Cancer Biology and Tumor Suppressor Genes

  • Carcinogenic Agents

  • Damage DNA leading to mutations.

  • Affect key regulatory systems in the cell cycle.

  • Key Regulatory Systems:

  • Proto-Oncogenes:

    • When mutated, become oncogenes, promoting tumor formation.

  • Tumor Suppressor Genes:

    • Regulate cell growth and suppress tumor formation.
    • Examples: p53 and retinoblastoma (Rb).

  • Tumor Suppressor Genes:

  • p53:

    • Regulates the cell cycle, specifically the transition from G1 to S phase.
    • Functions as a "traffic cop" for cell progression.
    • Checks DNA for mutations:
    • If mutations are present but repairable, calls for DNA repair enzymes.
    • If mutations are extensive, induces apoptosis by activating Bax to suppress BCL2, leading to cytochrome c release and cell death.
    • Both copies of p53 must be mutated for tumor formation (Knudson's two-hit hypothesis).
    • Loss of p53 is observed in >50% of cancers; mutations can be somatic or genetic (Li-Fraumeni syndrome).

  • Retinoblastoma (Rb):

  • Also regulates G1 to S phase transition.

  • Holds E2F transcription factor, which is released upon Rb phosphorylation by cyclin D/CDK4 complex.

  • A mutation in Rb leads to unregulated E2F release, causing unchecked cell cycle progression and tumor formation.

  • Similar to p53, both copies of Rb must be disrupted for tumor formation.

  • Sporadic Mutation results in unilateral retinoblastoma; Germline Mutation increases bilateral retinoblastoma risk and osteosarcoma association.

  • Apoptosis Regulation:

  • Essential to prevent normal cells from dying and induce death in mutated, damaged cells.

  • BCL2:

    • Stabilizes mitochondrial membrane to prevent cytochrome c release, blocking apoptosis.
    • Overexpression linked to follicular lymphoma via 14;18 translocation, disrupting normal apoptotic processes during B cell development in lymph nodes.

  • Telomerase:

  • Allows for cell immortality; upregulation prevents telomere shortening, avoiding cellular senescence.

  • Angiogenesis:

  • Necessary for tumor growth; tumors produce factors such as FGF and VEGF for blood supply.

  • Tumor Cell Mutation & Immune Surveillance:

  • Mutated tumor cells produce abnormal proteins that appear on MHC Class I.

  • CD8+ T cells recognize these proteins and kill tumor cells.

  • Tumors can evade immune response by downregulating MHC Class I expression.

  • Immunodeficiency increases cancer risk due to impaired immune surveillance.

  • Key Focus: CD8+ T cells and their recognition of abnormal proteins on MHC I are crucial for preventing tumor development.

  • Conclusion:

  • Understanding the multifaceted roles of tumor suppressor genes, apoptosis regulation, telomere maintenance, and immune interactions is crucial for comprehending cancer biology and tumor progression.