Cancer Biochemistry & Environmental Factors
Cancer is a group of diseases characterized by uncontrolled cell proliferation, invasion, and metastasis. It results from accumulated genetic and epigenetic alterations in cell growth control genes.
Molecular Basis of Cancer
- Proto-oncogenes → Oncogenes: Normal genes promoting growth become overactive. Activation by: point mutation (Ras), amplification (HER2/neu, MYCN), translocation (BCR-ABL in CML, c-Myc in Burkitt lymphoma). Oncogenes are gain-of-function (one mutant allele sufficient).
- Tumor Suppressor Genes (TSGs)→ loss of growth restriction: Both alleles must be lost (Knudson's Two-Hit Hypothesis). Examples: p53 (mutated in 50% of all cancers; "guardian of the genome"), Rb (retinoblastoma), APC (colon cancer), BRCA1/2, VHL, NF1/2, PTEN.
- DNA repair gene mutations: MLH1, MSH2 (Lynch syndrome), BRCA1/2 (breast/ovarian). Allow accumulation of further mutations.
- Apoptosis evasion: BCL-2 overexpression (t(14;18) in follicular lymphoma) blocks apoptosis.
- Telomere maintenance: Telomerase reactivated in ~85% of cancers → allows unlimited proliferation.
Hallmarks of Cancer (Hanahan & Weinberg)
- Sustaining proliferative signaling (growth factors, receptor mutations)
- Evading growth suppressors (loss of Rb, p53)
- Resisting cell death (BCL-2 overexpression)
- Enabling replicative immortality (telomerase)
- Inducing angiogenesis (VEGF overexpression)
- Activating invasion and metastasis (MMPs, EMT)
- Reprogramming energy metabolism (Warburg effect)
- Evading immune destruction
Warburg Effect (Aerobic Glycolysis)
Cancer cells preferentially use glycolysis even in the presence of O₂ (aerobic glycolysis). Produces 2 ATP per glucose vs 30–32 ATP (OXPHOS) — apparently inefficient but: ① Faster rate; ② Provides biosynthetic precursors (ribose-5-P for nucleotides, NADPH, amino acid precursors); ③ Creates acidic tumor microenvironment inhibiting immune cells. Basis of PET scan: ¹⁸F-FDG (glucose analog) taken up by metabolically active tumor cells → detected.
Carcinogens
- Chemical: PAHs (tobacco smoke, charred meat), Aflatoxin B1 (p53 mutation, hepatocellular carcinoma), Nitrosamines, Vinyl chloride (angiosarcoma), Benzene (leukemia), Asbestos (mesothelioma, lung), Arsenic (skin, bladder)
- Radiation: UV (pyrimidine dimers → NER defect → skin cancer), X-rays/γ-rays (DSBs → leukemia, thyroid), Radon (lung cancer)
- Viral: HPV 16/18 (E6/E7 inactivate p53/Rb → cervical, head/neck cancer), HBV/HCV (HCC), EBV (Burkitt lymphoma, NPC), HTLV-1 (T-cell leukemia), Helicobacter pylori (gastric MALT lymphoma, adenocarcinoma)
Tumor Markers (Biochemistry)
- PSA (Prostate-specific antigen): Prostate cancer screening
- AFP (α-fetoprotein): HCC, testicular germ cell tumors
- β-hCG: Choriocarcinoma, gestational trophoblastic disease
- CEA (Carcinoembryonic antigen): Colon, pancreas cancer (monitoring recurrence)
- CA-125: Ovarian cancer
- LDH: Lymphoma, testicular cancer
- Calcitonin: Medullary thyroid carcinoma