Abstract
Glioma stem cells (GSCs) play an important role in glioblastoma prognosis. Exosomes (EXs) mediate cell communication by delivering microRNAs (miRs). Glioblastoma has a high level of miR-21 which could upregulate vascular endothelial growth factor (VEGF) expression. We hypothesized GSC-EXs can promote the angiogenic ability of endothelial cells (ECs) through miR-21/VEGF signal. GSCs were isolated from U-251 cells with stem cell marker CD133. GSCs transfected without or with scramble or miR-21 mimics were used to produce GSC-EXscon, GSC-EXssc and GSC-EXsmiR-21. Human brain ECs were co-cultured with vehicle, GSC-EXscon, GSC-EXssc or GSC-EXsmiR-21 plus VEGF siRNAs (siRNAVEGF). After 24 hours, the angiogenic abilities of ECs were evaluated. The levels of miR-21, VEGF and p-Flk1/VEGFR2 were determined. Results showed: 1) Over 90% of purified GSCs expressed CD133; 2) The levels of miR-21 and VEGF in GSCs and GSC-EXs were up-regulated by miR-21 mimic transfection; 3) Compared to GSC-EXscon or GSC-EXssc, GSC-EXsmiR-21 were more effective in elevating the levels of miR-21 and VEGF, and the ratio of p-Flk1/VEGFR2 in ECs; 4) GSC-EXsmiR-21 were more effective in promoting the angiogenic ability of ECs than GSC-EXscon or GSC-EXssc, which were remarkably reduced by siRNAVEGF pretreatment. In conclusion, GSC-EXs can promote the angiogenic ability of ECs by stimulating miR-21/VEGF/VEGFR2 signal pathway.
Highlights
Glioblastoma is the most common and malignant brain tumor in adults
Results showed: 1) Over 90% of purified Glioma stem cells (GSCs) expressed CD133; 2) The levels of miR-21 and vascular endothelial growth factor (VEGF) in GSCs and GSC-derived EXs (GSC-EXs) were up-regulated by miR-21 mimic transfection; 3) Compared to GSC-EXscon or GSC-EXssc, GSC-EXsmiR-21 were more effective in elevating the levels of miR-21 and VEGF, and the ratio of p-Flk1/VEGFR2 in endothelial cells (ECs); 4) GSC-EXsmiR-21 were more effective in promoting the angiogenic ability of ECs than GSC-EXscon or GSC-EXssc, which were remarkably reduced by siRNAVEGF pretreatment
GSC-EXs can promote the angiogenic ability of ECs by stimulating miR-21/VEGF/VEGFR2 signal pathway
Summary
Glioblastoma is the most common and malignant brain tumor in adults. The ineffectiveness of the treatments majorly result from the tumor cellular heterogeneity, the high migratory capability of glioblastoma and chemoresistance [2]. Cancer stem cells have been suggested to participate in tumor growth and radio- or chemo- resistance [3, 4]. Increasing evidence suggests that the aggressiveness and unresponsiveness of glioblastoma might be related to the presence of GSCs [9, 10]. GSCs can promote tumor angiogenesis [11] and have been shown to be resistant to cell death following growth factors withdrawal [12, 13]. Understanding the mechanism of how GSCs promote metastasis of glioblastoma will be important for developing efficient therapeutic strategies
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