Lecture 19

The Molecular Basis of Cancer

• Oncogenesis is the formation or induction of tumors, involving mutant forms of normal genes called proto-oncogenes, which code for oncoproteins.
• Genetic damage, acquired through environmental agents or inherited, is the fundamental principle of carcinogenesis, resulting in a single progenitor cell that has incurred genetic damage and undergoes clonal expansion.
• Carcinogenesis involves the accumulation of mutations over time, as well as one-off catastrophic events.

Mutations in Cancer

• Driver mutations confer a growth advantage on cells and are located in cancer genes.
• Passenger mutations do not confer a growth advantage.

Normal Cellular Processes

• Dependence on growth factors and cell/tissue-specific signals is a normal characteristic of cells.
• Loss of these signals leads to apoptosis.
• Anchorage-dependent proliferation requires interaction with the extracellular matrix (ECM) through transmembrane proteins (integrins).
• Contact inhibition occurs when cells are in contact with each other, inhibiting proliferation and movement.
• Normal somatic cells have a limited number of divisions before entering senescence.

The Hallmarks of Cancer

• Sustaining proliferative signaling: oncogenes promote uncontrolled cell proliferation through mechanisms such as stimulating independent growth factor secretion, mutated growth factor receptors, and over-expressed nuclear transcription factors.

Oncogenes and Tumor Suppressor Genes

• Oncogenes are mutated forms of proto-oncogenes that promote cancer cell growth autonomously.
• Oncoproteins (products of oncogenes) promote uncontrolled cell proliferation.
• Mechanisms of self-sufficiency in growth signals include:
  • Stimulus-independent secretion of growth factors
  • Mutation/over-expression of growth factor receptors
  • Mutation in genes encoding signaling proteins from receptor to nucleus
  • Over-expression of nuclear transcription factors promoting cell cycle
  • Mutations in cyclin genes resulting in uncontrolled cell proliferation
• Tumor suppressor genes encode proteins that inhibit cellular proliferation by regulating the cell cycle.
• Mutation in tumor suppressor genes leads to uninhibited cell proliferation.

Tumor Suppressor Genes

• Both copies of the gene must be lost for carcinogenesis to occur (autosomal recessive).
• In cases with familial predisposition, affected persons inherit one defective copy of a tumor suppressor gene and lose the second one through somatic mutation.
• Examples of tumor suppressor genes include:
  • RB gene in retinoblastoma
  • P53 in human cancers
  • APC in Adenomatous polyposis coli

Cell Cycle Regulation

• The RB gene prepares for mitosis and controls the cell cycle.
• DNA damage checkpoint arrests the cell cycle, allowing for DNA repair or apoptosis.
• P53 is a tumor suppressor gene that maintains the integrity of the genome and senses DNA damage, assisting in DNA repair by arresting the cell cycle and inducing DNA repair genes.