Summary

Tissue factor (TF) is a transmembrane glycoprotein that complexeswith factor VIIa to initiate blood coagulation. We previously reportedthat expression of high levels of TF in a human melanoma cell line promotesmetastasis. Both the cytoplasmic domain of TF and its extracellulardomain complexed with factor VIIa are required for the metastaticeffect. To further explore the mechanism of TF-mediated metastasis,we investigated the possibility that a protease-activated receptor(PAR) might play a role. For this purpose, we first determined the expressionlevels of the known PARs (PAR1-4) in a human melanomacell line, SIT1, that has low endogenous levels of TF and low metastaticpotential. We found negligible levels of all of the known PARsand transfection of this cell line with human TF cDNA did not alterexpression of the known PARs. To study the possible role of PAR1 inTF-mediated metastasis, we prepared a panel of transfected cell lineswith varying levels of TF and PAR1. Our studies show that TF promotesmetastasis by a pathway that does not involve high expressionof known PARs by tumor cells. In addition, while overexpression ofPAR1 is insufficient to induce metastasis in cells with low TF expression,it enhances the metastatic potential of cells with high TF expression,indicating a possible synergy between TF and PAR1 in promotingmetastasis.