Cancer Biology Basics

Hallmarks of Cancer - Rebel Cell Rules

• Sustaining proliferative signaling: Uncontrolled cell growth.
• Evading growth suppressors: Ignoring "stop" signals (e.g., p53, RB loss).
• Resisting cell death: Bypassing apoptosis.
• Enabling replicative immortality: Unlimited cell divisions (telomerase).
• Inducing angiogenesis: Forming new blood vessels (VEGF).
• Activating invasion & metastasis: Spreading to distant sites.
• Deregulating cellular energetics: Warburg effect (aerobic glycolysis).
• Avoiding immune destruction: Hiding from immune system.
• Genome instability & mutation: ↑ Genetic alterations.
• Tumor-promoting inflammation: Inflammation aiding cancer.

⭐ Loss of function of the TP53 tumor suppressor gene is the most common genetic alteration in human cancers, occurring in >50% of cases.

Oncogenes & TSGs - Genes Gone Wild

• Oncogenes: Arise from proto-oncogenes; drive cell growth (gain-of-function).
  • "Gas pedal" ➔ Uncontrolled proliferation.
  • Activation: Mutation, amplification, translocation.
  • Examples: RAS, MYC, HER2/neu (ERBB2), ABL, EGFR.
  • Dominant: Single allele mutation is sufficient.
• Tumor Suppressor Genes (TSGs): Normally halt cell cycle, induce apoptosis, or repair DNA.
  • "Brake pedal" ➔ Failure to control growth.
  • Inactivation: Mutations, deletions, methylation (loss-of-function).
  • Knudson's "two-hit" hypothesis often applies.
  • Examples: p53, RB1 (retinoblastoma), BRCA1/2, APC, PTEN.
  • 📌 Oncogenes = On (accelerate); TSGs = Stop (brake).

⭐ p53, the "guardian of the genome," is mutated in over 50% of human cancers.

Cell Cycle & Regulation - Cell Cycle Chaos

• Phases: G1 (growth), S (DNA synthesis), G2 (mitotic prep), M (mitosis). (📌 Mnemonic: Go Sally Go Make)
• Key Regulators:
  • Cyclins (D, E, A, B) activate CDKs (e.g., CDK4/6, CDK2, CDK1).
  • CDK Inhibitors (CKIs e.g., p16, p21, p27) halt progression.
• Checkpoints (Fail-safes):
  • G1/S (Restriction Point): Governed by Rb, p53. Checks DNA integrity.
  • G2/M: Ensures DNA replication complete, damage repaired.
  • Spindle Assembly (M): Confirms correct chromosome attachment.
• Cancer = Dysregulation:
  • Checkpoint failure (e.g., TP53, RB1 gene mutations) → uncontrolled proliferation.
  • Oncogenes (e.g., Cyclin D) overexpressed; Tumor Suppressor Genes lost.

⭐ TP53, the "guardian of the genome," is mutated in over 50% of human cancers, causing G1/S checkpoint failure & genomic instability.

Metastasis & Angiogenesis - The Great Escape

• Metastasis: Cancer cells spread from primary to distant sites, forming secondary tumors.
  • Routes: Lymphatic (common for carcinomas), Hematogenous (common for sarcomas), Transcoelomic.
  • Common Sites: Lung, Liver, Bone, Brain (📌 LLBB: "Love Large Big Breakfast").
  • Mechanism: "Seed and Soil" (Paget) - tumor cells ("seed") require a favorable microenvironment ("soil").

• Angiogenesis: Formation of new blood vessels; vital for tumor growth > 1-2 mm & metastasis.
  • "Angiogenic Switch": Balance shifts to favor pro-angiogenic factors.
  • Pro-angiogenic: VEGF, bFGF, PDGF.
  • Anti-angiogenic: Thrombospondin-1, Angiostatin.
  • 💡 Anti-VEGF therapy (e.g., Bevacizumab) is a key strategy.

  ⭐ VEGF is a primary driver of tumor angiogenesis.

High‑Yield Points - ⚡ Biggest Takeaways

• Oncogenes (e.g., RAS, MYC) drive cancer by promoting uncontrolled cell growth.
• Inactivation of tumor suppressor genes like p53 (genome guardian) and RB is critical for cancer development.
• Metastasis, the spread to distant sites, is the main cause of cancer mortality.
• Angiogenesis (new blood vessel formation, e.g., via VEGF) is essential for tumor growth.
• Cancer arises from a multi-step accumulation of genetic/epigenetic changes.
• Key hallmarks include evading apoptosis, limitless replication, and tissue invasion_._