The angiogenic switch leads to a metabolic shift in human glioblastoma

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 19; no. 3; pp. 383 - 393
• Main Authors: Talasila, Krishna M, Røsland, Gro V, Hagland, Hanne R, Eskilsson, Eskil, Flønes, Irene H, Fritah, Sabrina, Azuaje, Francisco, Atai, Nadia, Harter, Patrick N, Mittelbronn, Michel, Andersen, Michael, Joseph, Justin V, Hossain, Jubayer Al, Vallar, Laurent, Noorden, Cornelis J F van, Niclou, Simone P, Thorsen, Frits, Tronstad, Karl Johan, Tzoulis, Charalampos, Bjerkvig, Rolf, Miletic, Hrvoje
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.03.2017
• Subjects: Animals; Basic and Translational Investigations; Brain Neoplasms - blood supply; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Hypoxia; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioblastoma - blood supply; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glycolysis; Humans; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Rats; Rats, Nude; Transcription Factors - metabolism; Transcriptional Activation; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; hypoxia; glioblastoma; invasion; angiogenesis; glycolysis
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/now175

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.