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dc.contributor.authorFack, Freden_US
dc.contributor.authorEspedal, Heidien_US
dc.contributor.authorKeunen, Olivieren_US
dc.contributor.authorGolebiewska, Annaen_US
dc.contributor.authorObad, Ninaen_US
dc.contributor.authorHarter, Patrick N.en_US
dc.contributor.authorMittelbronn, Michelen_US
dc.contributor.authorBähr, Oliveren_US
dc.contributor.authorWeyerbrock, Astriden_US
dc.contributor.authorStuhr, Linda Elin Birkhaugen_US
dc.contributor.authorMiletic, Hrvojeen_US
dc.contributor.authorSakariassen, Per Øysteinen_US
dc.contributor.authorStieber, Danielen_US
dc.contributor.authorRygh, Cecilie Brekkeen_US
dc.contributor.authorLund-Johansen, Mortenen_US
dc.contributor.authorZheng, Liangen_US
dc.contributor.authorGottlieb, Eyalen_US
dc.contributor.authorNiclou, Simone P.en_US
dc.contributor.authorBjerkvig, Rolfen_US
dc.date.accessioned2015-02-27T13:27:47Z
dc.date.available2015-02-27T13:27:47Z
dc.date.issued2015-01eng
dc.identifier.issn0001-6322
dc.identifier.issn1432-0533
dc.identifier.urihttps://hdl.handle.net/1956/9446
dc.description.abstractAnti-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.en_US
dc.language.isoengeng
dc.publisherSpringereng
dc.relation.ispartof<a href="http://hdl.handle.net/1956/9447" target="blank">Multimodal Imaging of Physiologic Changes Induced by Anti-Angiogenic Therapy in Glioblastoma</a>eng
dc.rightsAttribution CC BYeng
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/eng
dc.subjectGlioblastomaeng
dc.subjectbevacizumabeng
dc.subjectMetabolismeng
dc.subjectAdaptationeng
dc.titleBevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomasen_US
dc.typePeer reviewed
dc.typeJournal article
dc.description.versionpublishedVersionen_US
dc.rights.holderCopyright The Author(s) 2014.
dc.identifier.doihttps://doi.org/10.1007/s00401-014-1352-5
dc.source.journalActa Neuropathologica
dc.source.40129
dc.source.141
dc.source.pagenumber115-131


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