Abstract
Objective: to investigate the effects of all-trans retinoic acid (ATRA) on vasculogenic mimicry formation in glioma stem cells. Methods: U87 stem cells were harvested through a suspension culture assay from the U87 cells, identified by CD133 and nestin, and counted by a flow cytometry. To investigate the VM formation ability of U87 stem cells with the treatment of various concentrations of ATRA, a Matrigel-based tube formation assay was used in the present study in vitro and tube-like structure (typical tube, TT; atypical tube AT) was observed and counted. Then the expressions of VEGF, VEGFR-2 and CD133 were measured throughout real time q-PCR, western blotting and immunofluorescence techniques. The data, presented as the mean ± standard deviation, were analyzed using SPSS software. One-way analysis of variance was used to compare groups and Fisher’s least significant difference tests were performed for subsequent comparisons between groups. P Results: Most of the harvested spheroid cells were positive for nestin and 88.4% were positive forCD133. The CD133+ U87 cells were cultured into tube like structure loaded on the top of Matrigel and the quantity of tubes was decreased under the treatment of ATRA. In addition, the expressions of VEGF, VEGFR-2 and CD133 were significantly reduced under the treatment of ATRA, particularly in the higher concentration groups (20 and 40 μmol, P Conclusions: ATRA may inhibit the establishment of VM differing from stem cells in glioma, and these effects may attribute to the effects of ATRA’s promotion of the differentiation of stem cells and/or down regulation of the expressions of proangiogenic factors VEGF and its receptor VEGFR-2. Thus, the results of the present study indicated a novel idea for the treatment of GBM and enriched the anti-glioma mechanisms of ARTA.
Highlights
Glioma is one of the most frequent types of tumors of the central nervous system in adults
Since vascular mimicry (VM) was found and described as a new vascular channel formation without any endothelial cell in human melanoma at the first time in 1999 [10], this novel tube was described in a lot of tumors, including lung cancer [22], glioblastoma [23], breast cancer [24] bladder cancer [25], ovarian cancer [26], hepatocellular cancer [27], gastric cancer [28], etc
Increasing evidence suggests that cancer stem cells (CSCs) are involved in VM formation [24] [26] [27] [30] [31]
Summary
Glioma is one of the most frequent types of tumors of the central nervous system in adults. Recent studies demonstrated that at least five mechanisms by which gliomas achieve neovascularization have been described: vascular co-option, angiogenesis, vasculogenesis, vascular mimicry (VM), and glioblastoma-endothelial cell trans differentiation [9]. All-trans retinoic acid (ATRA) was reported to be able to promote the proliferation and induce the differentiation of brain tumor stem cells [16] [17], and our early studies found that ATRA might influence the expression of VEGF which represents a major stimulatory factor for the initiation of angiogenesis [18], above all, it might be possible to use ATRA to inhibit the formation of VM. The present study was aiming to investigate the effects of ATRA upon the VM formation of U87 stem cells and its possible mechanisms
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