Abstract
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.Graphical abstractᅟ
Highlights
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
Characterization of U251 cell-derived exosomes To determine whether U251 cell-derived exosomes were successfully purified, firstly, the proteins acquired from U251 cell-derived exosomes were separated by 10%
We found that the U251 cell-derived exosomes promoted the migration and invasion of human bone marrow mesenchymal stem cells (hBMSCs), possibly by modulating the expression of genes encoding matrix metalloproteinases (MMPs), which play an important role in tumor invasion and metastasis [37]
Summary
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. Stem cell therapy is a new treatment option for glioma and has been evaluated in preclinical studies [1] This approach involves the use of mesenchymal stem cells (MSCs), which can carry therapeutic factors and exert a potent anti-tumor effect [2], to alter the behavior of cancer cells. Tumors consist of two principal structures: the parenchyma, or tumor cells, and the stroma, a supportive structure containing connective tissue, blood vessels [3], and macrophages, endothelial cells, lymphocytes, fibroblasts, and other mesenchymal cells. These stroma cells secrete hormones, cytokines, chemokines, and proteases to modulate the tumor microenvironment [4]. Tumor-associated stroma is a typical feature of neoplastic tissues and play a role in tumor growth, invasion, and metastasis by interacting with cancer cells [5]
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