Enrichment of human osteosarcoma stem cells based on hTERT transcriptional activity

// Ling Yu 1,2 , Shiqing Liu 1 , Chun Zhang 1 , Bo Zhang 1 , Bruno M. Simões 2 , Rachel Eyre 2 , Yi Liang 3 , Huichao Yan 4 , Zheng Wu 5 , Weichun Guo 1 , Robert B. Clarke 2 1 Department of Orthopedics, Renmin Hospital of Wuhan University, Jiefang Road, Wuhan, Hubei, P.R. China 2 Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, UK 3 State Key Laboratory of Oncology in Southern China and the Department of Experimental Research, Sun Yat-Sen University Cancer Center, Dongfeng Road, Guangzhou, Guangdong, P.R. China 4 Opening Laboratory for Oversea Scientists, Wuhan University School of Basic Medical Science, Donghu Road, Wuhan, Hubei, P.R. China 5 Department of Radiation Oncology, Tumor Hospital Xiangya School of Medicine of Central South University, Tongzipo Road, Changsha, Hunan, P.R.China Correspondence: Robert B Clarke, email: // Correspondence: Shiqing Liu, email: // Keywords : Osteosarcoma; Heterogeneity; Cancer stem cells; Telomerase; Metastasis; Drug resistance Received : October 30, 2013 Accepted : November 3, 2013 Published : November 5, 2013 Abstract Telomerase is crucial for the maintenance of stem/progenitor cells in adult tissues and is detected in most malignant cancers, including osteosarcoma. However, the relationship between telomerase expression and cancer stem cells remains unknown. We observed that sphere-derived osteosarcoma cells had higher telomerase activity, indicating that telomerase activity might be enriched in osteosarcoma stem cells. We sorted subpopulations with high or low telomerase activity (TEL) using hTERT transcriptional promoter-induced green fluorescent protein (GFP). The TEL pos cells showed an increased sphere and tumor propagating capacity compared to TEL neg cells, and enhanced stem cell-like properties such as invasiveness, metastatic activity and resistance to chemotherapeutic agents both in vitro and in vivo . Furthermore, the telomerase inhibitor MST312 prevented tumorigenic potential both in vitro and in vivo , preferentially targeting the TEL pos cells. These data support telomerase inhibition as a potential targeted therapy for osteosarcoma stem-like cells.