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Tumor-Derived Matrix Metalloproteinase-1 Targets Endothelial Proteinase-Activated Receptor 1 Promoting Endothelial Cell Activation

¹ Department of Dermatology, ² Institute of Physiology II, ³ Interdisziplinäres Zentrum für Klinische Forschung Münster; ⁴ Ludwig Boltzmann Institute for Immunobiology and Cell Biology of the Skin; and ⁵ Department of Medicine B, University of Münster, Münster, Germany; and ⁶ Center for Blood Research Institute for Biomedical Research, Department of Pathology, Harvard Medical School, Boston

Requests for reprints: Stefan W. Schneider, Department of Dermatology, University of Muenster, Von-Esmarch Strasse 58, 48149 Muenster, Germany. Phone: 49-251-83-56525; Fax: 49-251-83-56541; E-mail: sschnei{at}mednet.uni-muenster.de.

In the vascular system, circulating tumor cells interact with endothelial cells. Tumor-endothelial cross-talk transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state called endothelial cell activation (ECA). In the present study, we analyze the potential of metastatic tumor-derived soluble factors to transform the vascular endothelium into a prothrombotic and proinflammatory activated state. Supernatant from cultured melanoma and colon cancer cells (A375, WM9, A7, and HT-29) induced an acute activation of macrovascular and microvascular endothelial cells (human umbilical vein endothelial cells and human dermal microvascular endothelial cells) as shown by intracellular calcium flux and secretion of von Willebrand factor and interleukin-8, all markers of acute ECA. This process was inhibited using specific proteinase-activated receptor 1 (PAR1) inhibitors (RWJ-58259 and SCH-79797), indicating a mediating role for endothelial thrombin receptors. Immunofluorescence, Western blot analysis, and collagenase activity assay of tumor cells and culture supernatant revealed the presence of matrix metalloproteinase-1 (MMP-1), a recently described activator of PAR1. Inhibition of MMP-1 in supernatant from cultured tumor cells significantly attenuated ECA. Additional studies using isolated human MMP-1 (5 nmol/L) proved the presence of a functional MMP-1/PAR1 axis in tumor-endothelial communication. These findings show a new pathway of tumor-endothelial cross-talk via an intravascular MMP1/PAR1 axis in microvascular and macrovascular endothelium. Inhibition of this cross-talk may be a powerful means to prevent tumor-induced ECA and thus thrombotic and inflammatory cell adhesion. (Cancer Res 2006; 66(15): 7766-74)

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