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

Abstract

Glioblastomas (GBMs) and brain metastases demonstrate avid uptake of 18fluoro-2-deoxyglucose (FDG) by positron emission tomography (PET) and display perturbations of intracellular metabolite pools by 1H magnetic resonance spectroscopy (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. FDG-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation compared to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain malignancies to oxidize glucose in the tricarboxylic acid cycle is unknown. Here we studied the metabolism of human brain tumors in situ. [U-13C]glucose was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. Analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the TCA 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-CoA 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 malignancies growing in their native microenvironment.

Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism

“…Glioblastoma is a deadly brain tumor for which there are limited therapies and chemoradioresistance remains a serious problem to be conquered. Altered glucose metabolism in glioblastoma has been extensively investigated in vitro (5,24,25) and, more recently, in vivo in patients (26) and in human orthotopic glioblastoma models (27). These studies established that glucose is oxidized in the citric acid cycle in addition to confirming that there is a significant fraction of glucose that is shunted to lactate generation.…”

Exploring cancer metabolism using stable isotope-resolved metabolomics (SIRM)

“…To this end, multiple cancer biological models have been used in SIRM studies, including 2D and 3D cell culture, animal tumor models derived spontaneously from defined oncogenic lesions or from implanted tissue/cells, and human tumors analyzed in vivo or ex vivo following surgical resection (35). Regardless of the model, most tumors and derived cells profiled by SIRM recapitulate Warburg's original findings and disprove the canard that tumor cells necessarily have dysfunctional mitochondria (36) by demonstrating that Glc-derived 13 C incorporation into the Krebs cycle can be enhanced in cancerous versus paired non-cancerous tissues (37)(38)(39). Thus, SIRM profiling is excellently suited for uncovering novel aspects of cancer metabolism in model systems and directly in human subjects.…”

Simultaneous Steady-state and Dynamic 13C NMR Can Differentiate Alternative Routes of Pyruvate Metabolism in Living Cancer Cells

“…These same activities were detected in mouse and human tumors by infusing 13 C-enriched glucose before surgery, extracting metabolites from surgically resected tumor tissue, and analyzing 13 C enrichment patterns by NMR (26,28). We also used hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate to quantify flux into lactate (31).…”