5. Tumor growth 2.0 - Stages of carcinogenesis

List stages of carcinogenesis

1. initiation

2. promotion

3. progression

A. Initiation

• Definition: The first step. A normal cell sustains irreversible DNA damage (mutation) from a carcinogen (chemical, physical, or biological).

• Key Characteristics:

  • It is rapid and irreversible.

  • The cell must undergo at least one cycle of proliferation for the DNA damage to be "locked in" (fixed) before DNA repair mechanisms can fix it.

  • An initiated cell looks normal and functions normally, but it is altered and has the potential to become a tumor.

  • Initiation alone is not sufficient for tumor formation.

B. Promotion

• Definition: The second step. The initiated, mutated cell is stimulated to divide and proliferate by agents called promoters.

• Key Characteristics:

  • Promoters are not mutagenic themselves (they don't damage DNA). They only cause cellular proliferation.

  • This process is reversible (if the promoter is removed early on, the tumor doesn't form).

  • Hormones (e.g., estrogen) and chronic inflammation are classic endogenous promoters.

  • The Order Matters: To form a tumor, a cell must be exposed to an Initiator first, followed by repeated exposure to a Promoter. (Promoter first, or Initiator followed by a long delay before Promoter, does not work).

  • Result: Creates a large clone of initiated cells (a benign tumor or pre-malignant lesion).

C. Progression

• Definition: The final stage where the benign/pre-malignant lesion acquires additional mutations, becoming fully malignant.

• Key Characteristics:

  • Characterized by tumor heterogeneity (subclones of cells develop within the tumor, each with different mutations).

  • Driven by genomic instability.

  • Cells acquire the hallmarks of cancer: independent growth, evasion of apoptosis, immortality, angiogenesis, and the ability to invade/metastasize.

Pathophysiology of Invasion and Metastasis

A. Invasion of the Extracellular Matrix (ECM)

To spread, carcinoma cells must break through the basement membrane and navigate the surrounding connective tissue (stroma). This requires four steps:

1. Loosening of Cell-Cell Contacts:

   • Normal epithelial cells are glued together by E-cadherins.

   • Malignant cells often downregulate or mutate E-cadherin, allowing them to detach from their neighbors.

2. Degradation of the ECM:

   • Tumor cells (or the stromal cells they hijack) secrete proteolytic enzymes like Matrix Metalloproteinases (MMPs), specifically MMP-9 (a gelatinase) and Cathepsin D.

   • These enzymes chew up the basement membrane (type IV collagen) and interstitial connective tissue.

3. Attachment to Novel ECM Components:

   • Normal epithelial cells die if they detach from the basement membrane (a process called anoikis).

   • Tumor cells change their integrin receptors to attach to the newly exposed, degraded ECM proteins (like fibronectin and laminin) to pull themselves forward and avoid death.

4. Migration:

   • Tumor cells "crawl" through the degraded matrix, stimulated by autocrine motility factors and cleavage products of the ECM.

B. Vascular Dissemination and Homing (Metastasis)

Once in the blood or lymph, tumor cells face a hostile environment (shear stress, immune cells). Only a tiny fraction survive.

1. Intravasation: Entering the blood or lymphatic vessel.

2. Survival in Circulation:

   • Tumor cells often aggregate with platelets to form a tumor embolus. The platelets act as a "shield," hiding the tumor cells from natural killer (NK) cells and protecting them from the sheer forces of blood flow.

3. Arrest and Extravasation:

   • The tumor embolus gets stuck in the first capillary bed it encounters.

   • The cells adhere to the endothelium, retract it, and squeeze out into the new tissue.

4. Homing (Where do they go?):

   • Usually dictated by vascular anatomy (e.g., GI tract cancers commonly spread to the liver via the portal vein).

   • Sometimes dictated by specific "seed and soil" mechanisms: The tumor cell (seed) has specific chemokine receptors that match chemokines produced only in specific organs (soil).

   • Classic exceptions to anatomical spread: Prostate cancer often goes to bone; Lung cancer often goes to the adrenals and brain.

Explain role of tumor angiogenesis

A tumor cannot grow larger than 1-2 mm unless it develops its own blood supply. Without blood, the center of the tumor becomes hypoxic and dies (necrosis).

• The Angiogenic Switch:

  • Hypoxia in the center of the tumor triggers the production of HIF-1α (Hypoxia-Inducible Factor).

  • HIF-1α travels to the nucleus and turns on the transcription of pro-angiogenic factors, primarily VEGF (Vascular Endothelial Growth Factor) and bFGF (Basic Fibroblast Growth Factor).

• Characteristics of Tumor Vessels:

  • Unlike normal blood vessels, tumor vessels are leaky, chaotic, tortuous, and structurally abnormal. This leakiness actually aids in tumor cells escaping into the circulation (metastasis).