has been activated by mutation or overexpression. Results in a dominant gain of function phenotype • Growth Factors, Growth Factor Receptors, G-proteins, Kinases, Gene Regulatory Proteins
- 10. Common Human Oncogenes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
- 11. How are oncogenes activated? • Point mutation-eg. K-ras, • Amplification-eg. N-myc, MDM2, Her2/neu/ErbB2 • Chromosome translocation-eg. c-myc, bcr- abl • Overexpression due to DNA demethylation
- 13. List of carcinogens Chemical • Asbestos • Arsenic • Chromium • Polyaromatic hydocarbons • dichlorodiphenyl- trichloroethane (DDT) Physical • Gamma radiation • UV light • Radon • X-rays • Viruses*
- 14. Viruses and cancer • Viruses account for 15% of all cancers • DNA viruses • Epstein-Barr virus • Human papilloma virus • Hepatitis B virus • RNA viruses • HIV-1 • HTLV-1 • HTLV-2
- 15. Tumor Suppressor Genes • Genes that are normally involved in the inhibition of cell growth and proliferation. • Two Hit Hypothesis: Tumor suppressor genes act in a recessive manner • Need loss of both alleles to progress towards cancer Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002
- 16. Common Human Tumor Suppressor Genes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
- 17. Mechanisms of tumor suppressor gene inactivation • Deletion • Point mutation • Mutation followed by duplication • Loss of heterozygosity • DNA methylation • Post-translational mechanism-binding to DNA viral oncoproteins
- 18. Retinoblastoma (Rb) Tumor Suppressor Gene Rb prevents E2F transcription factor from transcribing genes inappropriately Loss of Rb allows for unregulated gene transcription The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
- 20. p53 Tumor Suppressor Gene p53 is the single most common target for genetic insults leading to cancer DNA damage stabilizes p53 and allows for p53 accumulation p53 induces p21 (CDKN1A, CIP1, WAF1) to cause cell cycle arrest The state in which p53 is mutated is referred to as Li Fraumani syndrome Robbins & Cotran Basic Pathology 7th ed
- 21. Multiple Hit Hypothesis Cancer is due to an accumulation of genetic insults (oncogene activation, loss of tumor suppressor genes)
- 22. Oncogene Addiction Hypothesis • Cells become addicted to persistent oncogene activity for proliferation • Become unresponsive to any other mitogenic (growth) stimuli • Turn off MYC and cells can respond to other stimuli • Tumor cells begin to become more normal
- 23. MYC Oncogene Addiction in Hepatocellular Carcinoma Felsher, et al.
- 24. MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandi S, Bachman MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. Nature. Vol431, 2004.
- 26. The Concept of Gene Therapy