Abstract

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-13C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13C 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.

Original languageEnglish (US)
Pages (from-to)1234-1244
Number of pages11
JournalNMR in Biomedicine
Volume25
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Metabolism
Brain Neoplasms
Tumors
Brain
Glucose
Lactic Acid
Neoplasms
Citric Acid Cycle
Fluorodeoxyglucose F18
Deoxyglucose
Metabolites
Nuclear magnetic resonance spectroscopy
Magnetic Resonance Spectroscopy
Carbon
Acetyl Coenzyme A
Positron emission tomography
Glioblastoma
Glutamine
Pyruvic Acid
Positron-Emission Tomography

Keywords

  • Cancer
  • Glioblastoma
  • Glucose
  • Glutamine
  • Metabolism
  • NMR
  • Warburg effect

ASJC Scopus subject areas

  • Spectroscopy
  • Molecular Medicine
  • Radiology Nuclear Medicine and imaging

Cite this

@article{8a62ae9a75954803932a7813b9333b2c,
title = "Metabolism of [U-13C]glucose in human brain tumors in vivo",
abstract = "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-13C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13C 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.",
keywords = "Cancer, Glioblastoma, Glucose, Glutamine, Metabolism, NMR, Warburg effect",
author = "Maher, {Elizabeth A.} and Isaac Marin-Valencia and Bachoo, {Robert M.} and Tomoyuki Mashimo and Jack Raisanen and Hatanpaa, {Kimmo J.} and Ashish Jindal and Jeffrey, {F. Mark} and Changho Choi and Christopher Madden and Dana Mathews and Pascual, {Juan M.} and Mickey, {Bruce E.} and Malloy, {Craig R.} and Deberardinis, {Ralph J.}",
year = "2012",
month = "11",
doi = "10.1002/nbm.2794",
language = "English (US)",
volume = "25",
pages = "1234--1244",
journal = "NMR in Biomedicine",
issn = "0952-3480",
publisher = "John Wiley and Sons Ltd",
number = "11",

}

TY - JOUR

T1 - Metabolism of [U-13C]glucose in human brain tumors in vivo

AU - Maher, Elizabeth A.

AU - Marin-Valencia, Isaac

AU - Bachoo, Robert M.

AU - Mashimo, Tomoyuki

AU - Raisanen, Jack

AU - Hatanpaa, Kimmo J.

AU - Jindal, Ashish

AU - Jeffrey, F. Mark

AU - Choi, Changho

AU - Madden, Christopher

AU - Mathews, Dana

AU - Pascual, Juan M.

AU - Mickey, Bruce E.

AU - Malloy, Craig R.

AU - Deberardinis, Ralph J.

PY - 2012/11

Y1 - 2012/11

N2 - 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-13C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13C 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.

AB - 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-13C]Glucose (uniformly labeled glucose, i.e. d-glucose labeled with 13C 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.

KW - Cancer

KW - Glioblastoma

KW - Glucose

KW - Glutamine

KW - Metabolism

KW - NMR

KW - Warburg effect

UR - http://www.scopus.com/inward/record.url?scp=84868117861&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868117861&partnerID=8YFLogxK

U2 - 10.1002/nbm.2794

DO - 10.1002/nbm.2794

M3 - Article

VL - 25

SP - 1234

EP - 1244

JO - NMR in Biomedicine

JF - NMR in Biomedicine

SN - 0952-3480

IS - 11

ER -