Protease inhibitor PP5/TFP1-2 expression in breast cancer

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Recently, there are many reports demonstrating that blood-clotting system is closely involved in the mechanism of cancer invasion and metastasis. Tissue factor (TF) initiates blood clotting by direct activation of factor X in association with factor VIIa. TF is known to be important not only in blood clotting but also in development of vascular system, angiogenesis or production of VEGF. We demonstrated that 1) TF cytoplasmic tail communicates with action cytoskeleton via an action binding protein ABP280, 2) TF expressing tumor cells obtain elevated capacity of cell adhesion and migration in factor VIIa or anti-TF antibody dependent manner, 3) TF mediated adhesion induced phosphorylation of focal adhesion kinase (FAK). We further obtained several important findings by immunohistochemical studies on bladder cancer tissues. TF expression was observed in cancer cells, especially in invasion front, and factor VIIa immunoreactivity was demonstrated around small vessels of invasion front, which may come from blood. One could speculate that TF expressing cancer cells may migrate towards vessels by factor VIIa around them and this system may be involved in the intravasation step of cancer metastasis. We also evaluated the expression of TFPI-1 and TFPI-2, which are native inhibitors of factor X activation by TF, in surgically resected breast cancer tissues in combination with non-cancerous tissues by RT-PCR. Expression of TFPI-2 seemed to be attenuated in cancer tissues. Immunohistological studies for TF in combination with TFPIs in breast cancer tissues should be needed.