How Cancer Develops: From Mutation to Metastasis – A Stepwise Model

Carcinogenesis is a multistep process requiring accumulation of driver mutations that confer hallmark capabilities (Hanahan & Weinberg).

Classic Steps

1. Initiation: DNA damage (carcinogens: tobacco, UV, radiation, viruses, chemicals) → mutation in oncogene or tumor suppressor.
2. Promotion: Clonal expansion of initiated cell (epigenetic, inflammatory signals).
3. Progression: Genomic instability → additional mutations → invasion, angiogenesis, metastasis.

Hallmarks of Cancer (Updated)

• Sustained proliferative signaling.
• Evading growth suppressors.
• Resisting cell death (apoptosis).
• Enabling replicative immortality (telomerase).
• Inducing angiogenesis (VEGF).
• Activating invasion & metastasis (EMT).
• Reprogramming energy metabolism (Warburg effect).
• Evading immune destruction (PD-L1, MHC loss).
• Genome instability & mutation.
• Tumor-promoting inflammation.

Key Molecular Pathways

• RTK/RAS/PI3K/AKT/mTOR (growth).
• p53/RB (cell cycle/DNA repair).
• Wnt/β-catenin, Notch, Hedgehog (stemness).

Clinical Translation

• Prevention: reduce carcinogen exposure, vaccinate (HPV, HBV), chemoprevention (tamoxifen, aspirin).
• Screening: detect at pre-malignant or early stage (colonoscopy, LDCT, mammogram, Pap/HPV).
• Targeted therapy: match driver mutation (EGFR, ALK, BRAF, HER2, BCR-ABL).
• Immunotherapy: checkpoint inhibitors (PD-1/PD-L1, CTLA-4), CAR-T.