Differential expression of protease-activated receptors-1 and-2 in stromalfibroblasts of normal, benign, and malignant human tissues

The serine proteases thrombin and trypsin are among many factors that malig nant cells secrete into the extracellular space to mediate metastatic proce sses such as cellular invasion, extracellular matrix degradation, angiogene sis, and tissue remodeling. The degree of protease secretion from malignant cells has been correlated to their metastatic potential. Protease activate d receptors (PAR)-1 and -2, which are activated by thrombin and trypsin res pectively, have not been extensively characterized in human tumors in situ. We investigated the presence of PAR-I and PAR-2 in human normal, benign an d malignant tissues using immunohistochemistry and in situ hybridization. O ur results demonstrate PAR-I and PAR-2 expression in the tumor cells, mast cells, macrophages, endothelial cells, and vascular smooth muscle cells of the metastatic tumor microenvironment. Most notably, an up-regulation of PA R-1 and PAR-2 observed in proliferating, smooth muscle actin (SMA)-positive stromal fibroblasts surrounding the carcinoma cells was not observed in no rmal or benign conditions. Furthermore, in vitro studies using proliferatin g, SMA-positive, human dermal fibroblasts, and scrape-wounded human dermal fibroblasts demonstrated the presence of PAR-1 and PAR-2 not detected in qu iescent, Sh SMA-negative cultures. PAR-1 and PAR-2 in the cells forming the tumor microenvironment suggest that these receptors mediate the signaling of secreted thrombin and trypsin in the processes of cellular metastasis.