Harvey's Garden

General oncology

5 min read

Carcinogenesis

Carcinogens

  • Chemical & Environmental Carcinogens
    • Aflatoxins (from Aspergillus) → Hepatocellular carcinoma
      • Associated with stored grains/nuts in humid climates.
      • Mechanism: Induces p53 mutation (G:C → T:A transversion).
    • Alkylating agents (e.g., chemotherapeutics like cyclophosphamide) → Leukemia/Lymphoma
      • Common long-term side effect of chemo.
    • Aromatic amines (e.g., aniline dyes, benzidine) → Transitional cell carcinoma of the bladder
      • Classic Hx: Worker in textile or dye industry.
    • Arsenic → Squamous cell carcinoma of the skin, Lung cancer, Angiosarcoma of the liver.
      • Exposure: Herbicides, metal smelting, contaminated water.
    • Asbestos → Bronchogenic carcinoma (most common malignancy), Mesothelioma (most specific).
      • Classic Hx: Plumber, shipyard worker, insulation installer.
      • Histology: Asbestos (ferruginous) bodies.
    • Benzene → Acute myeloid leukemia (AML)
      • Exposure: Industrial solvent, found in gasoline. Causes bone marrow suppression.
    • Cigarette Smoke → Transitional cell carcinoma (bladder), Squamous cell carcinoma (cervix, esophagus, larynx, lung), Small cell carcinoma (lung), Renal cell carcinoma, Pancreatic adenocarcinoma.
      • Polycyclic aromatic hydrocarbons are a key component.
    • Ethanol → Squamous cell carcinoma (esophagus), Hepatocellular carcinoma.
    • Nitrosamines (smoked foods) → Gastric adenocarcinoma (intestinal type).
    • Radon → Lung cancer
      • Second leading cause after smoking; risk is synergistic with smoking.
      • Exposure: Decay of uranium in soil, accumulates in basements.
    • Vinyl chloride → Angiosarcoma of the liver.
      • Exposure: Used in making PVC pipes.
  • Oncogenic Viruses
    • Epstein-Barr Virus (EBV) → Burkitt lymphoma, Hodgkin lymphoma (mixed cellularity subtype), Nasopharyngeal carcinoma, primary CNS lymphoma in immunocompromised pts.
    • Hepatitis B Virus (HBV) & Hepatitis C Virus (HCV) → Hepatocellular carcinoma.
      • Chronic inflammation → cirrhosis → carcinoma.
    • Human Herpesvirus 8 (HHV-8) → Kaposi sarcoma.
      • Classic settings: Elderly Eastern European men, AIDS pts, transplant recipients.
    • Human Papillomavirus (HPV) → Squamous cell carcinoma (cervix, anus, vagina, vulva), Adenocarcinoma of the cervix, Oropharyngeal cancer.
      • High-risk types: 16, 18.
      • Mechanism: E6 gene product inhibits p53; E7 gene product inhibits Rb.
  • Other Infectious Agents
    • Helicobacter pylori → Gastric adenocarcinoma & MALT Lymphoma.
    • Schistosoma haematobium → Squamous cell carcinoma of the bladder.
      • Endemic to Middle East, Africa. Classic Hx: Male from Egypt with hematuria.
    • Clonorchis sinensis (Chinese liver fluke) → Cholangiocarcinoma.
      • Ingestion of undercooked fish.
  • Radiation
    • Ionizing radiation (e.g., nuclear accidents, radiotherapy) → Papillary carcinoma of the thyroid, Leukemias (AML, CML).
    • Non-ionizing radiation (UVB sunlight) → Basal cell carcinoma, Squamous cell carcinoma, Melanoma of the skin.
      • Mechanism: Forms pyrimidine dimers in DNA, normally repaired by nucleotide excision repair.

Defense mechanisms of malignant cells

I. Immune Evasion

  • ↓ MHC Class I Expression: Prevents tumor antigen presentation to CD8+ cytotoxic T-cells, rendering the cancer cell “invisible.”
  • Upregulation of Immune Checkpoints:
    • PD-L1 (on tumor cell) binds PD-1 (on T-cell) → induces T-cell exhaustion/anergy. (Target of Pembrolizumab, Nivolumab).
    • CTLA-4 (on T-cell) outcompetes CD28 for B7 (on APCs) → inhibits T-cell activation. (Target of Ipilimumab).
  • Immunosuppressive Microenvironment:
    • Secretion of TGF-β and IL-10 → inhibit T-cells and NK cells.
    • Recruitment of regulatory immune cells: Tregs, Myeloid-Derived Suppressor Cells (MDSCs), and M2 Macrophages.
  • Antigen Loss: Tumor cells lose expression of recognizable neoantigens through mutation, leading to immune escape.

II. Drug Resistance

  • Increased Drug Efflux:
    • Upregulation of P-glycoprotein (MDR1 gene product), an ATP-dependent pump that removes chemo drugs (e.g., Vinca alkaloids, taxanes) from the cell.
  • Modification of Drug Targets:
    • Gene Amplification: e.g., DHFR amplification confers resistance to Methotrexate.
    • Mutation: e.g., Kinase domain mutations in CML confer resistance to Imatinib.
  • Enhanced DNA Repair: Increased capacity to repair damage caused by alkylating agents or radiation.
  • Inhibition of Apoptosis:
    • Upregulation of anti-apoptotic proteins (e.g., Bcl-2).
    • Inactivation of pro-apoptotic proteins (e.g., mutations in TP53).
  • Drug Inactivation: Cancer cells produce enzymes that metabolize and inactivate drugs.

Metastasis

Mechanisms of metastasis

  • Epithelial-Mesenchymal Transition (EMT): A crucial process where epithelial cancer cells lose their cell-cell adhesion and polarity to gain migratory and invasive mesenchymal properties.
    • ↓ E-cadherin (Epithelial): Loss of this key adhesion molecule disrupts tight cell-cell junctions, increasing motility. This is a hallmark of EMT.
    • ↑ N-cadherin (Neural): A “cadherin switch” can promote invasion by increasing affinity for stromal cells.
    • Transcription Factors: EMT is driven by transcription factors like SNAIL, SLUG, and TWIST.
  • Extracellular Matrix (ECM) Degradation: Tumor cells secrete proteolytic enzymes to break down the ECM and basement membrane.
    • Matrix Metalloproteinases (MMPs): A family of zinc-dependent endopeptidases that degrade collagen and other ECM components. MMPs also release bioactive molecules (e.g., growth factors) from the ECM.
    • Cathepsins: These proteases also contribute to ECM degradation and are often highly expressed in invasive tumors.
  • Mesenchymal-Epithelial Transition (MET): The reverse process of EMT, where metastatic cells at a secondary site regain epithelial characteristics to form a new tumor. This is critical for successful colonization.

Types of metastasis

  • Carcinomas → Primarily Lymphatic spread to regional lymph nodes.
  • Sarcomas → Primarily Hematogenous spread.

A helpful mnemonic for these exceptions is “Four Rare Hematogenous Carcinomas”:

  • Follicular Thyroid Carcinoma: Invades capsular blood vessels, a key feature distinguishing it from follicular adenoma.
  • Renal Cell Carcinoma (RCC): Classically invades the renal vein and can extend as a tumor thrombus into the inferior vena cava (IVC) and even the right atrium.
  • Hepatocellular Carcinoma (HCC): Frequently invades the portal and hepatic veins.
  • Choriocarcinoma: A highly aggressive tumor of trophoblastic tissue that rapidly invades blood vessels, leading to early hematogenous spread to the lungs.

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