CD90low glioma-associated mesenchymal stromal/stem cells promote temozolomide resistance by activating FOXS1-mediated epithelial-mesenchymal transition in glioma cells

Stem Cell Research & Therapy

Wei Xiang¹  Yu-jie Zhou¹  Han Tian¹  Dong-ye Yi¹  Hong-yang Zhao¹  Nan-xiang Xiong¹  Xiao-bing Jiang¹  Peng Fu¹  Hao-fei Wang¹  Bing-zhou Xue¹  Qing Zhang²  Ahmed Abdelmaksou³  Jian Xue⁴  Min-xuan Sun⁵ 

[1] Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China;Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China;Brain Tumor Research Center, Beijing Neurosurgical Institute, Capital Medical University, 100050, Beijing, China;Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China;Department of Neurosurgery, Faculty of Medicine, Helwan University, 11435, Cairo, Egypt;Henan Vocational University of Science and Technology, 466000, Zhoukou, China;Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, 215163, Suzhou, China;

关键词: Glioma;    Chemotherapy resistance;    EMT;    Glioma-associated mesenchymal stromal/stem cells (gaMSCs);    FOXS1;   

DOI  :  10.1186/s13287-021-02458-8

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY