Paradoxical pro-invasive effect of the serine proteinase inhibitor tissue factor pathway inhibitor-2 on human hepatocellular carcinoma cells

We have previously shown that human liver myofibroblasts promote in vitro i nvasion of human hepatocellular carcinoma (HCC) cells through a hepatocyte growth factor (HGF)/urokinase/plasmin-dependent mechanism. In this study, w e demonstrate that myofibroblasts synthesize the serine proteinase inhibito r tissue factor pathway inhibitor-2 (TFPI-8). Despite the fact that recombi nant TFPI-2 readily inhibits plasmin, we show that it potentiates HGF-induc ed invasion of HCC cells and is capable of inducing invasion on its own. Fu rthermore, HCC cells stably transfected with a TFPI-2 expression vector bec ame spontaneously invasive. HCC cells express tissue factor and specificall y factor VII, Addition of an antibody to factor VII abolished the pro-invas ive effect of TFPI-2. We suggest that TFPI-2 induces invasion following bin ding to a tissue factor-factor VIIa complex preformed on HCC cells. Our dat a thus demonstrate an original mechanism of cell invasion that may be speci fic for liver tumor cells.