Metastasis

Metastasis is a multi-step process, where the tumor cells overcome several challenges to spread from the primary site to form secondary tumors in the body. As few as one  in a million cells manage to achieve metastasis.

Normal cells are confined to their tissue of origin by cell-cell adhesion and the basement membrane, which is a physical barrier present between tissues. Cancer cells overcome the tissue constraints by a process called epithelial to mesenchymal transition or EMT.

This transition activates two transcription factors, Snail and Twist, which promote the expression of genes involved in cell migration and down-regulate the cell-adhesion factors such as E-cadherin.

Transformed cells then penetrate the basement membrane by extending invadopodia, the actin-rich protrusions. Invadopodia secrete proteases, which degrade the basement membrane.

Once they are freed from the tissue constraints, the transformed cells reach the blood vessel by modifying the extracellular matrix.

Tumor cells then breakdown the basement membrane of the vessel and squeeze through the epithelial cells’ tight junctions to enter the blood circulation by a process called intravasation.

The majority of the circulating tumor cells or CTCs die during circulation due to lack of cell-cell adhesion and also by immune surveillance. Some CTCs secrete substances like thrombin, and cancer procoagulant, to stimulate platelet coating around them. This helps CTCs escape the shear  stress during circulation and also to escape immune surveillance.

In addition, certain CTCs express survivin proteins that suppress the action of cytotoxic natural killer cells.

Initially, the CTCs adhere weakly to the endothelial cells via adhesion molecules and roll along the vessel lining until they form a firm attachment to the vessel. Then they squeeze through the vessel’s endothelial lining, digest the basement membrane and enter a new, distant tissue by a process called extravasation.

Once in the new site, the tumor cells adapt to the foreign tissue environment to form microcolonies and eventually proliferate to form macroscopic secondary tumors.