Background/Aims: Tumor vascular formation and maintenance are crucial events in glioblastoma development. Mesenchymal stem cells (MSCs) have been shown to differentiate into pericytes and contribute to neovascularization in the glioma microenvironment. Moreover, glioblastoma-derived mesenchymal stem cells (gb-MSCs), which consist of CD90^-MSCs and CD90⁺MSCs, are a subpopulation of MSCs that are more active in glioma vascularization. However, the functions of gb-MSCs and the microRNA (miRNA) modifications in the glioblastoma microenvironment have not yet been fully elucidated. Here, we focus on the pericyte differentiation potential of gb-MSCs and miRNA modifications in gb-MSCs during new vascular formation and glioblastoma growth. Methods: In vitro, surface markers of gb-MSCs were detected by flow cytometry; the differentiation potential was evaluated by Oil Red O staining, Alizarin Red staining and Alcian blue staining; the proliferation and migration of gb-MSCs in different conditioned media were analyzed by the cck8 test and wound-healing assay, respectively; gb-MSC to pericyte transition was detected by immunofluorescence staining and western blot assay; angiogenetic capacity was analyzed by tube formation assay; and levels of cytokines in different supernatant were determined by ELISA. Additionally, RNA was isolated from gb-MSCs, and miRNA modifications were analyzed using the RAffymetrix miRNA microarray Results: We showed that glioblastoma-conditioned medium increased gb-MSC proliferation and migration and was capable of inducing gb-MSC differentiation into pericytes. Glioblastoma secreted angiogenic factors and gb-MSCs incubated in malignant glioblastoma-conditioned medium formed more tube-like structures, and these cells also adhered to tube-like vessels formed by human umbilical vein endothelial cells (HUVECs) on Matrigel to maintain tumor vascular structure in vitro. miRNA expression were also modified in gb-MSCs cultured in malignant glioblastoma-conditioned medium in vitro. Conclusion: These results provide new insight into the functional effects of a subpopulation of MSCs in glioblastoma and may help in the development of novel therapies for solid tumors.

Abstract. High-grade glioma is a richly neovascularized brain solid tumor with a poor prognosis. Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial cell proliferation and angiogenesis, which has shown clinical efficacy in recurrent glioblastoma. MEDLINE/PubMed, EMBASE and Web of Science databases were searched for relevant studies that compared bevacizumab plus combined radiotherapy/temozolomide (RT/TMZ) with RT/TMZ alone in newly diagnosed glioblastoma (GBM). Of all the studies identified, three comparative trials were included in the systematic review. All three enrolling trials, including a total of 1,738 patients, investigated bevacizumab or placebo plus combined RT/TMZ treatment in glioblastoma. The result showed no increased overall survival (OS) (pooled hazard ratio (HR), 1.04; 95% confidence interval (CI), 0.84-1.29; P=0.71) but increased progression-free survival (HR, 0.74; 95% CI, 0.62-0.88; P=0.0009). However, the two randomized double-blind placebo-control trials exemplified a high rate of adverse events of the bevacizumab compared with the placebo group while discrepant points were noted in term of quality-of-life outcome. Additionally, bevacizumab plus RT/TMZ did not increase the 6-month survival rate [odd ratios (ORs), 0.65; 95% CI, 0.37-1.13; P=0.13). Overall, addition of bevacizumab to radiotherapy-temozolomide treatment may be an effective therapy strategy for improving progression-free survival. OS and the 6-month survival rate was not prolonged and there was questionable efficacy of bevacizumab on the quality-of-life of glioblastoma patients, thus further clinical trials should be performed.

This current study intends to investigate the effect of microRNA-128 (miR-128) on cisplatin (DDP) resistance in glioma SHG-44 cells. SHG-44/DDP cells were transfected with miR-128 antisense oligonucleotide (ASO) and assigned into blank, resistance, NC, anti-miR-128, miR-128 mimic, si-JAG1, and anti-miR-128 + si-JAG1 groups. qRT-PCR and Western blotting were employed for determining expression of miR-128, JAG1, Bax and Bcl-2. MTT assay, Giemsa staining, and flow cytometry were applied to detect DDP resistance, cellular morphology, and cell cycle, respectively. JAG1 is targeted and negatively regulated by miR-128. In in vitro experiments, compared with the blank group, the rest groups exhibited declined miR-28 and Bax expression, lowered cell inhibition rate and apoptosis rate, but elevated JAG1 and Bcl-2 expression with cells arrested in the S phase. Compared with the resistance group, the anti-miR-128 group showed decreasedBax expression along with a lowered cell inhibition rate and apoptosis rate, but increased JAG1 and Bcl-2 expression with reduced cells arrested in the S phase; while the miR-128 mimic group showed an opposite trend; the si-JAG1 group showed decreased Bcl-2 expression and reduced cells in the S phase. In in vivo experiments, compared with the resistance group, the tumor growth rate, tumor volume, and weight as well as JAG1 expression accelerated in the anti-miR-128 group; whereas the miR-128 mimic and si-JAG1 groups exhibited an opposite trend. Our findings demonstrated that miR-128 ASO transfection might down-regulate the expression of miR-128 in SHG-44/DDP and up-regulate the DDP resistance in SHG-44/DDP cells, providing a potential treatment target for glioma.