Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway.
Lung tumor exosomes induce a pro-inflammatory phenotype in mesenchymal stem cells via NFκB-TLR signaling pathway.
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DOI：
10.1186/s13045-016-0269-y
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发表时间：
2016-04-18
影响因子：
28.5
通讯作者：
Zhao RC
中科院分区：
文献类型：
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作者：
Li X;Wang S;Zhu R;Li H;Han Q;Zhao RC
在肿瘤微环境中，癌细胞和其他细胞成分之间的持续相互作用是维持肿瘤进展所必需的。越来越多的证据表明，外泌体是一种新型的细胞通讯方式，在这种串扰中发挥着重要作用。外泌体可以促进细胞间蛋白质、脂质和 miRNA/mRNA/DNA 的直接细胞间转移。由于间充质干细胞（MSCs）可以被吸引到肿瘤部位并成为肿瘤微环境的重要组成部分，因此迫切需要揭示肿瘤外泌体对MSCs的影响并进一步探索潜在的分子机制。从肺癌细胞系 A549 中收获外泌体并添加到 MSC 中。通过 RT-PCR 和 ELISA 分析外泌体处理的 MSC 中炎症相关细胞因子的分泌。通过体内小鼠异种移植模型评估外泌体处理的 MSC 对肺肿瘤细胞的生长促进作用。通过人Toll样受体信号通路PCR阵列、RT-PCR和Western blot检测外泌体处理的MSC中涉及的信号通路。数据显示，肺肿瘤细胞 A549 衍生的外泌体可以在称为 P-MSC 的 MSC 中诱导促炎表型，显着增加 IL-6、IL-8 和 MCP-1 的分泌。 P-MSCs在小鼠异种移植模型中促进肺肿瘤生长的能力大大增强。对 P-MSC 信号通路的分析揭示了 NF-κB 的快速触发。通过 siRNA 和 TLR2 中和抗体对 Toll 样受体 2 (TLR2) 进行基因消除，可以阻断外泌体对 NF-κB 的激活。我们进一步发现肺肿瘤外泌体表面存在的 Hsp70 有助于 A549 外泌体诱导 P-MSC。我们的研究提出了一种新机制，肺肿瘤细胞来源的外泌体可诱导 MSC 的促炎活性，从而获得肿瘤支持特性。本文的在线版本 (doi:10.1186/s13045-016-0269-y) 包含补充材料，可供授权用户使用。
In tumor microenvironment, a continuous cross-talk between cancer cells and other cellular components is required to sustain tumor progression. Accumulating evidence suggests that exosomes, a novel way of cell communication, play an important role in such cross-talk. Exosomes could facilitate the direct intercellular transfer of proteins, lipids, and miRNA/mRNA/DNAs between cells. Since mesenchymal stem cells (MSCs) can be attracted to tumor sites and become an important component of the tumor microenvironment, there is an urgent need to reveal the effect of tumor exosomes on MSCs and to further explore the underlying molecular mechanisms. Exosomes were harvested from lung cancer cell line A549 and added to MSCs. Secretion of inflammation-associated cytokines in exosome-treated MSCs were analyzed by RT-PCR and ELISA. The growth-promoting effect of exosome-treated MSCs on lung tumor cells was evaluated by in vivo mouse xenograft model. Signaling pathway involved in exosomes-treated MSCs was detected by PCR array of human toll-like receptor signaling pathway, RT-PCR, and Western blot. Data showed that lung tumor cell A549-derived exosomes could induce a pro-inflammatory phenotype in MSCs named P-MSCs, which have significantly elevated secretion of IL-6, IL-8, and MCP-1. P-MSCs possess a greatly enhanced ability in promoting lung tumor growth in mouse xenograft model. Analysis of the signaling pathways in P-MSCs revealed a fast triggering of NF-κB. Genetic ablation of Toll-like receptor 2 (TLR2) by siRNA and TLR2-neutralizing antibody could block NF-κB activation by exosomes. We further found that Hsp70 present on the surface of lung tumor exosomes contributed to the induction of P-MSCs by A549 exosomes. Our studies suggest a novel mechanism by which lung tumor cell-derived exosomes induce pro-inflammatory activity of MSCs which in turn get tumor supportive characteristics. The online version of this article (doi:10.1186/s13045-016-0269-y) contains supplementary material, which is available to authorized users.