Von Willebrand Factor Synergizes with Tumor-Derived Extracellular Vesicles to Promote Gastric Cancer Metastasis

ABSTRACT Cells of gastric cancer invade local tissue extensively and also metastasize through the circulation to remote organs. Patients with metastasized gastric cancer have poor outcomes. Cancer cells are known to release extracellular vesicles (EVs) that contribute to cancer progression, but how cancer cell-derived EVs promote cancer growth and metastasis remains poorly understood. We have recently reported that levels of circulating gastric cancer cell-derived EVs (gcEVs) and the adhesive ligand von Willebrand factor (VWF) are associated with cancer metastasis and poor prognosis of patients, but the underlying mechanism of this gcEV-VWF interaction was not known. Here we report results from a study designed to investigate the synergistic action of VWF and gcEVs in vitro and in mouse models. We showed that VWF in cancer-bearing mice was hyperadhesive and became microvesicle-bound. EV-bound VWF mediated the adhesion of gcEVs to the endothelium to disrupt endothelial integrity and facilitate the transendothelial migration of cancer cells and pulmonary metastasis. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 or promoting gcEV clearance by the scavenging factor lactadherin prevented pulmonary metastasis in mice. These results highlight the synergistic action of gcEVs and VWF in promoting gastric cancer metastasis and identifying new targets for its prevention. Key point: Author contributions Hyperadhesive VWF becomes microvesicle-bound to induce endothelial leakage and promote the pulmonary metastasis of gastric cancer in mice. Reducing VWF activity by ADAMTS-13 and accelerating microvesicle clearance by lactadherin reduces pulmonary metastasis of gastric cancer.