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首页> 外文期刊>NMR in biomedicine >Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mousemodel of human brain tumors
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Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mousemodel of human brain tumors

机译：人类脑肿瘤原位小鼠模型中通过戊糖磷酸途径的葡萄糖代谢，糖酵解和克雷布斯循环

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It has been hypothesized that increased flux through the pentose phosphate pathway (PPP) is required to support the metabolic demands of rapid malignant cell growth. Using orthotopic mouse models of human glioblastoma (GBM) and renal cell carcinoma metastatic to brain, we estimated the activity of the PPP relative to glycolysis by infusing [1,2-~(13)C_2]glucose. The [3-~(13)C]lactate/[2,3-~(13)C_2]lactate ratio was similar for both the GBM and brain metastasis and their respective surrounding brains (GBM, 0.197±0.011 and 0.195±0.033, respectively (p = 1); metastasis: 0.126 and 0.119±0.033, respectively). This suggests that the rate of glycolysis is significantly greater than the PPP flux in these tumors, and that the PPP flux into the lactate pool is similar in both tumors. Remarkably, ~(13)C–~(13)C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrastwith GBM, ~(13)C multiplets of γ-aminobutyric acid (GABA) differed fromits precursor glutamate, suggesting that GABA did not derive from a common glutamate precursor pool. In addition, the orthotopic renal tumor, the patient’s primary renal mass and brain metastasis were all strongly immunopositive for the 67-kDa isoform of glutamate decarboxylase, as were 84% of tumors on a renal cell carcinoma tissue microarray of the same histology, suggesting that GABA synthesis is cell autonomous in at least a subset of renal cell carcinomas. Taken together, these data demonstrate that ~(13)C-labeled glucose can be used in orthotopicmouse models to study tumor metabolismin vivo and to ascertain new metabolic targets for cancer diagnosis and therapy.
机译：已经假设需要增加通过戊糖磷酸途径（PPP）的通量来支持快速恶性细胞生长的代谢需求。使用人类成胶质细胞瘤（GBM）和转移到大脑的肾细胞癌的原位小鼠模型，我们通过注入[1,2-〜（13）C_2]葡萄糖来估计PPP相对于糖酵解的活性。 [3-〜（13）C]乳酸盐/ [2,3-〜（13）C_2]乳酸盐的比率在GBM和脑转移以及它们各自周围的大脑中相似（GBM，0.197±0.011和0.195±0.033， （p = 1）;转移率分别为0.126和0.119±0.033）。这表明在这些肿瘤中糖酵解速率明显大于PPP通量，并且在两种肿瘤中进入乳酸盐池的PPP通量相似。值得注意的是，在两种肿瘤类型的克雷布斯循环中间体衍生的分子中均观察到〜（13）C–〜（13）C偶联，这表明葡萄糖氧化。与GBM相比，在肾细胞癌中，γ-氨基丁酸（GABA）的〜（13）C多重峰与其前体谷氨酸不同，这表明GABA并非源自共同的谷氨酸前体库。此外，原位肾肿瘤，患者的原发性肾脏肿块和脑转移都对谷氨酸脱羧酶的67 kDa亚型具有强烈的免疫阳性作用，在相同组织学的肾细胞癌组织微阵列上，有84％的肿瘤也是如此。 GABA合成在至少一部分肾细胞癌中是细胞自主的。综上所述，这些数据表明〜（13）C标记的葡萄糖可用于原位小鼠模型中以研究体内肿瘤代谢，并确定新的代谢靶点用于癌症的诊断和治疗。

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