Tumor-Endothelial MMP1/PAR1 Crosstalk Promotes Formation of UL-VWF-Strings on Human Endothelium.

Extravasation of circulating tumor cells relies on efficient tumor-endothelial crosstalk. Only recently, we were able to demonstrate, that tumor-derived MMP-1 is capable of activating endothelial expressed PAR1 in the macro- and microvasculature (Cancer Res, in press). In the present study we further explore the implications of endothelial PAR1 activation on VWF release under shear flow. For this purpose, we designed a nano-fluidic assay, that allows high-resolution analysis of human platelet-endothelial interactions under shear flow. By immunofluorescence studies and in the absence of ADAMTS13, we are capable of visualizing the activation of human endothelial cells by tumor-derived supernatant, displayed by the formation of UL-VWF platelet strings. Using MMP-1 and PAR1 antagonists, we can significantly inhibit this process. Our findings provide a molecular mechanism of communication between tumor and endothelial cells. Tumor-induced UL-VWF formation contributes to the understanding of thrombus formation as seen in cancer patients.