Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose

Subjects

Abstract

In this study, we monitored glycolysis in mouse lymphoma and lung tumors by measuring the conversion of hyperpolarized [U-2H, U-13C]glucose to lactate using 13C magnetic resonance spectroscopy and spectroscopic imaging. We observed labeled lactate only in tumors and not in surrounding normal tissue or other tissues in the body and found that it was markedly decreased at 24 h after treatment with a chemotherapeutic drug. We also detected an increase in a resonance assigned to 6-phosphogluconate in the pentose phosphate pathway. This technique could provide a new way of detecting early evidence of tumor treatment response in the clinic and of monitoring tumor pentose phosphate pathway activity.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: [U-2H, U-13C]glucose signals are detectable in vivo.
Figure 2: 13C spectroscopic imaging showing the spatial distribution of labeled glucose and lactate.
Figure 3: 13C MR spectrum from an untreated subcutaneous EL4 lymphoma tumor.

References

  1. Gatenby, R.A. & Gillies, R.J. Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer 4, 891–899 (2004).

    Article  CAS  Google Scholar 

  2. Hsu, P.P. & Sabatini, D.M. Cancer cell metabolism: Warburg and beyond. Cell 134, 703–707 (2008).

    Article  CAS  Google Scholar 

  3. Vander Heiden, M.G., Cantley, L.C. & Thompson, C.B. Understanding the Warburg Effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  4. Cairns, R.A., Harris, I.S. & Mak, T.W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011).

    Article  CAS  Google Scholar 

  5. Brindle, K. New approaches for imaging tumour responses to treatment. Nat. Rev. Cancer 8, 94–107 (2008).

    Article  CAS  Google Scholar 

  6. Weber, W.A. Use of PET for monitoring cancer therapy and for predicting outcome. J. Nucl. Med. 46, 983–995 (2005).

    PubMed  CAS  Google Scholar 

  7. Mason, G.F. et al. Simultaneous determination of the rates of the TCA cycle, glucose-utilization, α-ketoglutarate glutamate exchange, and glutamine synthesis in human brain by NMR. J. Cereb. Blood Flow Metab. 15, 12–25 (1995).

    Article  CAS  Google Scholar 

  8. Ardenkjaer-Larsen, J.H. et al. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc. Natl. Acad. Sci. USA 100, 10158–10163 (2003).

    Article  CAS  Google Scholar 

  9. Kurhanewicz, J. et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia 13, 81–97 (2011).

    Article  CAS  Google Scholar 

  10. Brindle, K.M., Bohndiek, S.E., Gallagher, F.A. & Kettunen, M.I. Tumor imaging using hyperpolarized 13C magnetic resonance spectroscopy. Magn. Reson. Med. 66, 505–519 (2011).

    Article  Google Scholar 

  11. Day, S.E. et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat. Med. 13, 1382–1387 (2007).

    Article  CAS  Google Scholar 

  12. Ward, C.S. et al. Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy. Cancer Res. 70, 1296–1305 (2010).

    Article  CAS  Google Scholar 

  13. Witney, T.H., Kettunen, M.I. & Brindle, K.M. Kinetic modeling of hyperpolarized 13C label exchange between pyruvate and lactate in tumor cells. J. Biol. Chem. 286, 24572–24580 (2011).

    Article  CAS  Google Scholar 

  14. Allouche-Arnon, H., Lerche, M.H., Karlsson, M., Lenkinski, R.E. & Katz-Brull, R. Deuteration of a molecular probe for DNP hyperpolarization—a new approach and validation for choline chloride. Contrast Media Mol. Imaging 6, 499–506 (2011).

    Article  CAS  Google Scholar 

  15. Meier, S., Jensen, P.R. & Duus, J.Ø. Real-time detection of central carbon metabolism in living Escherichia coli and its response to perturbations. FEBS Lett. 585, 3133–3138 (2011).

    Article  CAS  Google Scholar 

  16. Meier, S., Karlsson, M., Jensen, P.R., Lerche, M.H. & Duus, J.O. Metabolic pathway visualization in living yeast by DNP-NMR. Mol. Biosyst. 7, 2834–2836 (2011).

    Article  CAS  Google Scholar 

  17. Harris, T., Frydman, L. & Degani, H. Hyperpolarized 13C NMR studies of glucose metabolism in living breast cancer cell cultures. NMR Biomed. 26, 1831–1843 (2013).

    Article  CAS  Google Scholar 

  18. Allouche-Arnon, H. et al. In vivo magnetic resonance imaging of glucose—initial experience. Contrast Media Mol. Imaging 8, 72–82 (2013).

    Article  CAS  Google Scholar 

  19. Nelson, S.J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013).

    Article  CAS  Google Scholar 

  20. Gumaa, K.A. & McLean, P. The pentose phosphate pathway of glucose metabolism. Biochem. J. 115, 1009–1029 (1969).

    PubMed  PubMed Central  CAS  Google Scholar 

  21. Marin-Valencia, I. et al. Glucose metabolism via the pentose phosphate pathway, glycolysis and Krebs cycle in an orthotopic mouse model of human brain tumors. NMR Biomed. 25, 1177–1186 (2012).

    Article  CAS  Google Scholar 

  22. Rivenzon-Segal, D., Margalit, R. & Degani, H. Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo C-13 MRS. Am. J. Physiol. Endocrinol. Metab. 283, E623–E630 (2002).

    Article  CAS  Google Scholar 

  23. Poptani, H. et al. Cyclophosphamide treatment modifies tumor oxygenation and glycolytic rates of RIF-1 tumors: C-13 magnetic resonance spectroscopy, Eppendorf electrode, and redox scanning. Cancer Res. 63, 8813–8820 (2003).

    PubMed  CAS  Google Scholar 

  24. Madsen, P.L., Cruz, N.F., Sokoloff, L. & Dienel, G.A. Cerebral oxygen/glucose ratio is low during sensory stimulation and rises above normal during recovery: Excess glucose consumption during stimulation is not accounted for by lactate efflux from or accumulation in brain tissue. J. Cereb. Blood Flow Metab. 19, 393–400 (1999).

    Article  CAS  Google Scholar 

  25. Neely, J.R., Whitmer, J.T. & Rovetto, M.J. Effect of coronary blood-flow on glycolytic flux and intracellular pH in isolated rat hearts. Circ. Res. 37, 733–741 (1975).

    Article  CAS  Google Scholar 

  26. Kennedy, B.W.C., Kettunen, M.I., Hu, D.-E. & Brindle, K.M. Probing lactate dehydrogenase activity in tumors by measuring hydrogen/deuterium exchange in hyperpolarized L-[1-13C,U-2H]Lactate. J. Am. Chem. Soc. 134, 4969–4977 (2012).

    Article  CAS  Google Scholar 

  27. Kettunen, M.I. et al. Magnetization transfer measurements of exchange between hyperpolarized [1-13C]pyruvate and [1-13C]lactate in a murine lymphoma. Magn. Reson. Med. 63, 872–880 (2010).

    Article  CAS  Google Scholar 

  28. Park, J.M. et al. Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging. Neuro-oncol. 15, 433–441 (2013).

    Article  CAS  Google Scholar 

  29. Lodi, A., Woods, S.M. & Ronen, S.M. Treatment with the MEK inhibitor U0126 induces decreased hyperpolarized pyruvate to lactate conversion in breast, but not prostate, cancer cells. NMR Biomed. 26, 299–306 (2013).

    Article  CAS  Google Scholar 

  30. Riganti, C., Gazzano, E., Polimeni, M., Aldieri, E. & Ghigo, D. The pentose phosphate pathway: An antioxidant defense and a crossroad in tumor cell fate. Free Radic. Biol. Med. 53, 421–436 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work was supported by a Cancer Research UK Programme grant (C197/A3514) and by a Translational Research Program Award from The Leukemia & Lymphoma Society to K.M.B. T.B.R. is a recipient of an Intra-European Marie Curie (FP7-PEOPLE-2009-IEF, Imaging Lymphoma) fellowship and a Long-term European Molecular Biology Organization (EMBO-ALT-1145-2009) fellowship. E.M.S. is a recipient of a fellowship from the European Union Seventh Framework Programme (FP7/2007-2013) under the Marie Curie Initial Training Network METAFLUX (project number 264780). E.M.S. acknowledges the educational support of Programme for Advanced Medical Education from Calouste Gulbenkian Foundation, Champalimaud Foundation, Ministerio de Saude and Fundacao para a Ciencia e Tecnologia, Portugal. The polarizer and related materials were provided by GE Healthcare. The authors thank F. Gallagher for help with the polarizer. The laboratory is a member of and receives support from the Cancer Research UK & Engineering and Physical Science Research Council Cancer Imaging Center in Cambridge and Manchester.

Author information

Authors and Affiliations

Authors

Contributions

T.B.R. and M.I.K. designed the research; T.B.R., E.M.S., B.W.C.K., D.-E.H. and M.I.K. performed the research; T.B.R. and M.I.K. analyzed data; and T.B.R., M.I.K. and K.M.B. wrote the paper.

Corresponding author

Correspondence to Kevin M Brindle.

Ethics declarations

Competing interests

The hyperpolarizer is on loan from GE Healthcare and is the subject of a research agreement between the University of Cambridge, Cancer Research UK and GE Healthcare.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 (PDF 227 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rodrigues, T., Serrao, E., Kennedy, B. et al. Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose. Nat Med 20, 93–97 (2014). https://doi.org/10.1038/nm.3416

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3416

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing