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Epithelial-to-mesenchymal transition (EMT) is a process where cancer cells lose cell-cell adhesion and gain migratory properties. Transcription factors like Snail and Twist activate genes for cell migration while downregulating E-cadherin, an adhesion protein. This allows cancer cells to escape tissue constraints and enter the bloodstream to begin metastasis.

Cancer cells extend actin-rich protrusions called invadopodia that secrete proteases to degrade the basement membrane. These proteases break down the physical barrier separating tissues, allowing transformed cells to reach blood vessels and modify the surrounding extracellular matrix for further invasion.

Most circulating tumor cells (CTCs) die during circulation due to lack of cell-cell adhesion and immune surveillance by natural killer cells. However, some CTCs survive by secreting substances like thrombin and cancer procoagulant to attract platelets, which shield them from immune attack and shear stress.

Cancer cells employ multiple immune evasion strategies during circulation. Blood platelets coat CTCs and transfer major histocompatibility complex (MHC) molecules to help them evade natural killer cells. Additionally, certain CTCs express survivin proteins that suppress cytotoxic natural killer cell activity, improving survival rates.

Extravasation is the process where circulating tumor cells squeeze through vessel endothelial lining and digest the basement membrane to enter distant tissues. Once in the new site, tumor cells adapt to the foreign tissue environment, form microcolonies, and eventually proliferate into macroscopic secondary tumors through mesenchymal-to-epithelial transition.

Metastasis is extremely rare because as few as one in a million cancer cells successfully complete the entire process. Tumor cells face multiple barriers including tissue constraints, immune surveillance, and circulation stress. The genetic heterogeneity among tumor cell populations and complexity of metastasis make cancer difficult to cure.

Creating therapeutics that specifically target metastasis stages—such as EMT inhibition, intravasation prevention, or CTC survival suppression—could reduce cancer deaths. Since metastasis involves distinct molecular steps, stage-specific interventions may be more effective than broad approaches in preventing secondary tumor formation and improving patient outcomes.