Abstract
BackgroundThe tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells.MethodsHuman glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated.ResultsConditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation.ConclusionsCD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.
Highlights
The tumour microenvironment contributes to chemotherapy resistance in gliomas, and gliomaassociated mesenchymal stromal/stem cells are important stromal cell components that play multiple roles in tumour progression
We show that FOXS1 expression in glioma cells was increased by secretion of IL-6 in conditioned media, which originated mainly from the CD90low gliomaassociated mesenchymal stromal/stem cells (gaMSCs) subpopulation
Glioma cells cultured in gaMSC-conditioned media show increased TMZ resistance ability To investigate the effect of gaMSCs on the tumour behaviour of glioma cells, the media of gaMSCs isolated from glioblastoma specimens were collected for glioma cell culture in this study
Summary
The tumour microenvironment contributes to chemotherapy resistance in gliomas, and gliomaassociated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. Whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. We explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells. Clinical data suggest that the poor prognosis of combined therapy is the result of acquired resistance of glioma tumour cells to TMZ [3]. Several resistance mechanisms, including DNA repair enzyme activity, overexpression of oncogene mutations, involvement of autophagy and the existence of glioma stem cells, have been proven [3,4,5]. The role of the tumour microenvironment in the chemotherapeutic resistance of gliomas is rarely explored [6]
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