Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis
Gastric cancer cell-derived extracellular vesicles disrupt endothelial integrity and promote metastasis
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胃癌细胞来源的细胞外囊泡破坏内皮完整性并促进转移
DOI：
10.1016/j.canlet.2022.215827
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Min Li
中科院分区：
文献类型：
--
作者：
Min Wang;Wei Cai;Ai-Jun Yang;Chen-Yu Wang;Chen-Li Zhang;Wei Liu;Xiao-Feng Xie;Yuan-Yuan Gong;Ying-Ying Zhao;Wen-Cheng Wu;Quan Zhou;Chan-Yuan Zhao;Jing-Fei Dong;Min Li
内皮细胞是控制跨内皮细胞沟通的关键屏障。癌症组织中的血管发育不良，通透性强。然而，通过这些“泄漏”的血管释放的循环癌细胞如何破坏远程器官的完整血管系统以转移，目前还知之甚少。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，研究了癌细胞来源的细胞外小泡(CEV)在调节癌症转移中的作用。我们做了几个新奇的观察。首先，胃癌患者的转移率与血浆CEV水平密切相关。其次，培养的内皮细胞吞噬CEV，导致细胞骨架重排，连接蛋白钙粘素和CD31的低表达，并形成大的细胞间隙，允许癌细胞跨内皮迁移。动力蛋白抑制剂Dyasore通过阻断CEV的内吞作用来阻止CEV引起的内皮细胞变化。第三，CEV破坏了荷瘤小鼠的内皮屏障，促进了癌症的转移。最后，乳胶粘附素促进循环CEV的清除，从而减少转移。这些结果表明CEV在促进胃癌转移中起着重要作用。·CEV通过破坏内皮细胞的完整性促进胃癌的转移。·CEV通过激活内皮细胞和诱导细胞骨架重组而导致血管渗漏。·戴纳索和乳胶粘附素可减少CEV诱导的转移。
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. • CEVs promoted the metastasis of gastric cancer by disrupting endothelial integrity. • CEVs induce vascular leakage by activating endothelial cells and inducing cytoskeletal reorganization. • Dynasore and lactadherin could reduce CEV-induced metastasis.