A link between coagulation factors and tumor progression and metastasis is recognized, but the molecular basis remains poorly understood.62 Thrombin, the main effector protease of the coagulation cascade, elicits its response through activation of G protein-coupled protease activated receptors (PARs) designated PAR-1 through PAR-4.63 Activation of PAR-1 induces proliferate signaling and migratory responses in a variety of cells. Increased PAR-1 mRNA and protein expression has been associated with breast carcinoma cell invasion, whereas it was minimal or absent in noninvasive cell lines and normal breast epithelial tissue specimens.64,65 PAR-1 is irreversibly proteolytically activated, internalized, and directly sorted to lysosomes critical for signal termination. Aberrant trafficking of PAR-1 associated with constitutive signaling has been suggested to contribute to and to enhance cellular inva sion.66 PAR-1 receptors are also involved in the metastatic potential and angiogenesis of melanoma.67 Inhibitors of thrombin show encouraging results in clinical trials.
PAR-2, cleaved and activated by trypsin, appears to be highly expressed in human pancreatic and colon cancer.68,69 The expression of PAR-2 was found to be greater in tissues with infiltrative growth patterns and in those accompanied by severe fibrosis, suggesting that the activation of PAR-2 is involved in cancer invasion and the induction of fibrosis in human pancreatic cancer.68 Tumor-derived trypsin is believed to contribute to the growth and invasion of colon cancer cells through activation of PAR-2 via transactivation of the EGFR and activation of p44/p42 MAPKs.69
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