Protease signaling in tumor progression

Protease-activated receptors (PARs) constitute a family four of G-protein coupled receptors that mediate cellular responses to serine proteases. Best known as receptors for the coagulation protease thrombin, PARs can also be activated by other coagulation proteases, intestinal proteases and proteases released by epithelial cells and granulocytes. Many tumor cells express PARs, and protease agonists are often either co-expressed by the tumor cells or present in the tumor stroma. Tumors and their microenvironment should thus provide fertile ground for protease signaling, raising the question of whether this mechanism contributes to tumor progression. Cellular responses to PAR activation defined in vitro are consistent with possible roles in promoting proliferation, survival and/or malignant transformation of the tumor cells themselves and with activation of host endothelial cells and platelets to promote angiogenesis and metastasis. Indeed, expression of PARs and their potential agonists correlates with malignancy in several types of human cancer, and mouse models have pointed to a possible role in invasion and hematogenous metastasis. Whether PARs make important contributions to the biology of human tumors and/or whether they will provide useful markers of the malignant phenotype remains to be determined.