Mesenchymal stem cells promote osteosarcoma cell survival and drug resistance through activation of STAT3

Abstract

// Bing Tu 1, 2, * , Jing Zhu 3, * , Shen Liu 2 , Lei Wang 1 , Qiming Fan 1 , Yongqiang Hao 1 , Cunyi Fan 2 , Ting-Ting Tang 1 1 Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China 2 Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China 3 Department of Integrative Medicine and Neurobiology, Fudan University, Shanghai 200032, China * These authors have contributed equally to this work Correspondence to: Ting-Ting Tang, email: ttt@sjtu.edu.cn Keywords: osteosarcoma, mesenchymal stem cells, chemotherapy, STAT3 Received: January 06, 2016      Accepted: June 09, 2016      Published: June 22, 2016 ABSTRACT Increasing evidence suggests that the tumor microenvironment plays a key role in the development of drug resistant tumor cells. In this study, we tried to determine whether the mesenchymal stem cells (MSCs) in the tumor microenvironment contribute to the increased chemoresistance of osteosarcoma. We found that exposure of Saos-2 and U2-OS cells to MSCs conditioned medium (CM) increased the viable cells in the presence of therapeutic concentrations of doxorubicin or cisplatin. Meanwhile, the MSC CM-associated pro-proliferative effects were accompanied by reduced caspase 3/7 activity and Annexin V binding. We confirmed that STAT3 activation by IL-6 regulates MSCs-induced chemoresistance. Blockade of this signal re-sensitized drug-resistant Saos-2 cells to drug treatment. Using a osteosarcoma mouse model with co-injection of MSCs with Saos-2cells, we found that inhibition of STAT3 prolonged the survival time of tumor bearing mice by suppressing tumor growth and increasing the sensitivity of tumor cells to doxorubicin. Finally, we demonstrated that increased expression of p-STAT3, multidrug resistance protein (MRP) and P-glycoprotein (MDR-1) was associated with high chemotherapy resistance in clinical osteosarcoma samples. Collectively, our findings suggest that MSCs within the tumor microenvironment may represent a new target to enhance chemotherapeutic efficacy in osteosarcoma patients.