Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells.
Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells.
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DOI：
10.1371/journal.pone.0084256
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kim CW
中科院分区：
文献类型：
--
作者：
Lee JK;Park SR;Jung BK;Jeon YK;Lee YS;Kim MK;Kim YG;Jang JY;Kim CW
外泌体是由多种细胞类型释放的小膜囊泡。外泌体含有遗传物质，如mrna和microrna (miRNAs)，这意味着它们可能在细胞间通讯中起关键作用。间充质干细胞（Mesenchymal stem cells, MSCs）具有分化为多种细胞类型的潜力，可以迁移到肿瘤部位，并在肿瘤进展中发挥复杂的作用。为了阐明MSCs在肿瘤微环境中的作用，以往的研究提出了MSCs的多种机制，如免疫调节和分泌因子。然而，msc来源的外泌体对肿瘤微环境的旁分泌作用仍有待探索。本研究的假设是，msc来源的外泌体可能通过转移其分子内容来重编程肿瘤行为。为了验证这一假设，从MSCs中分离并表征了外泌体。与其供体细胞相比，msc衍生的外泌体显示出不同的蛋白质和RNA谱，这些囊泡可能被乳腺癌细胞内化。结果表明，msc来源的外泌体显著下调肿瘤细胞中血管内皮生长因子（VEGF）的表达，从而抑制体外和体内血管生成。此外，miR-16，一种已知靶向VEGF的miRNA，在msc来源的外泌体中富集，它是msc来源的外泌体抗血管生成作用的部分原因。这些结果表明，间充质干细胞衍生的外泌体可能是肿瘤微环境中细胞间通讯的重要媒介，并通过转移抗血管生成分子来抑制血管生成。
Exosomes are small membrane vesicles released by a variety of cell types. Exosomes contain genetic materials, such as mRNAs and microRNAs (miRNAs), implying that they may play a pivotal role in cell-to-cell communication. Mesenchymal stem cells (MSCs), which potentially differentiate into multiple cell types, can migrate to the tumor sites and have been reported to exert complex effects on tumor progression. To elucidate the role of MSCs within the tumor microenvironment, previous studies have suggested various mechanisms such as immune modulation and secreted factors of MSCs. However, the paracrine effects of MSC-derived exosomes on the tumor microenvironment remain to be explored. The hypothesis of this study was that MSC-derived exosomes might reprogram tumor behavior by transferring their molecular contents. To test this hypothesis, exosomes from MSCs were isolated and characterized. MSC-derived exosomes exhibited different protein and RNA profiles compared with their donor cells and these vesicles could be internalized by breast cancer cells. The results demonstrated that MSC-derived exosomes significantly down-regulated the expression of vascular endothelial growth factor (VEGF) in tumor cells, which lead to inhibition of angiogenesis in vitro and in vivo. Additionally, miR-16, a miRNA known to target VEGF, was enriched in MSC-derived exosomes and it was partially responsible for the anti-angiogenic effect of MSC-derived exosomes. The collective results suggest that MSC-derived exosomes may serve as a significant mediator of cell-to-cell communication within the tumor microenvironment and suppress angiogenesis by transferring anti-angiogenic molecules.
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