Microfluidic reveals generation of platelet-strings on tumoractivated endothelium

Summary

Neoplastic diseases are often associated with thromboembolic events,however the precise mechanism underlying this observation is a matter of ongoing investigation. It is known that matrixmetalloproteinase- 1 (MMP-1) canonically activates the thrombin receptor (PAR-1) and we recently reported that highly metastatic tumor cells of melanoma and colon cancer are secreting matrixmetalloproteinase-1. This tumor-derived MMP1 was shown to be a major activator of endothelial PAR-1, thus leading to endothelial cell activation. As tumor-induced thrombosis is a characteristic of metastazing tumors, we investigated whether tumor-derived supernatant (TUSN) from melanoma and colon cancer may induce adhesion of circulating platelets,an initial step in thrombus formation.A time-course study revealed that TU-SN induces a rapid secretion of von Willebrand factor (VWF) within minutes. Using a novel microfluidic device we analyzed platelet-endothelial interactions in a closed circuit. Immunofluorescence imaging showed that TU-SN rapidly induces platelet- string formation via secreted VWF. We demonstrated that tumor-derived supernatant is a potent agonist inducing platelet adhesion under flow conditions.

Keywords

von Willebrand factor - platelet physiology - cancer - imaging

^* Current address for TG.

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