Paper I
Question
Metastatic cascade
Answer
The metastatic cascade is the sequence of steps by which malignant cells spread from a primary tumour to establish secondary growths at distant sites.
1. Local invasion
- Tumour cells detach from neighbouring cells (loss of E-cadherin-mediated cell adhesion)
- Degrade the extracellular matrix and basement membrane via proteolytic enzymes (matrix metalloproteinases)
- Attach to and invade through the altered extracellular matrix
2. Intravasation
- Tumour cells penetrate through vascular or lymphatic basement membranes to enter the circulation
3. Survival in circulation
- Circulating tumour cells must evade immune surveillance (e.g., by forming platelet aggregates around themselves, which also shields them from natural killer cells) and physical shear stress
- Most circulating tumour cells die; only a small fraction survive
4. Adhesion at a distant site
- Surviving tumour cells arrest in the microvasculature of a distant organ, adhering to endothelium (via adhesion molecules) or becoming trapped by vessel calibre
5. Extravasation
- Tumour cells exit the vasculature into the surrounding tissue parenchyma, using similar mechanisms to local invasion (proteolysis, migration)
6. Colonization (formation of metastatic deposit)
- Tumour cells must proliferate in the new microenvironment, which requires establishing a supportive stroma and inducing angiogenesis (via VEGF and other angiogenic factors) to sustain growth of the metastatic deposit
- The concept of “seed and soil” explains organ tropism — certain tumours preferentially metastasize to specific organs based on compatibility between tumour cell properties (the “seed”) and the local microenvironment (the “soil”)