title: Metabolic activation of mitochondria in glioma stem cells promotes cancer development through a reactive oxygen species-mediated mechanism.
abstract: BACKGROUND
  Cancer stem cells (CSCs) possess characteristics associated with normal stem cells, specifically the abilities to renew themselves and to give rise to all cell types (differentiation). It is assumed that induction of differentiation in CSCs would reduce their ability to form tumors. What triggers CSC differentiation and the role of "differentiation" in tumorigenesis remain elusive.
  
  
  METHODS
  Glioma stem cell (GSC) lines and subcutaneous as well as orthotopic xenografts established from fresh surgical specimens of glioblastoma multiforme were used.
  
  
  RESULTS
  Exposure of GSCs to serum activates mitochondrial respiration and causes an increase in mitochondrial reactive oxygen species (ROS) as well as oxidative stress responses, leading to the appearance of differentiation morphology and a deceased expression of CSC markers. Chemical perturbation of the mitochondrial electron transport chain causes ROS increase and further downregulation of stem cell markers, while antioxidant N-acetyl-cysteine reduces ROS and suppresses the differentiation of GSCs. Surprisingly, the serum-induced differentiated GSCs exhibit greater ability to form tumor in both orthotopic and subcutaneous xenograft models, which can be suppressed by N-acetyl-cysteine. Mitochondrial ROS from the serum-stimulated cells triggered the activation of nuclear factor-kappa-B (NFκB) pathway, which is a potential mechanism for the promotion of tumorigenesis.
  
  
  CONCLUSIONS
  This study suggests that ROS generated from active mitochondrial respiration in the presence of serum is critical in CSCs activation, which promotes tumor development in vivo.
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. yuanshq@sysucc.org.cn.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. luyx@sysucc.org.cn.
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. yangjing@sysucc.org.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. gchen@mdanderson.org.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. sangbae.kim@uth.tmc.edu.
authors.forename: Sangbae
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. lfeng@mdanderson.org.
authors.forename: Li
authors.initials: L
authors.lastname: Feng
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. mogasawara@mdanderson.org.
authors.forename: Marcia
authors.initials: M
authors.lastname: Ogasawara
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. amian84@hotmail.com.
authors.forename: Naima
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. wqlu@mdanderson.org.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. huz012@eng.ucsd.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. jliu7@mdanderson.org.
authors.forename: Jinyun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuro-Oncology, University of Utah, Salt Lake City, UT, USA. howard.colman@hsc.utah.edu.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. jlee@mdanderson.org.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Laboratory of Molecular Neuro-oncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. xiaonan@bcm.edu.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. xurh@sysucc.org.cn.
authors.forename: Rui-Hua
authors.initials: RH
authors.lastname: Xu
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. phuang@mdanderson.org.|Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, USA. phuang@mdanderson.org.
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, 651 E Dongfeng Road, Guangzhou, Guangdong, 510060, China. wangfeng@sysucc.org.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003470:Culture Media; D004579:Electron Transport; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000975:Antioxidants; D003470:Culture Media; D016328:NF-kappa B; D017382:Reactive Oxygen Species