Human glioma stem-like cells induce malignant transformation of bone marrow mesenchymal stem cells by activating TERT expression
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Yaodong Zhao1,2,*, Jinsheng Chen1,3,*, Xingliang Dai1,4,*, Honghua Cai1, Xiaoyan Ji1, Yujing Sheng1, Hairui Liu1, Lin Yang1, Yanming Chen4, Dengguo Xi1, Minfeng Sheng4, Yanping Xue1, Jia Shi1, Jiachi Liu1, Xiaonan Li5 and Jun Dong 1,4
1Brain Tumor Research Laboratory, 2nd Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China
2Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, China
3Department of Neurosurgery, People’s Hospital of Susong, Susong, Anhui Province 246500, China
4Department of Neurosurgery, 2nd Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China
5Laboratory of Molecular Neuro-oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
*These authors have contributed equally to this work
Jun Dong, email: [email protected]
Keywords: glioma stem-like cells; bone marrow mesenchymal stem cells; TERT; malignant transformation
Received: July 18, 2016 Accepted: October 12, 2017 Published: November 06, 2017
We investigated whether glioma stem-like cells (GSCs) malignantly transformed bone marrow mesenchymal stem cells (tBMSCs) in the tumor microenvironment. Transplantation of enhanced green fluorescence protein (EGFP)-labeled BMSCs into irradiated athymic nude mice was followed by intracranial injection of red fluorescent protein-expressing glioma stem-like cells (SU3-RFP-GSCs). Singly cloned EGFP-BMSCs, harvested from the intracranial tumors showed TERT overexpression, high proliferation, colony formation and invasiveness in Transwell matrigel assays. Transfection of normal BMSCs with TERT (TERT-BMSCs) enhanced proliferation, colony formation and invasiveness, though these characteristics remained lower than in tBMSCs. The tBMSCs and TERT-BMSCs showed high surface expression of CD44, CD105, CD29 and CD90 and an absence of CD31, CD34, CD45, and CD11b, as in normal BMSCs. Alizarin red S and oil red O staining confirmed tBMSCs and TERT-BMSCs transdifferentiated into osteocytes and adipocytes, respectively. When normal BMSCs were indirectly co-cultured in medium from SU3-RFP-GSCs, they exhibited increased growth and proliferation, suggesting paracrine factors from GSCs induced their malignant transformation. Tumorigenicity assays in athymic nude mice showed that transplanted tBMSCs and TERT-BMSCs generated 100% and 20% subcutaneous tumors, respectively, while normal BMSCs generated no tumors. GSCs thus induce malignant transformation of BMSCs by activating TERT expression in BMSCs.
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