Extracellular vesicles, hyperadhesive von willebrand factor, and outcomes of gastric cancer: a clinical observational study.

Von Willebrand factor (VWF) is an adhesive ligand critical for maintaining hemostasis. However, it has also been increasingly recognized for its role in cancer development because it has been shown to mediate the adhesion of cancer cells to endothelial cells, promote the epithelial-mesenchymal transition, and enhance angiogenesis. We have previously shown that gastric cancer cells synthesize VWF, which mediates the interaction between the cancer and endothelial cells to promote cancer growth. Here, we report results from a clinical observational study that demonstrate the association of VWF in plasma and on the surface of extracellular vesicles (EVs) with the pathological characteristics of gastric cancer. We found that patients with gastric cancer had elevated and intrinsically hyperadhesive VWF in their peripheral blood samples. VWF was detected on the surface of EVs from cancer cells, platelets, and endothelial cells. Higher levels of these VWF-bound EVs were associated with cancer aggression and poor clinical outcomes for patients. These findings suggest that VWF+ EVs from different cell types serve collectively as a new class of biomarkers for the outcome assessment of gastric cancer patients.

Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis.

The endothelium is the critical barrier that controls transendothelial communications. Blood vessels in cancer tissue are poorly developed and highly permeable. However, it is poorly understood how circulating cancer cells released through these "leaky" vessels break the intact vasculature of remote organs to metastasize. We investigated the roles of cancer cell-derived extracellular vesicles (CEVs) in regulating cancer metastasis by analyzing samples from gastric cancer patients, performing in vitro experiments, and studying mouse models. We made several novel observations. First, the rate of metastasis was closely associated with plasma levels of CEVs in patients with gastric cancer. Second, cultured endothelial cells endocytosed CEVs, resulting in cytoskeletal rearrangement, low expression of the junction proteins cadherin and CD31, and forming large intercellular gaps to allow the transendothelial migration of cancer cells. The dynamin inhibitor Dynasore prevented these CEV-induced changes of endothelial cells by blocking CEVs endocytosis. Third, CEVs disrupted the endothelial barrier of cancer-bearing mice to promote cancer metastasis. Finally, lactadherin promoted the clearance of circulating CEVs to reduce metastasis. These results demonstrate the essential role of CEVs in promoting the metastasis of gastric cancer.