Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas

Fred Fack, Heidi Espedal, Olivier Keunen, Anna Golebiewska, Nina Obad, Patrick N. Harter, Michel Mittelbronn, Oliver Bähr, Astrid Weyerbrock, Linda Stuhr, Hrvoje Miletic, Per Sakariassen, Daniel Stieber, Cecilie B. Rygh, Morten Lund-Johansen, Liang Zheng, Eyal Gottlieb, Simone P. Niclou, Rolf Bjerkvig*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

94 Citations (Scopus)

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 13C6-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 13C6-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.

Original languageEnglish
Pages (from-to)115-131
Number of pages17
JournalActa Neuropathologica
Volume129
Issue number1
DOIs
Publication statusPublished - 17 Jan 2015

Keywords

  • Adaptation
  • Bevacizumab
  • Glioblastoma
  • Metabolism

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