title: Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas.
abstract: Anti-angiogenic therapy in glioblastoma (GBM) has unfortunately not led to the anticipated improvement in patient prognosis. We here describe how human GBM adapts to bevacizumab treatment at the metabolic level. By performing (13)C6-glucose metabolic flux analysis, we show for the first time that the tumors undergo metabolic re-programming toward anaerobic metabolism, thereby uncoupling glycolysis from oxidative phosphorylation. Following treatment, an increased influx of (13)C6-glucose was observed into the tumors, concomitant to increased lactate levels and a reduction of metabolites associated with the tricarboxylic acid cycle. This was confirmed by increased expression of glycolytic enzymes including pyruvate dehydrogenase kinase in the treated tumors. Interestingly, L-glutamine levels were also reduced. These results were further confirmed by the assessment of in vivo metabolic data obtained by magnetic resonance spectroscopy and positron emission tomography. Moreover, bevacizumab led to a depletion in glutathione levels indicating that the treatment caused oxidative stress in the tumors. Confirming the metabolic flux results, immunohistochemical analysis showed an up-regulation of lactate dehydrogenase in the bevacizumab-treated tumor core as well as in single tumor cells infiltrating the brain, which may explain the increased invasion observed after bevacizumab treatment. These observations were further validated in a panel of eight human GBM patients in which paired biopsy samples were obtained before and after bevacizumab treatment. Importantly, we show that the GBM adaptation to bevacizumab therapy is not mediated by clonal selection mechanisms, but represents an adaptive response to therapy.
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg.
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.forename: Heidi
authors.initials: H
authors.lastname: Espedal
authors.forename: Olivier
authors.initials: O
authors.lastname: Keunen
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.forename: Nina
authors.initials: N
authors.lastname: Obad
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Oliver
authors.initials: O
authors.lastname: Bähr
authors.forename: Astrid
authors.initials: A
authors.lastname: Weyerbrock
authors.forename: Linda
authors.initials: L
authors.lastname: Stuhr
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Per Ø
authors.initials: PØ
authors.lastname: Sakariassen
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Cecilie B
authors.initials: CB
authors.lastname: Rygh
authors.forename: Morten
authors.initials: M
authors.lastname: Lund-Johansen
authors.forename: Liang
authors.initials: L
authors.lastname: Zheng
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D009368:Neoplasm Transplantation; D018384:Oxidative Stress / Q000187:drug effects; D011877:Radionuclide Imaging; D011923:Rats, Nude
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D005973:Glutamine; D000068258:Bevacizumab; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D005978:Glutathione