Fack Fred, Espedal Heidi, Keunen Olivier, Golebiewska Anna, Obad Nina, Harter Patrick N, Mittelbronn Michel, 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, Bjerkvig Rolf
NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Strassen, Luxembourg.
Acta Neuropathol. 2015 Jan;129(1):115-31. doi: 10.1007/s00401-014-1352-5. Epub 2014 Oct 17.
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.
遗憾的是，胶质母细胞瘤（GBM）的抗血管生成疗法并未带来预期的患者预后改善。我们在此描述人类GBM如何在代谢水平上适应贝伐单抗治疗。通过进行¹³C6 - 葡萄糖代谢通量分析，我们首次表明肿瘤会向无氧代谢进行代谢重编程，从而使糖酵解与氧化磷酸化解偶联。治疗后，观察到¹³C6 - 葡萄糖进入肿瘤的通量增加，同时乳酸水平升高以及与三羧酸循环相关的代谢物减少。这在经治疗的肿瘤中糖酵解酶包括丙酮酸脱氢酶激酶的表达增加得到了证实。有趣的是，L - 谷氨酰胺水平也降低了。通过磁共振波谱和正电子发射断层扫描获得的体内代谢数据评估进一步证实了这些结果。此外，贝伐单抗导致谷胱甘肽水平降低，表明该治疗在肿瘤中引起了氧化应激。免疫组织化学分析证实了代谢通量结果，显示在贝伐单抗治疗的肿瘤核心以及浸润脑内的单个肿瘤细胞中乳酸脱氢酶上调，这可能解释了贝伐单抗治疗后观察到的侵袭增加。在一组八名人类GBM患者中进一步验证了这些观察结果，这些患者在贝伐单抗治疗前后获取了配对的活检样本。重要的是，我们表明GBM对贝伐单抗治疗的适应不是由克隆选择机制介导的，而是代表了对治疗的适应性反应。
