title: The angiogenic switch leads to a metabolic shift in human glioblastoma.
abstract: Invasion and angiogenesis are major hallmarks of glioblastoma (GBM) growth. While invasive tumor cells grow adjacent to blood vessels in normal brain tissue, tumor cells within neovascularized regions exhibit hypoxic stress and promote angiogenesis. The distinct microenvironments likely differentially affect metabolic processes within the tumor cells.
  
  
  
  In the present study, we analyzed gene expression and metabolic changes in a human GBM xenograft model that displayed invasive and angiogenic phenotypes. In addition, we used glioma patient biopsies to confirm the results from the xenograft model.
  
  
  
  We demonstrate that the angiogenic switch in our xenograft model is linked to a proneural-to-mesenchymal transition that is associated with upregulation of the transcription factors BHLHE40, CEBPB, and STAT3. Metabolic analyses revealed that angiogenic xenografts employed higher rates of glycolysis compared with invasive xenografts. Likewise, patient biopsies exhibited higher expression of the glycolytic enzyme lactate dehydrogenase A and glucose transporter 1 in hypoxic areas compared with the invasive edge and lower-grade tumors. Analysis of the mitochondrial respiratory chain showed reduction of complex I in angiogenic xenografts and hypoxic regions of GBM samples compared with invasive xenografts, nonhypoxic GBM regions, and lower-grade tumors. In vitro hypoxia experiments additionally revealed metabolic adaptation of invasive tumor cells, which increased lactate production under long-term hypoxia.
  
  
  
  The use of glycolysis versus mitochondrial respiration for energy production within human GBM tumors is highly dependent on the specific microenvironment. The metabolic adaptability of GBM cells highlights the difficulty of targeting one specific metabolic pathway for effective therapeutic intervention.
authors: Department of Biomedicine, University of Bergen, Norway.|KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.
authors: Krishna M
authors: KM
authors: Talasila
authors: Department of Biomedicine, University of Bergen, Norway.
authors: Gro V
authors: GV
authors: Røsland
authors: Department of Biomedicine, University of Bergen, Norway.
authors: Hanne R
authors: HR
authors: Hagland
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors: Eskil
authors: E
authors: Eskilsson
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors: Irene H
authors: IH
authors: Flønes
authors: NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg.
authors: Sabrina
authors: S
authors: Fritah
authors: NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg.
authors: Francisco
authors: F
authors: Azuaje
authors: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors: Nadia
authors: N
authors: Atai
authors: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Patrick N
authors: PN
authors: Harter
authors: Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Michel
authors: M
authors: Mittelbronn
authors: Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors: Michael
authors: M
authors: Andersen
authors: Department of Biomedicine, University of Bergen, Norway.|KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.
authors: Justin V
authors: JV
authors: Joseph
authors: Department of Biomedicine, University of Bergen, Norway.|KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors: Jubayer Al
authors: JA
authors: Hossain
authors: Department of Oncology, Luxembourg Institute of Health, Luxembourg.
authors: Laurent
authors: L
authors: Vallar
authors: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors: Cornelis J F van
authors: CJ
authors: Noorden
authors: KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.|NorLux Neuro-oncology Laboratory, Luxembourg Institute of Health, Luxembourg.
authors: Simone P
authors: SP
authors: Niclou
authors: KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.|Molecular Imaging Center, Department of Biomedicine, University of Bergen, Norway.
authors: Frits
authors: F
authors: Thorsen
authors: Department of Biomedicine, University of Bergen, Norway.
authors: Karl Johan
authors: KJ
authors: Tronstad
authors: Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors: Charalampos
authors: C
authors: Tzoulis
authors: Department of Biomedicine, University of Bergen, Norway.|KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.|Department of Neurology, Haukeland University Hospital, Bergen, Norway.
authors: Rolf
authors: R
authors: Bjerkvig
authors: Department of Biomedicine, University of Bergen, Norway.|KG Jebsen Brain Tumor Research Centre, University of Bergen, Norway.|Department of Pathology, Haukeland University Hospital, Bergen, Norway.
authors: Hrvoje
authors: H
authors: Miletic
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014157:Transcription Factors
keywords: angiogenesis; glioblastoma; glycolysis; hypoxia; invasion