Mesenchymal stem cells (MSCs) have been widely studied as an attractive therapeutic agent for the treatment of tumors. However, the adverse effects of the tumor paracrine factors who affect MSCs are still unclear. In this study, we report for the first time that C6 glioma-conditioned medium (GCM) induces malignant transformation of MSCs. In contrast to MSCs, the transformed mesenchymal stem cells (TMCs) exhibited tumor cell characterizations in vitro and highly tumorigenic in vivo. Furthermore, GCM and recombinant S100B increased receptor for advanced glycation end products (RAGE) and its downstream Akt1, STAT3 genes expression as well as phosphorylation and transcriptional activation. Finally, blockage of S100B-RAGE interaction by RAGE inhibitor FPS-ZM1 attenuated GCM and S100B-induced Akt1, STAT3 activation, abolished its cell proliferation, migration and invasion actions. Together, these results suggest that the RAGE pathway may play a possible role in malignant transformation procedure of MSCs, and that this process may be mediated through S100B. (C) 2017 Published by Elsevier Inc.