Proto Oncogen and Oncogen
•
Oncogen
–Proteins that possess the ability to cause cellular transformation.
–Act in a dominant fashion, either overexpression or activating mutations.
Cellular transformation.
morphologic changes,loss of contact
inhibition,anchorage independent growth,ability to form tumors when transplanted into nude mice.
•
Proto-oncogene.
–Potential to become activated into a cancer causing oncogene.
–Have been found in all multicellular organisms. –Would be involved : basic essential functions of
12/4/2010
Proto-oncogenes
•
1.Growth Factors
–Stimulate cells in stationary stage to enter the cell cycle.
–Occurs in a two stage process :
• Stimulation to proceed into G1provided by PDGF,EGF,followed by progression factors :IGF to progress through the cell cycle.
•
2.Growth factor receptors
–Link the information from extracellular environment (GF) to a number of different intracellular signaling pathways.
12/4/2010
•
3. Signal transducers.
–Cytoplasmic nonreceptor tyrosine kinases. –Proteins with enzyme activity such as
phospholipase C , PI3-K
–Adaptor proteins : Grb2
–SH2 and SH3 domain.
•
4. Nuclear proto-oncogne and transcription
factors.
–Involved in the control of gene expression by their action on DNA itself
Mechanisms of oncogene activation
•
1. Structural alteration.
–Point mutations–Chromosomal translocation
–Truncated form of protein (transition mutation)
•
2. Amplification
12/4/2010
Apoptosis
•
Programmed cell death
•
Intracellular machinery responsible for
apoptosis is called caspases.
•
Caspases
• Synthesized in the cell as inactive precursor called procaspases
Tumor suppressor genes
•
Play an important role in tumorigenesis.
•
Involved in the control of abnormal cell
proliferation.
•
Loss or inactivation : association with the
development of malignancy.
Tumorsuppressor genes
• The majority of p53 mutations (80%) in breast cancer are missense, while 20%: nonsense mutations, deletions, insertions
• P53 protein (21kD) normally inhibits Cdk (Cyclin dependent kinase) enzymes.
12/4/2010
Carcinogenics
• Radiant energy • Chemical compounds
• Viruses ( DNA virus,RNA virus, Adeno virus)
• These act by causing mutations or by introducing novel genes into cells
• Familial conditions (Tumor suppressor genes) • Oxidative damage to DNA increase the
Tumor metastasis
• Metastasis is the most dangerous property of tumor cells
• The cell grow as secondary tumors
• Many changes have been documented at the surfaces of malignant cells
12/4/2010
The invasion-metastasis cascade
Chiang A and Massague J. N Engl J Med 2008;359:2814-2823
Patterns of metastatic spread of solid tumor
