Apoptosis and cancer

Apoptosis - The Good Goodbye

• Programmed cell death (“cellular suicide”) that eliminates damaged cells, executed by caspases.
• Intrinsic Pathway: Mitochondrial; regulated by the Bcl-2 family. Anti-apoptotic Bcl-2 blocks cytochrome c release; pro-apoptotic Bax/Bak promote it.
• Extrinsic Pathway: Initiated by ligand binding to death receptors like FAS (CD95).
• Cancers evade apoptosis via p53 mutations, ↑Bcl-2 expression, or ↓FAS receptor levels.

⭐ Follicular lymphoma's t(14;18) translocation places the BCL2 gene by the Ig heavy chain locus, causing its overexpression and preventing B-cell apoptosis.

Apoptosis Pathways - Death's Decision Tree

• Two main routes to programmed cell death, both converging on caspases.

• Intrinsic (Mitochondrial) Pathway

  • Triggered by: DNA damage (via p53), loss of survival signals, ER stress.
  • Regulated by BCL-2 family proteins:
    • Pro-apoptotic: BAX and BAK create pores in the mitochondrial membrane.
    • Anti-apoptotic: BCL-2 and BCL-xL prevent pore formation, blocking cytochrome c release. Cancer often overexpresses these.
  • Execution: Leaked cytochrome c binds Apaf-1, activating initiator Caspase-9.

• Extrinsic (Death Receptor) Pathway

  • Triggered by: External ligands binding to cell surface death receptors.
    • FasL binding to Fas (CD95).
    • TNF-α binding to TNFR1.
  • Execution: Receptor binding recruits FADD (Fas-Associated Death Domain), which activates initiator Caspase-8.

⭐ Exam Favorite: Overexpression of BCL-2 is a hallmark of follicular lymphoma, resulting from the t(14;18) translocation. This prevents apoptosis and promotes cell survival, contributing to the malignancy.

Evasion of Apoptosis - Cancer's Great Escape

• Core Principle: To survive, cancer cells must disable apoptosis (programmed cell death). This is primarily achieved by disrupting the balance of pro- and anti-apoptotic proteins, a key hallmark of cancer.

• Intrinsic (Mitochondrial) Pathway Disruption: The most common target.

  • ↑ Anti-apoptotic Proteins: Overexpression of BCL-2, BCL-xL, and MCL-1.
    • These proteins prevent cytochrome c release from mitochondria, thus blocking caspase activation.
    • 📌 Bcl-2 = "Be Cool, Live 2-day!"
  • ↓ Pro-apoptotic Effectors: Inactivation of BAX and BAK, which normally form pores in the mitochondria.
  • Loss of p53: Mutated p53 fails to induce apoptosis by transcribing pro-apoptotic genes like BAX.

⭐ Exam Favorite: Overexpression of BCL-2 is the classic mechanism in follicular lymphoma, driven by the t(14;18) translocation. This places the BCL2 gene next to the highly active immunoglobulin heavy chain gene promoter.

• Extrinsic (Death Receptor) Pathway Disruption:
  • Reduced surface expression of the Fas (CD95) receptor.
  • Secretion of decoy receptors that bind FasL but fail to transduce the death signal.

• Cancer cells evade apoptosis, a key hallmark enabling uncontrolled proliferation and survival.
• Dysregulation of the intrinsic (mitochondrial) pathway is the most common mechanism.
• Mutations in p53 are critical, as it normally triggers apoptosis following DNA damage.
• Overexpression of anti-apoptotic proteins like Bcl-2 prevents cell death (e.g., follicular lymphoma).
• Executioner caspases are often inhibited, blocking the final apoptotic steps.
• Cancer therapies often aim to reactivate dormant apoptotic pathways.