Tumor Metastasis in VWF Deficient Mice: The Contributions of PGE2 and VEGF

Dysregulation of the hemostatic system in malignancy leads to a hypercoagulable state and thrombotic complications. In addition to thrombosis, growing evidence from both human and animal studies, suggests that constituents of the hemostatic system also play an important role in tumor progression and metastasis. Platelets contribute to metastasis by protecting tumor cells from immune detection and inducing epithelial-mesenchymal transition, thereby facilitating the extravasation of circulating tumor cells out of the vasculature. Moreover, platelet-tumor cell interactions have been shown to promote prostaglandin E2 (PGE₂) synthesis, an important modulator of angiogenesis and proliferation. The role of von willebrand factor (VWF) in malignancy has been of particular interest as it serves as an adhesive link between platelets and endothelium, and could possibly facilitate platelet interactions with tumor cells. Yet, the absence of VWF is associated with increased metastatic potential in a B16 melanoma mouse model, suggesting that the primary contribution of VWF to the metastatic model may not be platelet mediated. We employed a combined approach using cell lines and mouse models to explore the interaction of platelets and VWF in metastasis.

In vitro studies using lung and melanoma cells lines show that the interaction of resting and activated platelets with tumor cells leads to upregulation of COX-2 expression and PGE₂ biosynthesis but does stimulate VEGF-A production. In an experimental metastasis model of C57BL/6 wild type and VWF null mice, the injection of B16 melanoma cells by tail vein yielded a significant increase in the number of pulmonary metastatic foci. PGE₂ measurements from mouse serum showed reduced levels of prostaglandin in VWF deficient mice injected with tumor, suggesting that the absence of VWF precludes an important tumor cell-platelet interaction that facilities PGE₂ production. Moreover, preliminary results show increased VEGF-A in VWF deficient mice, suggesting that increased metastasis in this model may be the result of dysregulated angiogenesis.

In conclusion, platelet-tumor cell interaction yield a pro-metastatic effect, in part mediated by PGE₂ production. Despite its unique role in platelet adhesion and thrombus formation, VWF does not facilitate the interaction of platelets and tumor cells to produce PGE₂. Its protective effect may lie in its ability to modulate angiogenesis via VEGF-specific pathways.