Metabolism of [U-13C]glucose in human brain tumors in vivo

被引:277
作者
Maher, Elizabeth A. [1 ,2 ,3 ,4 ]
Marin-Valencia, Isaac [2 ,5 ]
Bachoo, Robert M. [1 ,2 ,3 ,4 ]
Mashimo, Tomoyuki [1 ,3 ,4 ]
Raisanen, Jack [4 ,6 ]
Hatanpaa, Kimmo J. [4 ,6 ]
Jindal, Ashish [7 ]
Jeffrey, F. Mark [7 ]
Choi, Changho [7 ]
Madden, Christopher [4 ,8 ]
Mathews, Dana [9 ]
Pascual, Juan M. [2 ,5 ,10 ]
Mickey, Bruce E. [4 ,8 ]
Malloy, Craig R. [1 ,7 ,11 ]
DeBerardinis, Ralph J. [3 ,5 ,12 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Neurol & Neurotherapeut, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Harold C Simmons Canc Ctr, Dallas, TX 75390 USA
[4] Univ Texas SW Med Ctr Dallas, Annette G Strauss Ctr Neurooncol, Dallas, TX 75390 USA
[5] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA
[6] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA
[7] Univ Texas SW Med Ctr Dallas, Adv Imaging Res Ctr, Dallas, TX 75390 USA
[8] Univ Texas SW Med Ctr Dallas, Dept Neurol Surg, Dallas, TX 75390 USA
[9] Univ Texas SW Med Ctr Dallas, Dept Radiol, Dallas, TX 75390 USA
[10] Univ Texas SW Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA
[11] Vet Affairs N Texas Healthcare Syst, Med Serv, Lancaster, TX USA
[12] Univ Texas SW Med Ctr Dallas, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
基金
美国国家卫生研究院;
关键词
cancer; glioblastoma; metabolism; Warburg effect; glucose; glutamine; NMR; TRICARBOXYLIC-ACID CYCLE; CELL-GROWTH; C-13; NMR; CANCER; MUTATIONS; GLIOMA; LACTATE; FLUX; GLYCOLYSIS; PATHWAYS;
D O I
10.1002/nbm.2794
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Glioblastomas and brain metastases demonstrate avid uptake of 2-[18F]fluoro-2-deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by 1H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2-[18F]Fluoro-2-deoxyglucose-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ. [U-13?C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13?C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-coenzyme A pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment. Copyright (c) 2012 John Wiley & Sons, Ltd.
引用
收藏
页码:1234 / 1244
页数:11
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