[en] 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.
Disciplines :
Oncologie
Auteur, co-auteur :
Fack, Fred; NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg.
Espedal, Heidi
Keunen, Olivier
GOLEBIEWSKA, Anna ; NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg
Obad, Nina
Harter, Patrick N
MITTELBRONN, Michel ; Edinger Institute, Institute of Neurology, Goethe University, Hospital Frankfurt, Frankfurt am Main, Germany
Bähr, Oliver
Weyerbrock, Astrid
Stuhr, Linda
Miletic, Hrvoje
Sakariassen, Per Ø
Stieber, Daniel
Rygh, Cecilie B
Lund-Johansen, Morten
Zheng, Liang
Gottlieb, Eyal
NICLOU, Simone P. ; orLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg, KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
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