Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Institute of Integrated Traditional Chinese and Western Medicine, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China.
Institute of Pathology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China; Gansu Provincial Hospital, Lanzhou, China.
Cancer Lett. 2022 Oct 1;545:215827. doi: 10.1016/j.canlet.2022.215827. Epub 2022 Jul 14.
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.
内皮细胞是控制跨内皮通讯的关键屏障。肿瘤组织中的血管发育不良且高度通透。然而，目前还不清楚循环中的癌细胞如何通过这些“渗漏”的血管突破远处器官的完整血管系统进行转移。我们通过分析胃癌患者的样本、进行体外实验和研究小鼠模型，研究了癌细胞衍生的细胞外囊泡 (CEVs) 在调节癌症转移中的作用。我们有了一些新的发现。首先，胃癌患者血浆中 CEVs 的水平与转移率密切相关。其次，培养的内皮细胞内吞 CEVs，导致细胞骨架重排、连接蛋白 cadherin 和 CD31 的低表达，并形成大的细胞间间隙，允许癌细胞穿过内皮细胞迁移。通过阻断 CEVs 的内吞作用，动力蛋白抑制剂 Dynasore 阻止了这些 CEV 诱导的内皮细胞变化。第三，CEVs 破坏了携带肿瘤的小鼠的内皮屏障，促进了癌症转移。最后，乳粘连蛋白促进了循环 CEVs 的清除，从而减少了转移。这些结果表明 CEVs 在促进胃癌转移中起着重要作用。
