Mechanisms Coupling Thrombin-Mediated Proteolysis to Metastasis.

Multiple lines of evidence point to a link between coagulation factors and malignancy. Numerous clinical studies have demonstrated a strong correlation between tumor cell-associated tissue factor (TF) expression and poor outcome for many types of cancer. While TF expression by tumor cells could promote metastasis through several mechanisms, comparative analyses of TF-sufficient and TF-deficient tumor cell lines in mice with and without key circulating hemostatic factors point to thrombin as the premier downstream effector coupling TF to metastasis. Furthermore, it appears that thrombin supports metastasis through mechanism(s) that are highly dependent on the availability of fibrinogen, factor XIII, and platelet function. The metastatic potential of TF-expressing tumor cells has been shown to be strongly diminished in mice with genetic defects in either fibrin formation or stabilization (e.g., Fib−/−, fXIII−/−), or platelet disorders (e.g., NF-E2−/−, Gαq−/−, PAR-4−/−). Interestingly, one mechanism through which tumor-cell-associated TF, prothrombin, and the platelet/fibrinogen axis all appear to support metastasis is by impeding natural killer (NK) cell-mediated clearance of newly formed micrometastases. While these results demonstrate a novel link between the hemostatic and innate immune systems, limiting NK cell function is clearly not the only mechanism coupling thrombin to tumor cell metastasis. Signaling through protease activated receptors (PARs) on cells other than platelets has been suggested to support tumor stroma formation and angiogenesis. Furthermore, thrombin-mediated signaling via PARs expressed by tumor cells themselves has been shown to support metastatic potential. Finally, thrombin may support metastatic potential by acting in concert on multiple substrates (e.g., platelet and endothelial cell-associated PARs, fibrinogen, fXIII, etc.) to promote the sustained, stable adherence of circulating tumor cells in distant vascular beds. In summary, thrombinmediated proteolysis appears to influence both extracellular and intracellular events vital to tumor cell dissemination. Therapeutic strategies designed to block tumor cell-associated thrombin generation/activity could prove effective in preventing or eliminating metastatic disease.