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Questions {❓}

• Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis?

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         headline:Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas
         description: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.
         datePublished:2014-10-17T00:00:00Z
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      headline:Bevacizumab treatment induces metabolic adaptation toward anaerobic metabolism in glioblastomas
      description: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.
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         Glioblastoma
         Bevacizumab
         Metabolism
         Adaptation
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         Neurosciences
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         name:Department of Pathology, Haukeland University Hospital, The Gade Institute, Bergen, Norway
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         name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
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         name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
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         name:Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway
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         name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
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         type:PostalAddress
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         name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
         type:PostalAddress
      name:University of Bergen
      address:
         name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
         type:PostalAddress
      name:Centre de Recherche Public de la Santé
      address:
         name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
         type:PostalAddress
      name:University of Bergen
      address:
         name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
         type:PostalAddress
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      address:
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            address:
               name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
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      name:Heidi Espedal
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            name:University of Bergen
            address:
               name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
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            name:Centre de Recherche Public de la Santé
            address:
               name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
               type:PostalAddress
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      affiliation:
            name:Centre de Recherche Public de la Santé
            address:
               name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
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            address:
               name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
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            name:Haukeland University Hospital, The Gade Institute
            address:
               name:Department of Pathology, Haukeland University Hospital, The Gade Institute, Bergen, Norway
               type:PostalAddress
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            name:University of Bergen
            address:
               name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
               type:PostalAddress
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            name:University of Bergen
            address:
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            address:
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            address:
               name:Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway
               type:PostalAddress
            type:Organization
      name:Morten Lund-Johansen
      affiliation:
            name:Haukeland University Hospital
            address:
               name:Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
               type:PostalAddress
            type:Organization
            name:University of Bergen
            address:
               name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
               type:PostalAddress
            type:Organization
      name:Liang Zheng
      affiliation:
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            address:
               name:Cancer Research UK, Beatson Institute, Glasgow, Scotland, UK
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            name:Centre de Recherche Public de la Santé
            address:
               name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
               type:PostalAddress
            type:Organization
            name:University of Bergen
            address:
               name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
               type:PostalAddress
            type:Organization
      name:Rolf Bjerkvig
      affiliation:
            name:Centre de Recherche Public de la Santé
            address:
               name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
               type:PostalAddress
            type:Organization
            name:University of Bergen
            address:
               name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
               type:PostalAddress
            type:Organization
            name:University of Bergen
            address:
               name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:Edinger Institute, Institute of Neurology, Goethe University, Hospital Frankfurt, Frankfurt am Main, Germany
      name:Edinger Institute, Institute of Neurology, Goethe University, Hospital Frankfurt, Frankfurt am Main, Germany
      name:Dr. Senckenberg Institute of Neurooncology, Goethe University, Hospital Frankfurt, Frankfurt am Main, Germany
      name:Department of Neurosurgery, University Hospital Freiburg, Freiburg, Germany
      name:Matrix Biology Group, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:Department of Pathology, Haukeland University Hospital, The Gade Institute, Bergen, Norway
      name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
      name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway
      name:Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway
      name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
      name:Cancer Research UK, Beatson Institute, Glasgow, Scotland, UK
      name:Cancer Research UK, Beatson Institute, Glasgow, Scotland, UK
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway
      name:NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg
      name:NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway
      name:KG Jebsen Brain Tumour Research Center, University of Bergen, Bergen, Norway

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