Role of protease-activated receptor 1 in tumor metastasis promoted by tissue factor

Tissue factor (TF) is a transmembrane glycoprotein that complexes with fact or VIIa to initiate blood coagulation. We previously reported that expressi on of high levels of TF in a human melanoma cell line promotes metastasis. Both the cytoplasmic domain of TF and its extracellular domain complexed wi th factor VIIa are required for the metastatic effect. To further explore t he mechanism of TF-mediated metastasis, we investigated the possibility tha t a protease-activated receptor (PAR) might play a role. For this purpose, we first determined the expression levels of the known PARs (PAR 1-4) in a human melanoma cell line, SIT1, that has low endogenous levels of TF and lo w metastatic potential. We found negligible levels of all of the known PARs and transfection of this cell line with human TF cDNA did not alter expres sion of the known PARs. To study the possible role of PAR1 in TF-mediated m etastasis, we prepared a panel of transfected cell lines with varying level s of TF and PAR1. Our studies show that TF promotes metastasis by a pathway that does not involve high expression of known PARs by tumor cells. In add ition, while overexpression of PAR1 is insufficient to induce metastasis in cells with low TF expression, it enhances the metastatic potential of cell s with high TF expression, indicating a possible synergy between TF and PAR 1 in promoting metastasis.