Cell Surface Tetraspanin Tspan8 Contributes to Molecular Pathways of Exosome-Induced Endothelial Cell Activation
Cell Surface Tetraspanin Tspan8 Contributes to Molecular Pathways of Exosome-Induced Endothelial Cell Activation
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DOI：
10.1158/0008-5472.can-09-2470
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发表时间：
2010-02-15
期刊：
影响因子：
11.2
通讯作者：
Zoeller, Margot
中科院分区：
文献类型：
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作者：
Nazarenko, Irina;Rana, Sanyukta;Zoeller, Margot
含有四跨膜蛋白Tspan 8的肿瘤来源的外泌体可以有效地诱导肿瘤和无肿瘤组织中的血管生成。然而，很少有信息存在外泌体-内皮细胞（EC）的相互作用或四跨膜蛋白，这是一个组成部分的外泌体的促血管生成的作用。在这项研究中，我们使用大鼠腺癌模型（AS-Tspan 8）来探讨外泌体Tspan 8对血管生成的影响。Tspan 8有助于选择性地将蛋白质和mRNA募集到外泌体中，包括涉及外泌体-EC结合和EC内化的CD 106和CD 49 d。我们发现EC内化含有Tspan 8-CD 49 d复合物的外泌体。外泌体摄取诱导血管内皮生长因子（VEGF）非依赖性调节几种血管生成相关基因，包括von Willebrand因子、Tspan 8、趋化因子CXCL 5和MIF、趋化因子受体CCR 1以及VEGF、VEGF受体2。EC摄取含有Tspan 8-CD 49 d复合物的外泌体伴随着EC祖细胞的增强的EC增殖、迁移、发芽和成熟。解开这些外泌体启动的EC调节的新途径可以为肿瘤诱导的血管生成的治疗干预提供新的选择。Cancer Res; 70（4）; 1668-78. (C)2010年AACR。
Tumor-derived exosomes containing the tetraspanin Tspan8 can efficiently induce angiogenesis in tumors and tumor-free tissues. However, little information exists on exosome-endothelial cell (EC) interactions or the proangiogenic role of tetraspanins, which are a constitutive component of exosomes. In this study, we used a rat adenocarcinoma model (AS-Tspan8) to explore the effects of exosomal Tspan8 on angiogenesis. Tspan8 contributed to a selective recruitment of proteins and mRNA into exosomes, including CD106 and CD49d, which were implicated in exosome-EC binding and EC internalization. We found that EC internalized Tspan8-CD49d complex-containing exosomes. Exosome uptake induced vascular endothelial growth factor (VEGF)-independent regulation of several angiogenesis-related genes, including von Willebrand factor, Tspan8, chemokines CXCL5 and MIF, chemokine receptor CCR1, and, together with VEGF, VEGF receptor 2. EC uptake of Tspan8-CD49d complex-containing exosomes was accompanied by enhanced EC proliferation, migration, sprouting, and maturation of EC progenitors. Unraveling these new pathways of exosome-initiated EC regulation could provide new options for therapeutic interference with tumor-induced angiogenesis. Cancer Res; 70(4); 1668-78. (C) 2010 AACR.