Thrombin generation and the pathogenesis of cancer.

Advanced cancer is associated with a hypercoagulable state that is triggered by tissue factor (TF). TF-initiated thrombin generation is crucial for metastasis through fibrin and platelet deposition, as well as thrombin-dependent protease-activated receptor (PAR) 1 signaling. Surprisingly, PAR2, which is not cleaved by thrombin, appears to cosignal with PAR1 to elicit thrombin effects in metastatic tumor cells. In contrast to TF-driven thrombin pathways in metastasis, direct TF signaling plays a role in angiogenesis-dependent tumor growth. In TF cytoplasmic-domain-deleted mice, PAR2-dependent angiogenesis and tumor growth is enhanced, demonstrating a role for host cell TF signaling. In tumor cells, TF-factor VIIa (FVIIa) activates PAR2 and thereby regulates proangiogenic growth factor expression as well as integrins involving crosstalk with the TF cytoplasmic domain. In addition to thrombin-PAR signaling in metastasis and TF-FVIIa-PAR2 signaling in tumor growth, it is likely that additional protease pathways will prove to be crucial activators of PARs in cancer. Transmembrane serine proteases as well as matrix metalloproteinase are prime candidates for accessory pathways to regulate metastasis, tumor expansion, and angiogenesis dependent on specific features of the local tumor microenvironment.