ADAMTS-13 Prevents VWF-Mediated Gastric Cancer Metastasis

BACKGROUND: Gastric cancer invades local tissue extensively and metastasizes through the circulation to remote organs. Patients with metastasized gastric cancer have poor clinical outcomes. The vasculature in the cancer niche is developed poorly, thus allowing cancer cells to be released into the circulation. However, it is poorly understood how cancer cells adhere to and transmigrate through the fully developed endothelium in remote organs and what key adhesive ligands are involved in the process. Here, we report results from a study designed to investigate the role of hyperadhesive VWF (von Willebrand factor) in promoting the pulmonary metastasis of gastric cancer. METHODS: We used mouse models to investigate the roles of hyperadhesive VWF in the pulmonary metastasis of gastric cancer. The findings from these mouse models were validated through in vitro experiments that specifically examined how VWF promoted gastric cancer-derived extracellular vesicles to activate endothelial cells and analyzed established databases of patients with gastric cancer. RESULTS: VWF in cancer-bearing mice became hyperadhesive and mediated the adhesion of gastric cancer-derived extracellular vesicles to the endothelium, where gastric cancer-derived extracellular vesicles caused endothelial permeability and promoted the transmigration of cancer cells to the interstitial tissue of the lungs. Reducing VWF adhesive activity by the metalloprotease ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type motifs, type 13) prevented the pulmonary metastasis of gastric cancer cells in mice. We further validated the findings in mice through targeted in vitro experiments and by associating VWF with the outcomes of patients with gastric cancer through established databases of patients with gastric cancer using bioinformatics tools. CONCLUSIONS: We show how VWF becomes hyperadhesive to promote the pulmonary metastasis of gastric cancer through its interaction with gastric cancer-derived extracellular vesicles and that the hyperadhesive activity of VWF is reduced by ADAMTS-13 to prevent the metastasis.