Wang Chen-Yu, Wang Min, Zhao Chan-Yuan, Zhou Quan, Zhang Xiao-Yu, Wang Feng-Xia, Dong Jia-Ming, Du Cun-Pu, Zhang Chen-Li, Dang Yun, Yang Ai-Jun, Dong Jing-Fei, Li Min
Institute of Pathology, School of Basic Medical Sciences (C.-y.W., M.W., C.-y.Z., Q.Z., X.-y.Z., J.-m.D., C.-p.D., C.-l.Z., Y.D., A.-j.Y., M.L.), Lanzhou University, China.
Experimental Teaching Center of Basic Medicine, School of Basic Medical Science (M.W.), Lanzhou University, China.
Arterioscler Thromb Vasc Biol. 2025 Jul;45(7):e271-e285. doi: 10.1161/ATVBAHA.125.322553. Epub 2025 May 8.
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.
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.
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.
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.
胃癌广泛侵犯局部组织，并通过循环系统转移至远处器官。发生转移的胃癌患者临床预后较差。肿瘤微环境中的血管系统发育不良，从而使癌细胞得以进入循环系统。然而，目前对于癌细胞如何黏附并穿越远处器官中发育完全的内皮细胞以及该过程涉及哪些关键黏附配体仍知之甚少。在此，我们报告一项旨在研究高黏附性血管性血友病因子（VWF）在促进胃癌肺转移中作用的研究结果。
我们使用小鼠模型来研究高黏附性VWF在胃癌肺转移中的作用。通过体外实验对这些小鼠模型的研究结果进行验证，该体外实验专门检测了VWF如何促进胃癌来源的细胞外囊泡激活内皮细胞，并分析了已建立的胃癌患者数据库。
荷瘤小鼠体内的VWF变得具有高黏附性，并介导胃癌来源的细胞外囊泡与内皮细胞的黏附，在此过程中，胃癌来源的细胞外囊泡导致内皮细胞通透性增加，并促进癌细胞向肺间质组织的迁移。通过金属蛋白酶ADAMTS-13（具有血小板反应蛋白基序的解整合素和金属蛋白酶13型）降低VWF的黏附活性可防止小鼠体内胃癌细胞的肺转移。我们通过有针对性的体外实验进一步验证了小鼠实验的结果，并使用生物信息学工具通过已建立的胃癌患者数据库将VWF与胃癌患者的预后相关联。
我们展示了VWF如何通过与胃癌来源的细胞外囊泡相互作用而变得具有高黏附性，从而促进胃癌的肺转移，并且ADAMTS-13可降低VWF的高黏附活性以防止转移。
