Role of von Willebrand factor in tumor metastasis.

Abstract

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a critical role in primary hemostasis, allowing the adhesion of platelets to the exposed subendothelium. The key role played by VWF in platelet adhesion suggests a potential implication in various pathologies where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. A number of potential receptors for VWF have been identified on tumor cells such as glycoprotein Ib or the alpha(IIb)beta(3) and alpha(v)beta(3) integrins and direct interactions between VWF and tumor cells have been reported. To address the role of VWF in an experimental metastasis model, we compared the formation of pulmonary metastatic foci in C57BL/6J wild-type and VWF-null mice following I.V. injection of murine melanoma B16-BL6 cells or Lewis lung carcinoma cells. Surprisingly we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice. Restoration of VWF plasma levels by co-injection of VWF with the tumor cells led to the correction of this pro-metastatic phenotype. In vitro analysis revealed that VWF did not influence tumor cell proliferation or invasion but induced cellular death. This result was confirmed in vivo where analysis of the early survival of tumor cells in the lungs revealed that the presence of VWF led to a decreased survival of these cells during the first 24 hours after injection. Our results suggest that VWF plays a role in tumor metastasis, independently of its role in hemostasis.