TY - JOUR
T1 - Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas
AU - Fack, Fred
AU - Espedal, Heidi
AU - Keunen, Olivier
AU - Golebiewska, Anna
AU - Obad, Nina
AU - Harter, Patrick N
AU - Mittelbronn, Michel
AU - Bähr, Oliver
AU - Weyerbrock, Astrid
AU - Stuhr, Linda
AU - Miletic, Hrvoje
AU - Sakariassen, Per Ø
AU - Stieber, Daniel
AU - Rygh, Cecilie B
AU - Lund-Johansen, Morten
AU - Zheng, Liang
AU - Gottlieb, Eyal
AU - Niclou, Simone P
AU - Bjerkvig, Rolf
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Angiogenesis Inhibitors/therapeutic use
KW - Animals
KW - Antibodies, Monoclonal, Humanized/therapeutic use
KW - Bevacizumab
KW - Brain/diagnostic imaging
KW - Brain Neoplasms/diagnostic imaging
KW - Female
KW - Glioblastoma/diagnostic imaging
KW - Glutamine/metabolism
KW - Glutathione/metabolism
KW - Glycolysis/drug effects
KW - Humans
KW - L-Lactate Dehydrogenase/metabolism
KW - Lactic Acid/metabolism
KW - Male
KW - Mice, SCID
KW - Mice, Transgenic
KW - Middle Aged
KW - Neoplasm Transplantation
KW - Oxidative Stress/drug effects
KW - Radionuclide Imaging
KW - Rats, Nude
U2 - 10.1007/s00401-014-1352-5
DO - 10.1007/s00401-014-1352-5
M3 - Article
C2 - 25322816
SN - 0001-6322
VL - 129
SP - 115
EP - 131
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
ER -