Adult Stem Cell Research Institute, Department of Obstetrics and Gynecology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Int J Oncol. 2012 Jan;40(1):130-8. doi: 10.3892/ijo.2011.1193. Epub 2011 Sep 8.
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 multilineages 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 α-SMA. Exosome treatment also induced increased expression of tumor-promoting factors SDF-1, VEGF, CCL5 and TGFβ. This phenomenon was correlated with increased expression of TGFβ receptor I and II. Analysis of SMAD2, a key player in the TGFβ 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 α-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.
外泌体是各种类型的细胞（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，因此根据细胞起源，预计会发挥多种生物学功能。间充质干细胞（MSCs）具有向多谱系分化的潜力，并且还可以作为肿瘤基质的前体细胞，包括肌成纤维细胞，为肿瘤进展提供有利环境。尽管已经揭示了肿瘤细胞与肿瘤微环境中的间充质干细胞之间的密切关系，但这种通讯方式尚不清楚。在这项研究中，我们通过用乳腺癌衍生的外泌体处理脂肪组织衍生的间充质干细胞（ADSCs）来研究肿瘤细胞衍生的外泌体对 MSCs 的影响。外泌体处理的 ADSC 表现出与肿瘤相关的肌成纤维细胞表型，α-SMA 的表达增加。外泌体处理还诱导了肿瘤促进因子 SDF-1、VEGF、CCL5 和 TGFβ 的表达增加。这种现象与 TGFβ 受体 I 和 II 的表达增加相关。对 TGFβ 受体介导的 SMAD 途径中的关键蛋白 SMAD2 的分析表明，外泌体处理增加了其磷酸化，并用 SMAD 介导途径的抑制剂 SB431542 处理抑制了其磷酸化，导致α-SMA 的表达减少。总之，我们的结果表明，肿瘤衍生的外泌体通过 SMAD 介导的信号通路诱导 ADSC 中的肌成纤维细胞表型和功能。总之，这项研究表明，肿瘤衍生的外泌体可以通过将肿瘤基质中的 MSC 转化为肿瘤微环境中的肿瘤相关肌成纤维细胞，促进肿瘤细胞的进展和恶性转化。
