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Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors

Authors

  • Isaac Marin-Valencia,

    1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Division of Pediatric Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Steve K. Cho,

    1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Dinesh Rakheja,

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Kimmo J. Hatanpaa,

    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Payal Kapur,

    1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Tomoyuki Mashimo,

    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Ashish Jindal,

    1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Vamsidhara Vemireddy,

    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Levi B. Good,

    1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Jack Raisanen,

    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Xiankai Sun,

    1. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Bruce Mickey,

    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Changho Choi,

    1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Masaya Takahashi,

    1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Osamu Togao,

    1. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Juan M. Pascual,

    1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Division of Pediatric Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    4. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Ralph J. DeBerardinis,

    1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Elizabeth A. Maher,

    1. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    4. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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  • Craig R. Malloy,

    Corresponding author
    1. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Medical Service, Veterans Affairs North Texas Healthcare System, Lancaster, TX, USA
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  • Robert M. Bachoo

    Corresponding author
    1. Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA
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R. M. Bachoo, Department of Neurology and Neurotherapeutics, Annette G. Strauss Center for Neuro-Onoclogy, UT Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75235, USA.

E-mail: Robert.bachoo@utsouthwestern.edu

C. Malloy, Mary Nell and Ralph B. Rogers Magnetic Resonance Center, 5323 Harry Hines Blvd., Dallas, TX 75390–8568, USA.

E-mail: craig.malloy@utsouthwestern.edu

Abstract

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 [1,2-13C2]glucose. The [3-13C]lactate/[2,3-13C2]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, 13C–13C coupling was observed in molecules derived from Krebs cycle intermediates in both tumor types, denoting glucose oxidation. In the renal cell carcinoma, in contrast with GBM, 13C multiplets of γ-aminobutyric acid (GABA) differed from its 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 13C-labeled glucose can be used in orthotopic mouse models to study tumor metabolism in vivo and to ascertain new metabolic targets for cancer diagnosis and therapy. Copyright © 2012 John Wiley & Sons, Ltd.

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