title: Metabolism of [U-13 C]glucose in human brain tumors in vivo.
abstract: Glioblastomas and brain metastases demonstrate avid uptake of 2-[(18) F]fluoro-2-deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by (1) H 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-[(18) F]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 (13) C 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 (13) C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. elizabeth.maher@utsouthwestern.edu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mashimo
authors.forename: Jack
authors.initials: J
authors.lastname: Raisanen
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.forename: Ashish
authors.initials: A
authors.lastname: Jindal
authors.forename: F Mark
authors.initials: FM
authors.lastname: Jeffrey
authors.forename: Changho
authors.initials: C
authors.lastname: Choi
authors.forename: Christopher
authors.initials: C
authors.lastname: Madden
authors.forename: Dana
authors.initials: D
authors.lastname: Mathews
authors.forename: Juan M
authors.initials: JM
authors.lastname: Pascual
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Mickey
authors.forename: Craig R
authors.initials: CR
authors.lastname: Malloy
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002247:Carbon Isotopes; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002952:Citric Acid Cycle; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D005998:Glycine / Q000096:biosynthesis; D006019:Glycolysis; D006801:Humans; D010084:Oxidation-Reduction
chemical_list: D001786:Blood Glucose; D002247:Carbon Isotopes; D000105:Acetyl Coenzyme A; D005947:Glucose; D005998:Glycine