胶质瘤细胞来源的外泌体通过激活糖酵解诱导间充质干细胞向肿瘤样表型转化。
Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis.
机构信息
The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.
The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China.
出版信息
Stem Cell Res Ther. 2019 Feb 15;10(1):60. doi: 10.1186/s13287-019-1149-5.
BACKGROUND
Exosomes are nanoscale membrane vesicles secreted by both normal and cancer cells, and cancer cell-derived exosomes play an important role in the cross-talk between cancer cells and other cellular components in the tumor microenvironment. Mesenchymal stem cells (MSCs) have tropism for tumors and have been used as tumor-tropic vectors for tumor therapy; however, the safety of such therapeutic use of MSCs is unknown. In this study, we investigated the role of glioma cell-derived exosomes in the tumor-like phenotype transformation of human bone marrow mesenchymal stem cells (hBMSCs) and explored the underlying molecular mechanisms.
METHODS
The effect of exosomes from U251 glioma cells on the growth of hBMSCs was evaluated with the CCK-8 assay, KI67 staining, and a cell cycle distribution assessment. The migration and invasion of hBMSCs were evaluated with a Transwell assay. A proteomics and bioinformatics approach, together with Western blotting and reverse transcriptase-polymerase chain reaction, was used to investigate the effect of U251 cell-derived exosomes on the proteome of hBMSCs.
RESULTS
U251 cell-derived exosomes induced a tumor-like phenotype in hBMSCs by enhancing their proliferation, migration, and invasion and altering the production of proteins involved in the regulation of the cell cycle. Moreover, U251 cell-derived exosomes promoted the production of the metastasis-related proteins MMP-2 and MMP-9, glioma marker GFAP, and CSC markers (CD133 and Nestin). The ten differentially expressed proteins identified participated in several biological processes and exhibited various molecular functions, mainly related to the inactivation of glycolysis. Western blotting showed that U251 cell-derived exosomes upregulated the levels of Glut-1, HK-2, and PKM-2, leading to the induction of glucose consumption and generation of lactate and ATP. Treatment with 2-deoxy-D-glucose significantly reversed these effects of U251 cell-derived exosomes on hBMSCs.
CONCLUSIONS
Our data demonstrate that glioma cell-derived exosomes activate glycolysis in hBMSCs, resulting in their tumor-like phenotype transformation. This suggests that interfering with the interaction between exosomes and hBMSCs in the tumor microenvironment has potential as a therapeutic approach for glioma. ᅟ.
背景
外泌体是由正常细胞和癌细胞分泌的纳米级膜囊泡，癌细胞来源的外泌体在肿瘤微环境中癌细胞与其他细胞成分的交流中发挥重要作用。间充质干细胞（MSCs）对肿瘤具有趋化性，并已被用作肿瘤趋向性载体进行肿瘤治疗；然而，这种 MSC 治疗用途的安全性尚不清楚。在这项研究中，我们研究了神经胶质瘤细胞衍生的外泌体在人骨髓间充质干细胞（hBMSCs）肿瘤样表型转化中的作用，并探讨了潜在的分子机制。
方法
通过 CCK-8 测定、KI67 染色和细胞周期分布评估，评估 U251 神经胶质瘤细胞来源的外泌体对 hBMSCs 生长的影响。用 Transwell 测定评估 hBMSCs 的迁移和侵袭。采用蛋白质组学和生物信息学方法，结合 Western blot 和逆转录-聚合酶链反应，研究 U251 细胞衍生的外泌体对 hBMSCs 蛋白质组的影响。
结果
U251 细胞衍生的外泌体通过增强 hBMSCs 的增殖、迁移和侵袭，改变细胞周期调节蛋白的产生，诱导 hBMSCs 产生肿瘤样表型。此外，U251 细胞衍生的外泌体促进了转移相关蛋白 MMP-2 和 MMP-9、神经胶质瘤标志物 GFAP 和 CSC 标志物（CD133 和 Nestin）的产生。鉴定的 10 种差异表达蛋白参与了几个生物学过程，并表现出各种分子功能，主要与糖酵解失活有关。Western blot 显示 U251 细胞衍生的外泌体上调了 Glut-1、HK-2 和 PKM-2 的水平，导致葡萄糖消耗和乳酸和 ATP 的产生增加。用 2-脱氧-D-葡萄糖处理可显著逆转 U251 细胞衍生的外泌体对 hBMSCs 的这些作用。
结论
我们的数据表明，神经胶质瘤细胞衍生的外泌体激活了 hBMSCs 中的糖酵解，导致其肿瘤样表型转化。这表明，干扰肿瘤微环境中外泌体与 hBMSCs 的相互作用具有作为神经胶质瘤治疗方法的潜力。
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