Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells
Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells
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DOI：
10.3892/ijo.2011.1193
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发表时间：
2012-01-01
影响因子：
5.2
通讯作者：
Lee, Kyo Won
中科院分区：
文献类型：
--
作者：
Cho, Jung Ah;Park, Ho;Lee, Kyo Won
外来体是由各种类型的细胞（包括肿瘤细胞）分泌到细胞外环境中的小膜囊泡。外泌体富含一组离散的细胞蛋白，因此预期根据细胞来源发挥不同的生物学功能。骨髓间充质干细胞（Mesenchymal stem cells，MSCs）具有分化为多系细胞的潜能，也可以作为肿瘤基质的前体细胞，包括肌成纤维细胞，为肿瘤的发展提供有利的环境。虽然肿瘤细胞和间充质干细胞在肿瘤微环境中的密切关系已经被揭示，但这种沟通是如何工作的却知之甚少。在这项研究中，我们通过用乳腺癌来源的外泌体处理脂肪组织来源的MSC（ADSC）来研究肿瘤细胞来源的外泌体对MSC的影响。外泌体处理的ADSC表现出肿瘤相关肌成纤维细胞的表型，α-SMA表达增加。外泌体处理还诱导肿瘤促进因子SDF-1、VEGF、CCL 5和TGF β的表达增加。这种现象与TGF β受体I和II的表达增加相关。SMAD 2是TGF β受体介导的SMAD途径中的关键参与者，其分析显示其磷酸化通过外泌体处理增加，并通过SB 431542（SMAD介导的途径的抑制剂）处理抑制，导致α-SMA的表达降低。总之，我们的结果表明，肿瘤来源的外泌体通过SMAD介导的信号通路诱导ADSC中的肌纤维母细胞表型和功能。总之，这项研究表明，肿瘤来源的外泌体可以通过将肿瘤基质内的MSC转化为肿瘤微环境中的肿瘤相关肌成纤维细胞来促进肿瘤细胞的进展和恶性化。
Exosomes are small membrane vesicles secreted into the extracellular environment by various types of cells, including tumor cells. Exosomes are enriched with a discrete set of cellular proteins, and therefore expected to exert diverse biological functions according to cell origin. Mesenchymal stem cells (MSCs) possess the potential for differentiation into multi-lineages and can also function as precursors for tumor stroma including myofibroblast that provides a favorable environment for tumor progression. Although a close relationship between tumor cells and MSCs in a neoplastic tumor microenvironment has already been revealed, how this communication works is poorly understood. In this study, we investigated the influence of tumor cell-derived exosomes on MSCs by treating adipose tissue-derived MSCs (ADSCs) with breast cancer-derived exosomes. The exosome-treated ADSCs exhibited the phenotypes of tumor-associated myofibroblasts with increased expression of alpha-SMA. Exosome treatment also induced increased expression of tumor-promoting factors SDF-1, VEGF, CCL5 and TGF beta. This phenomenon was correlated with increased expression of TGF beta receptor I and II. Analysis of SMAD2, a key player in the TGF beta receptor-mediated SMAD pathway, revealed that its phosphorylation was increased by exosome treatment and was inhibited by treatment with SB431542, an inhibitor of the SMAD-mediated pathway, resulting in decreased expression of alpha-SMA. Taken together, our results show that tumor-derived exosomes induced the myofibroblastic phenotype and functionality in ADSCs via the SMAD-mediated signaling pathway. In conclusion, this study suggests that tumor-derived exosomes can contribute to progression and malignancy of tumor cells by converting MSCs within tumor stroma into tumor-associated myofibroblasts in the tumor microenvironment.