Glioblastoma stem cells (GSCs) play a major role in brain tumor development, and they can be induced to undergo apparent differentiation morphology by serum. It is generally assumed that induction of differentiation by serum in cancer stem cells would reduce their ability to form tumors. However, how serum triggers such change in GSC differentiation status and whether it really affects their ability to form tumor remain unclear. Here we show that serum exposure activates mitochondrial respiration and causes an increase in mitochondrial ROS and stress responses, leading to NFκB activation and down-regulation of stem cell markers including CD133, Olig2, SOX2 and Notch1. Chemical perturbation of mitochondrial electron transport chain causes ROS increase in serum-induced GSCs and further decreases stem cell markers, while antioxidants reduce ROS and prevent the loss of stem markers. Surprisingly, the serum-induced GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by antioxidants. Our study suggests that stimulation of mitochondrial respiration and ROS generation is critical in activation of GSCs and promoting tumor development in vivo. Although exposure of glioma stem cells to serum causes a decrease in stem cell markers and a loss of neurosphere morphology, the seemingly differentiated GSCs surprisingly exhibit greater ability to form tumors in vivo. A decrease in expression of certain stem cell markers such as CD133 and SOX2 may not necessarily indicate a decrease in tumorigenicity in vivo, and that redox signaling may play a major role in regulation of tumor formation from cancer stem cells.

Citation Format: Feng Wang, Shuqiang Yuan, Gang Chen, Sangbae Kim, Jing Yang, Feng Li, Ju-Seog Lee, Xiao-Nan Li, Rui-hua Xu, Peng Huang. Role of mitochondrial ROS in activation of glioma stem cells and promotion of cancer development. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-58. doi:10.1158/1538-7445.AM2014-LB-58