ENHANCED EXPRESSION OF UROKINASE RECEPTOR-INDUCED THROUGH THE TISSUE FACTOR-FACTOR VIIA PATHWAY IN HUMAN PANCREATIC-CANCER

Overexpression of tissue factor (TF) is characteristically observed in advanced pancreatic cancer and has been associated with invasion and metastasis, Functional responses of TF activation are here investigate d using as a model system the human pancreatic cancer cell lines SW979 (which overexpresses TF) and MIAPaCa2 (which does not express detecta ble levels). After stimulation of these cell lines with factor VIIa (F VIIa), the only known TF ligand, expression of urokinase receptor (uPA R) gene was up-regulated in SW979 cells in a dose-dependent manner but not in MIAPaCa2 cells. Interestingly; urokinase (uPA) and its specifi c inhibitor PAI-1 were not up-regulated. Exposure to functionally inac tivated FVIIa did not show any effect on uPAR expression on SW979 cell s despite binding to TF with higher efficiency. The neutralizing anti- TF antibody 5G9 blocked the FVIIa-induced up-regulation of uPAR comple tely, whereas hirudin failed to block this up-regulation, Treatment of SW979 cells with Factor Xa did not up-regulate the expression of uPAR gene, whereas treatment with FVII induced the same level of enhanced uPAR gene expression as that with FVIIa, In the matrigel invasion assa y, enhanced invasion of SW979 cell line induced by FVIIa was completel y inhibited by anti-TF antibody and alpha(2)-antiplasmin, Moreover, th e endogenous levels of uPAR gene expression were significantly correla ted with the level of TF gene expression in 19 human cancer cell lines (P < 0.05), These data suggest that up-regulation of uPAR expression by tumor cells leading to tumor invasion is induced through the TF-FVI Ia pathway rather than TF-initiated thrombin generation. This is the f irst report that TF may be one of the key receptors that can up-regula te expression of the plasminogen activator receptor in human cancer ce lls to enhance tumor invasion and metastasis.