Exosomes from glioma cells induce a tumor-like phenotype in mesenchymal stem cells by activating glycolysis
Authors: Zhangqi Cao
Yan Hu
Yang Yang
Zhanjun Ma
Yan Wang
Xue Cui
Li Lu
Xuexi Wang
Guohu Chen
Yubao Lu
Journal: Stem Cell Research & Therapy (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Exosomes; Glioma cells; Glycolytic pathway; Mesenchymal stem cells; Proteomics
Affiliations: The Second Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China., The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, Gansu, China., Institute of Pharmacology, School of Basic Medical Science, Lanzhou University, Lanzhou, 730000, Gansu, China. ., Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou, 730000, Gansu, China. ., School of Basic Medical Sciences of Lanzhou University, School of Medicine, 205 Tianshui Rd South, Lanzhou, 730000, Gansu, China. ., School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China., School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, Gansu, China. .

Abstract:  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. 

Retracted: Yes

PubPeer comments:
 Table 1. The column headings promise to convert the numbers within each patient subgroup into percentages, but the rest of the table does not deliver. ![file] Fig 1C.  D, The Kaplan Meier survival curve of renal clear cell carcinoma patients based on miR-206 expression . ![file] K-M diagrams of this form, where survival plummets suddenly at 75 months, are unusually common in miR papers in this journal. What is the purpose of the spikes along the tops of the curves? To discourage pigeons from nesting on them? , 
 Fig 1A.  qRT-PCR was used to detect the differential expression of miR-206 in tumor tissues and adjacent tissues of renal clear cell carcinoma . Fig 3B, D.  B, qRT-PCR was used to observe the difference in the expression of ZEB2 in renal clear cell carcinoma tumor tissues and adjacent tissues.... D, There was a significant negative correlation between miR-206 and ZEB2 expression in renal clear cell carcinoma. ![file] I would have expected a closer relationship between the distribution of miR-206 shown in 1A and the distribution shown in 3D, and between the distribution of ZEB2 shown in 3B and the distribution shown in 3D. Here are [two other versions of the Fig 3D scatterplot] (h t Elisabeth Bik): ![] Please compare 3B with Fig 3B of [He et al (2019)] . ![] , 
 Fig 2D.  The flow cytometry assay was used to detect the apoptosis ability of CKI-1 and Caki-2 cell lines in renal clear cell carcinoma cells . ![file] The panels appear to be taken from a set of flow-cytometry scatterplots that was apparently stolen from the original researchers and has become widely circulated in the papermill industry. Here, Fig 3A from [Li et al (2019)] : ![] Fig 6A B of [Mei et al (2017)] . ![] ,