title: Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model.
abstract: BACKGROUND
  The metabolic preference of malignant glioma for glycolysis as an energy source is a potential therapeutic target. As a result of the cellular heterogeneity of these tumors, however, the relation between glycolytic preference, tumor formation, and tumor cell clonogenicity has remained unknown. To address this issue, we analyzed the metabolic profiles of isogenic glioma-initiating cells (GICs) in a mouse model.
  
  
  METHODS
  GICs were established by overexpression of H-Ras(V12) in Ink4a/Arf-null neural stem cells. Subpopulations of these cells were obtained by single-cell cloning, and clones differing in extracellular acidification potential were assessed for metabolic characteristics. Tumors formed after intracranial implantation of these clones in mice were examined for pathological features of glioma and expression of glycolytic enzymes.
  
  
  RESULTS
  Malignant transformation of neural stem cells resulted in a shift in metabolism characterized by an increase in lactic acid production. However, isogenic clonal populations of GICs manifested pronounced differences in glucose and oxygen consumption, lactate production, and nucleoside levels. These differences were paralleled by differential expression of glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2, with this differential expression also being evident in tumors formed by these clones in vivo.
  
  
  CONCLUSIONS
  The metabolic characteristics of glioma cells appear early during malignant transformation and persist until the late stages of tumor formation. Even isogenic clones may be heterogeneous in terms of metabolic features, however, suggesting that a more detailed understanding of the metabolic profile of glioma is imperative for effective therapeutic targeting.
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Isako
authors.initials: I
authors.lastname: Saga
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Shibao
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Jun
authors.initials: J
authors.lastname: Okubo
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Satoru
authors.initials: S
authors.lastname: Osuka
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujita
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Urakami
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kusuhara
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Division of Gene Regulation (I.S., S.S., J.O., S.O., Y.K., S.Y., S.F., H.S., O.S.) and Department of Neurosurgery, School of Medicine, Keio University, Tokyo, Japan (I.S., S.S., K.Y.); Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (J.O.); Department of Neurosurgery, Yokohama City University School of Medicine, Yokohama, Japan (S.Y.); Department of Neurosurgery, Toho University, Ohashi Hospital, Tokyo, Japan (S.F.); Regional Resources Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan (K.U., M.K.); Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo, Japan (H.S., O.S.).
authors.forename: Oltea
authors.initials: O
authors.lastname: Sampetrean
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology*; D014407:Tumor Cells, Cultured
keywords: GIC; Warburg effect; glioma stem cell; glioma-initiating cell; metabolism