Abstract
Like all cancers, brain tumors require a continuous source of energy and molecular resources for new cell production. In normal brain, glucose is an essential neuronal fuel, but the blood-brain barrier limits its delivery. We now report that nutrient restriction contributes to tumor progression by enriching for brain tumor initiating cells (BTICs) owing to preferential BTIC survival and to adaptation of non-BTICs through acquisition of BTIC features. BTICs outcompete for glucose uptake by co-opting the high affinity neuronal glucose transporter, type 3 (Glut3, SLC2A3). BTICs preferentially express Glut3, and targeting Glut3 inhibits BTIC growth and tumorigenic potential. Glut3, but not Glut1, correlates with poor survival in brain tumors and other cancers; thus, tumor initiating cells may extract nutrients with high affinity. As altered metabolism represents a cancer hallmark, metabolic reprogramming may maintain the tumor hierarchy and portend poor prognosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
12 September 2013
In the version of this article initially published online, author Bryan W. Day did not appear. The error has been corrected for the print, PDF and HTML versions of this article.
References
Stupp, R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 10, 459–466 (2009).
Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Galli, R. et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 64, 7011–7021 (2004).
Singh, S.K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).
Bao, S. et al. Brain tumor initiating cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).
Liu, G. et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol. Cancer 5, 67 (2006).
Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).
Peters, A. et al. The selfish brain: competition for energy resources. Neurosci. Biobehav. Rev. 28, 143–180 (2004).
Derr, R.L. et al. Association between hyperglycemia and survival in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 27, 1082–1086 (2009).
Panopoulos, A.D. et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res. 22, 168–177 (2012).
Ward, P.S. & Thompson, C.B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21, 297–308 (2012).
Li, Z. et al. Hypoxia-inducible factors regulate tumorigenic capacity of brain tumor initiating cells. Cancer Cell 15, 501–513 (2009).
Heddleston, J.M., Li, Z., McLendon, R.E., Hjelmeland, A.B. & Rich, J.N. The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8, 3274–3284 (2009).
Hjelmeland, A.B. et al. Acidic stress promotes a brain tumor initiating cell phenotype. Cell Death Differ. 18, 829–840 (2011).
Fellows, L.K. & Boutelle, M.G. Rapid changes in extracellular glucose levels and blood flow in the striatum of the freely moving rat. Brain Res. 604, 225–231 (1993).
Burgess, E.A. & Sylven, B. Glucose, lactate, and lactic dehydrogenase activity in normal interstitial fluid and that of solid mouse tumors. Cancer Res. 22, 581–588 (1962).
Laks, D.R. et al. Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27, 980–987 (2009).
Mathews, E.H., Liebenberg, L. & Pelzer, R. High-glycolytic cancers and their interplay with the body's glucose demand and supply cycle. Med. Hypotheses 76, 157–165 (2011).
Yoshioka, K. et al. A novel fluorescent derivative of glucose applicable to the assessment of glucose uptake activity of Escherichia coli. Biochim. Biophys. Acta 1289, 5–9 (1996).
Song, J. et al. Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision. Nature 489, 150–154 (2012).
Vannucci, S.J., Maher, F. & Simpson, I.A. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia 21, 2–21 (1997).
Nagamatsu, S., Sawa, H., Wakizaka, A. & Hoshino, T. Expression of facilitative glucose transporter isoforms in human brain tumors. J. Neurochem. 61, 2048–2053 (1993).
Boado, R.J., Black, K.L. & Pardridge, W.M. Gene expression of Glut3 and Glut1 glucose transporters in human brain tumors. Brain Res. Mol. Brain Res. 27, 51–57 (1994).
Freije, W.A. et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res. 64, 6503–6510 (2004).
Sun, L. et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9, 287–300 (2006).
Phillips, H.S. et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006).
Nutt, C.L. et al. Gene expression-based classification of malignant gliomas correlates better with survival than histological classification. Cancer Res. 63, 1602–1607 (2003).
Madhavan, S. et al. Rembrandt: helping personalized medicine become a reality through integrative translational research. Mol. Cancer Res. 7, 157–167 (2009).
Cancer Genome Atlas Research Network. Comprehensive genomic characterization define human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).
Verhaak, R.G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).
Noushmehr, H. et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510–522 (2010).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Loncaster, J.A. et al. Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix. Cancer Res. 61, 6394–6399 (2001).
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).
Yu, J. et al. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324, 797–801 (2009).
Younes, M., Lechago, L.V., Somoano, J.R., Mosharaf, M. & Lechago, J. Immunohistochemical detection of Glut3 in human tumors and normal tissues. Anticancer Res. 17, 2747–2750 (1997).
Younes, M., Brown, R.W., Stephenson, M., Gondo, M. & Cagle, P.T. Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival. Cancer 80, 1046–1051 (1997).
Ayala, F.R. et al. Glut1 and Glut3 as potential prognostic markers for oral squamous cell carcinoma. Molecules 15, 2374–2387 (2010).
Baer, S., Casaubon, L., Schwartz, M.R., Marcogliese, A. & Younes, M. Glut3 expression in biopsy specimens of laryngeal carcinoma is associated with poor survival. Laryngoscope 112, 393–396 (2002).
Gould, G.W. & Holman, G.D. The glucose transporter family: structure, function and tissue-specific expression. Biochem. J. 295, 329–341 (1993).
Charnley, N. et al. No relationship between 18F-fluorodeoxyglucose positron emission tomography and expression of Glut-1 and -3 and hexokinase I and II in high-grade glioma. Oncol. Rep. 20, 537–542 (2008).
Chung, J.K. et al. Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer. Nucl. Med. Commun. 25, 11–17 (2004).
Parsons, D.W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).
Novakovic, B., Gordon, L., Robinson, W.P., Desoye, G. & Saffery, R. Glucose as a fetal nutrient: dynamic regulation of several glucose transporter genes by DNA methylation in the human placenta across gestation. J. Nutr. Biochem. 24, 282–288 (2013).
Chen, Y., Shin, B.C., Thamotharan, S. & Devaskar, S.U. Creb1-Mecp2-(m)CpG complex transactivates postnatal murine neuronal glucose transporter isoform 3 expression. Endocrinology 154, 1598–1611 (2013).
Widschwendter, M. et al. Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157–158 (2007).
Wong, D.J. et al. Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2, 333–344 (2008).
Stoppini, L., Buchs, P.A. & Muller, D. A simple method for organotypic cultures of nervous tissue. J. Neurosci. Methods 37, 173–182 (1991).
Lathia, J.D. et al. Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells. PLoS ONE 6, e24807 (2011).
Acknowledgements
We thank the Cleveland Clinic Foundation Tissue Procurement Service, S. Staugatis, M. McGraw, the Flow Cytometry Core, S. Bao, T. Miller, D. Schonberg and Monica Venere; and the US National Institutes of Health: CA129958, CA116659 and CA154130 (J.N.R.); CA151522 (A.B.H.); CA157948 (J.D.L.), CA137443, NS063971, CA128269, CA101954 and CA116257 (A.E.S.); James S. McDonnell Foundation (J.N.R.); Voices Against Brain Cancer (J.D.L.); Ohio Department of Development Tech 09-071 (A.E.S.); American Brain Tumor Association (Y.K.); and Melvin Burkhardt Chair in Neurosurgical Oncology and Karen Colina Wilson Research Endowment (R.J.W.).
Author information
Authors and Affiliations
Contributions
Conception and experimental design: W.A.F., Q.W., Y.K., J.D.L., J.N.R. and A.B.H. Methodology and data acquisition: W.A.F., Q.W., M.H., N.R., A.E.S., R.J.W., I.N., J.N.S., B.W.S., B.W.D., M.L., J.D.L. and A.B.H. Analysis and interpretation of data: W.A.F., M.H., M.L., J.D.L., J.N.R. and A.B.H. Manuscript writing and/or revision: W.A.F., J.N.R. and A.B.H.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–10 and Supplementary Tables 1–4 (PDF 8368 kb)
Glucose restriction induces Nanog promoter–driven GFP expression
Glucose restriction induces Nanog promoter–driven GFP expression (AVI 18523 kb)
Rights and permissions
About this article
Cite this article
Flavahan, W., Wu, Q., Hitomi, M. et al. Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake. Nat Neurosci 16, 1373–1382 (2013). https://doi.org/10.1038/nn.3510
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn.3510
This article is cited by
-
Glucose transporter 3 (GLUT3) promotes lactylation modifications by regulating lactate dehydrogenase A (LDHA) in gastric cancer
Cancer Cell International (2023)
-
Nutrient transporters: connecting cancer metabolism to therapeutic opportunities
Oncogene (2023)
-
Establishing mammalian GLUT kinetics and lipid composition influences in a reconstituted-liposome system
Nature Communications (2023)
-
Targeting oncometabolism to maximize immunotherapy in malignant brain tumors
Oncogene (2022)
-
Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation
Cell Death & Differentiation (2022)