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Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.

ABSTRACT: Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA-hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem-like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exosomal content identified miR-1587 as a mediator of the exosomal effects on GSCs, in part via downregulation of the tumor-suppressive nuclear receptor corepressor NCOR1. Our results illuminate the tumor-supporting role for GA-hMSCs by identifying GA-hMSC-derived exosomes in the intercellular transfer of specific miRNA that enhance the aggressiveness of glioblastoma. Cancer Res; 77(21); 5808-19. ©2017 AACR.

SUBMITTER: Figueroa J

PROVIDER: S-EPMC5668150 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.

Figueroa Javier J Phillips Lynette M LM Shahar Tal T Hossain Anwar A Gumin Joy J Kim Hoon H Bean Andrew J AJ Calin George A GA Calin George A GA Fueyo Juan J Walters Edgar T ET Kalluri Raghu R Verhaak Roel G RG Lang Frederick F FF

Cancer research 20170830 21

Tumor-stromal communications impact tumorigenesis in ways that are incompletely understood. Here, we show that glioma-associated human mesenchymal stem cells (GA-hMSC), a newly identified stromal component of glioblastoma, release exosomes that increase the proliferation and clonogenicity of tumor-initiating glioma stem-like cells (GSC). This event leads to a significantly greater tumor burden and decreased host survival compared with untreated GSCs in orthotopic xenografts. Analysis of the exos ...[more]

PMID: 28855213

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Project description:BackgroundExosomes 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.MethodsThe 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.ResultsU251 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.ConclusionsOur 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.

Dataset Information

Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.

Publications

Exosomes from Glioma-Associated Mesenchymal Stem Cells Increase the Tumorigenicity of Glioma Stem-like Cells via Transfer of miR-1587.

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