What Is Cancer?
•Cancer is a large group of
diseases (over 200)
characterized by
uncontrolled growth and
spread of abnorma...
•At cellular level
• Excessive cellular proliferation
• Uncoordinated growth
• Tissue infiltration
•At molecular level
• D...
Normal Cells Vs. Cancer Cells
• Cancer cells:
• Lose control over growth
and multiplication
• Do not self-destruct when
th...
NORMAL CELL
growth factor
growth factor receptor
signal transduction
activation of
transcription
cytoplasm
nucleus
DNA
RNA...
NEOPLASTIC (malignant) CELLS
Increase
in growth
factors
Increase
in growth
factor
receptors
Increase in
signal
transductio...
Properties of cancer cells
•1: self-sufficient in growth signals
•2: insensitive to anti-growth
signals
•3: stimulate loca...
Classes of Genes Involved in
the Development of Tumour
• Non lethal genetic damage is the initiating
event in carcinogenes...
Oncogenes
• Oncogene: “onco” (cancer) gene
• 1989 Nobel Prize in Medicine or Physiology:
The Discovery of the Cellular Ori...
Oncogenes Cont’d
• Proto-oncogenes: normal cellular genes usually
involved in cell growth and/or cell division
• Oncogenes...
Common Human Oncogenes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c20...
How are oncogenes activated?
• Point mutation-eg. K-ras,
• Amplification-eg. N-myc, MDM2,
Her2/neu/ErbB2
• Chromosome tran...
List of carcinogens
Chemical
• Asbestos
• Arsenic
• Chromium
• Polyaromatic hydocarbons
• dichlorodiphenyl-
trichloroethan...
Viruses and cancer
• Viruses account for 15% of all cancers
• DNA viruses
• Epstein-Barr virus
• Human papilloma virus
• H...
Tumor Suppressor Genes
• Genes that are normally involved in the inhibition
of cell growth and proliferation.
• Two Hit Hy...
Common Human Tumor Suppressor
Genes
The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associat...
Mechanisms of tumor suppressor
gene inactivation
• Deletion
• Point mutation
• Mutation followed by duplication
• Loss of ...
Retinoblastoma (Rb) Tumor
Suppressor Gene
Rb prevents E2F transcription factor from transcribing genes
inappropriately
Los...
Genetics of Retinoblastoma
p53 Tumor Suppressor Gene
p53 is the single most
common target for genetic
insults leading to cancer
DNA damage stabilizes...
Multiple Hit Hypothesis
Cancer is due to an accumulation of genetic insults (oncogene
activation, loss of tumor suppressor...
Oncogene Addiction Hypothesis
• Cells become addicted to persistent
oncogene activity for proliferation
• Become unrespons...
MYC Oncogene Addiction in
Hepatocellular Carcinoma
Felsher, et al.
MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer
Shachaf CM, Kopelman AM,...
The Concept of Gene Therapy
Oncogenes
Oncogenes
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Oncogenes

  1. 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. 2. •At cellular level • Excessive cellular proliferation • Uncoordinated growth • Tissue infiltration •At molecular level • Disorder of growth regulatory genes Carcino genesis
  3. 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. 4. NORMAL CELL growth factor growth factor receptor signal transduction activation of transcription cytoplasm nucleus DNA RNA Carcino genesis
  5. 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. 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. 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. 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. 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. 10. Common Human Oncogenes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
  11. 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
  12. 12. List of carcinogens Chemical • Asbestos • Arsenic • Chromium • Polyaromatic hydocarbons • dichlorodiphenyl- trichloroethane (DDT) Physical • Gamma radiation • UV light • Radon • X-rays • Viruses*
  13. 13. 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
  14. 14. 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
  15. 15. Common Human Tumor Suppressor Genes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
  16. 16. 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
  17. 17. 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
  18. 18. Genetics of Retinoblastoma
  19. 19. 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
  20. 20. Multiple Hit Hypothesis Cancer is due to an accumulation of genetic insults (oncogene activation, loss of tumor suppressor genes)
  21. 21. 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
  22. 22. MYC Oncogene Addiction in Hepatocellular Carcinoma Felsher, et al.
  23. 23. 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.
  24. 24. The Concept of Gene Therapy
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