Cancer II: invasion and metastasis

1. Defines metastasis as spread to a distant, discontinuous site
2. Local invasion: loss of E-cadherin / EMT so cells detach
3. MMPs degrade basement membrane and extracellular matrix
4. Intravasation into blood or lymphatic vessels
5. Survival in circulation (shear stress, immune attack; platelets can protect)
6. Arrest in capillary bed and extravasation
7. Colonisation: proliferation and angiogenesis at the new site
8. Inefficiency: most circulating cells die; very few form metastases
9. Seed-and-soil / organ environment limits which sites are colonised
10. Clear, logical sequence using correct terminology

Metastasis is the spread of tumour cells to a distant site where they form a secondary tumour discontinuous with the primary. First, cells invade locally: loss of E-cadherin during epithelial–mesenchymal transition lets them detach, and matrix metalloproteinases degrade the basement membrane and extracellular matrix. Cells then intravasate into blood or lymphatic vessels. In the circulation they must survive shear stress and immune attack, often helped by coating with platelets. They arrest in a distant capillary bed, extravasate into the tissue and, if the environment is suitable, proliferate and stimulate angiogenesis to form a metastasis. The process is inefficient because every step is a barrier: the vast majority of cells entering the circulation are destroyed, and of those that extravasate, many remain dormant or die. As the seed-and-soil idea suggests, cells only colonise organs whose microenvironment supports them, so only a tiny fraction of shed cells ever form a clinically detectable metastasis.