Cancer Biology and Carcinogenesis

Hallmarks & Cell Cycle - Cancer's Playbook

• Key Hallmarks of Cancer:
  • Sustained proliferative signaling (e.g., oncogene activation)
  • Evading growth suppressors (e.g., loss of p53, Rb function)
  • Resisting cell death (e.g., anti-apoptotic protein upregulation)
  • Enabling replicative immortality (telomerase re-activation)
  • Inducing angiogenesis (VEGF signaling)
  • Activating invasion & metastasis (EMT process)
• Cell Cycle & Its Dysregulation:
  • Phases: G1 (growth) → S (DNA synthesis) → G2 (prep for mitosis) → M (mitosis).
  • Regulators: Cyclins (regulatory subunits) pair with Cyclin-Dependent Kinases (CDKs; catalytic subunits) to control progression.
  • Checkpoints: G1/S (restriction point; p53, Rb crucial) & G2/M ensure fidelity.

⭐ Li-Fraumeni syndrome: germline TP53 mutations cause high predisposition to diverse early-onset cancers.

Oncogenes & Suppressors - Genes Gone Wild

Cancer arises from genetic changes. Oncogenes act as accelerators, while Tumor Suppressor Genes (TSGs) are brakes.

⭐ The Philadelphia chromosome t(9;22) creates the BCR-ABL fusion oncogene in CML.

Carcinogenesis - Making of a Monster

• Steps: Initiation (irreversible DNA mutation), Promotion (reversible clonal expansion of initiated cells), Progression (malignant transformation, genetic instability, invasion).
• Carcinogens:
  • Chemical: Direct-acting; Procarcinogens (need activation, e.g., Aflatoxin B1 - liver; asbestos - lung; benzene - leukemia; PAHs - lung/skin).
  • Radiation: UV (pyrimidine dimers, e.g., $T-T$); Ionizing (DNA breaks).
  • Viral: HPV (E6 degrades p53, E7 inhibits RB); EBV (Burkitt's, Nasopharyngeal Ca); HBV/HCV (HCC); HTLV-1 (ATLL).

⭐ Aflatoxin B1, from Aspergillus on improperly stored grains/nuts, is a potent hepatocarcinogen, especially with chronic Hepatitis B/C.

Metastasis & Immunity - Spread & Evade

• Metastatic Cascade: Sequential steps for cancer spread.

![Metastatic cascade steps diagram](https://ylbwdadhbcjolwylidja.supabase.co/storage/v1/object/public/notes/L1/Internal_Medicine_Oncology_Cancer_Biology_and_Carcinogenesis/f37c7158-4adf-4e64-9c69-377c3af69578.png)

• Angiogenesis: New blood vessel formation, vital for tumor growth/spread. Key mediator: VEGF.
• Tumor Antigens:
  • TSA (Tumor-Specific Antigens): Unique to tumor cells (e.g., mutated oncogenes).
  • TAA (Tumor-Associated Antigens): Overexpressed/aberrantly expressed (e.g., HER2).
• Immune Surveillance & Immunoediting: (3 Es - Elimination, Equilibrium, Escape)
  • Tumor cells evolve to evade immune destruction.
• Mechanisms of Immune Evasion:
  • ↓MHC Class I expression (hides from CD8+ T cells).
  • ↑PD-L1 expression (inhibits T-cell attack via PD-1).
  • Secretion of immunosuppressive cytokines (e.g., TGF-β, IL-10).
  • Induction of Tregs.

⭐ Loss of E-cadherin function is crucial for epithelial-mesenchymal transition (EMT) and invasion.

High‑Yield Points - ⚡ Biggest Takeaways

• Hallmarks of Cancer include sustained proliferation, evading growth suppressors, angiogenesis, and invasion/metastasis.
• Tumor suppressor genes like p53 & Rb require two-hit inactivation (Knudson's hypothesis).
• Oncogenes such as RAS & MYC need one-hit activation for transformation.
• Carcinogenesis is a multi-step process: initiation, promotion, and progression.
• Key factors: chemical carcinogens (aflatoxin, asbestos) & viral carcinogens (HPV, EBV).
• Metastasis (invasion to colonization) is the primary cause of cancer mortality.
• Warburg effect: Cancer cells preferentially use aerobic glycolysis.