Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model

Isako Saga, Shunsuke Shibao, Jun Okubo, Satoru Osuka, Yusuke Kobayashi, Sachiko Yamada, Satoshi Fujita, Kenichi Urakami, Masatoshi Kusuhara, Kazunari Yoshida, Hideyuki Saya, Oltea Sampetrean

Research output: Contribution to journalArticle

23 Citations (Scopus)

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<sup>V12</sup> 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.

Original languageEnglish
Pages (from-to)1048-1056
Number of pages9
JournalNeuro-Oncology
Volume16
Issue number8
DOIs
Publication statusPublished - 2014

Fingerprint

Neoplastic Stem Cells
Glioblastoma
Glioma
Clone Cells
Neoplasms
Metabolome
Neural Stem Cells
Lactic Acid
Hexokinase
Pyruvate Kinase
Glycolysis
Enzymes
Nucleosides
Oxygen Consumption
Organism Cloning
Glucose
Therapeutics
Population

Keywords

  • GIC
  • Glioma stem cell
  • Glioma-initiating cell
  • Metabolism
  • Warburg effect

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology
  • Medicine(all)

Cite this

Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model. / Saga, Isako; Shibao, Shunsuke; Okubo, Jun; Osuka, Satoru; Kobayashi, Yusuke; Yamada, Sachiko; Fujita, Satoshi; Urakami, Kenichi; Kusuhara, Masatoshi; Yoshida, Kazunari; Saya, Hideyuki; Sampetrean, Oltea.

In: Neuro-Oncology, Vol. 16, No. 8, 2014, p. 1048-1056.

Research output: Contribution to journalArticle

Saga, Isako ; Shibao, Shunsuke ; Okubo, Jun ; Osuka, Satoru ; Kobayashi, Yusuke ; Yamada, Sachiko ; Fujita, Satoshi ; Urakami, Kenichi ; Kusuhara, Masatoshi ; Yoshida, Kazunari ; Saya, Hideyuki ; Sampetrean, Oltea. / Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model. In: Neuro-Oncology. 2014 ; Vol. 16, No. 8. pp. 1048-1056.
@article{f16fb05f2b104865b73eca97ef31c04a,
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-RasV12 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.",
keywords = "GIC, Glioma stem cell, Glioma-initiating cell, Metabolism, Warburg effect",
author = "Isako Saga and Shunsuke Shibao and Jun Okubo and Satoru Osuka and Yusuke Kobayashi and Sachiko Yamada and Satoshi Fujita and Kenichi Urakami and Masatoshi Kusuhara and Kazunari Yoshida and Hideyuki Saya and Oltea Sampetrean",
year = "2014",
doi = "10.1093/neuonc/nou096",
language = "English",
volume = "16",
pages = "1048--1056",
journal = "Neuro-Oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model

AU - Saga, Isako

AU - Shibao, Shunsuke

AU - Okubo, Jun

AU - Osuka, Satoru

AU - Kobayashi, Yusuke

AU - Yamada, Sachiko

AU - Fujita, Satoshi

AU - Urakami, Kenichi

AU - Kusuhara, Masatoshi

AU - Yoshida, Kazunari

AU - Saya, Hideyuki

AU - Sampetrean, Oltea

PY - 2014

Y1 - 2014

N2 - 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-RasV12 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.

AB - 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-RasV12 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.

KW - GIC

KW - Glioma stem cell

KW - Glioma-initiating cell

KW - Metabolism

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=84904335873&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904335873&partnerID=8YFLogxK

U2 - 10.1093/neuonc/nou096

DO - 10.1093/neuonc/nou096

M3 - Article

C2 - 24860177

AN - SCOPUS:84904335873

VL - 16

SP - 1048

EP - 1056

JO - Neuro-Oncology

JF - Neuro-Oncology

SN - 1522-8517

IS - 8

ER -