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 contrast with GBM, (13) C 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 (13) C-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.