Oncogenes

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

•At cellular level • Excessive cellular proliferation•Uncoordinated growth• Tissue infiltration

•At molecular level •Disorder of growth regulatory genes

Carcinogenesis

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

NORMAL CELLgrowth factorgrowth factor receptor

signal transduction

activation of transcription

cytoplasm

nucleusDNA

RNA

Carcinogenesis

NEOPLASTIC (malignant) CELLS

Increasein growth factors

Increasein growth factorreceptors

Increase in signal transduction

Increase in activation of transcription

- Disturbed processes of mitosis and protein synthesis

Carcinogenesis

Properties of cancer cells

•1: self-sufficient in growth signals•2: insensitive to anti-growth signals•3: stimulate local angiogenesis•4: evade apoptosis

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 gene3. Genes involved in DNA repair4. Genes involved in apoptosis

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)

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

Common Human Oncogenes

The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

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

List of carcinogens

Chemical• Asbestos• Arsenic• Chromium• Polyaromatic hydocarbons• dichlorodiphenyl-

trichloroethane (DDT)

Physical• Gamma radiation• UV light• Radon• X-rays• Viruses*

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

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

Common Human Tumor Suppressor Genes

The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

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

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

Genetics of Retinoblastoma

p53 Tumor Suppressor Gene

p53 is the single mostcommon target for geneticinsults leading to cancer

DNA damage stabilizes p53and allows for p53 accumulation

p53 induces p21 (CDKN1A, CIP1, WAF1) to cause cell cycle arrestThe state in which p53 is mutated is referred to as Li Fraumani syndrome

Robbins & Cotran Basic Pathology 7th ed

Multiple Hit Hypothesis

Cancer is due to an accumulation of genetic insults (oncogeneactivation, loss of tumor suppressor genes)

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

MYC Oncogene Addiction in Hepatocellular Carcinoma

Felsher, et al.

MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular CancerShachaf 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.

The Concept of Gene Therapy