Human glioma stem-like cells induce malignant transformation of bone marrow mesenchymal stem cells by activating TERT expression

// Yaodong Zhao 1, 2, * , Jinsheng Chen 1, 3, * , Xingliang Dai 1, 4, * , Honghua Cai 1 , Xiaoyan Ji 1 , Yujing Sheng 1 , Hairui Liu 1 , Lin Yang 1 , Yanming Chen 4 , Dengguo Xi 1 , Minfeng Sheng 4 , Yanping Xue 1 , Jia Shi 1 , Jiachi Liu 1 , Xiaonan Li 5 and Jun Dong 1, 4 1 Brain Tumor Research Laboratory, 2nd Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China 2 Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200080, China 3 Department of Neurosurgery, People’s Hospital of Susong, Susong, Anhui Province 246500, China 4 Department of Neurosurgery, 2nd Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province 215004, China 5 Laboratory 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 Correspondence to: Jun Dong, email: djdongjun@163.com 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 ABSTRACT 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.