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Functional Imaging in Oncology pp 147–180Cite as

Imaging of Tumor Metabolism: MR Spectroscopy

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Abstract

Reprogrammed tumor metabolism, which is characterized by alterations in glucose/lactate, glutamate/glutamine, choline, and glycine metabolism, is a hallmark of cancer. Recent findings are starting to unravel the interplay between oncogenic signaling pathways and aberrant tumor metabolism, and this has renewed the interest in imaging tumor metabolism. Changes in tumor metabolism modify the microenvironment and lead to the evolution and progression of primary tumors, as well as the development of tumor metastases. Magnetic resonance spectroscopy (MRS) provides a noninvasive way to examine tumor metabolism in living systems, ranging from cultured cancer cells, to tumor models in experimental animals, to humans in the clinical setting. In addition, the use of stable nonradioactive MR-active isotopes such as 31P, 19F, and 13C allows us to track the metabolism of molecular probes that contain these nuclei in tumors. With its high translational potential, MRS can provide prognostic information and can be used to monitor treatment responses in tumors. This book chapter covers the breadths of multinuclear MRS of tumor metabolism with a focus on preclinical studies.

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Abbreviations

3-APP:

3-aminopropyl phosphonate

5-FC:

5-fluorocytosine

5-FU:

5-fluorouracil

AKT:

Protein kinase B

AMPK:

Adenosine monophosphate-activated protein kinase

Asp-NAT:

Aspartate N-acetyltransferase

ATP:

Adenosine-5′-triphosphate

CA:

Carbonic anhydrase

CCL-103F:

1-(2-hydroxy-3-hexaflu–oroisopropoxy-propyl)-2-nitroimidazole

CCT:

CTP–phosphocholinecytidylyltransferase

CDP-Eth:

Cytidine diphosphate ethanolamine

CEST:

Chemical exchange saturation transfer

CF3PM:

5,6-dimethyl-4-[3-(2-nitro1-imidazolyl)-propylamino]-2-trifluoromethylpyrimidine hydrochloride

Cho:

Free choline

CHPT:

Cholinephosphotransferase

CHT:

High-affinity choline transporter

CK:

Choline kinase

CLT:

Choline transporter-like proteins

CoA:

Coenzyme A

Cr:

Creatine

CSI:

Chemical shift imaging

CTP:

Cytidine triphosphate

DNP:

Dynamic nuclear polarization

FGF:

Fibroblast growth factor

FID:

Free induction decay

FNuct:

Fluoronucleotides

Gln:

Glutamine

Glu:

Glutamate

Glx:

Sum of Glu and Gln

GPC:

Glycerophosphocholine

GPE:

Glycerophosphoethanolamine

HIF:

Hypoxia-inducible factor

HR-NMR:

High-resolution NMR

HSQC:

Heteronuclear single-quantum correlation spectroscopy

IEPA:

2-imidazole-1-yl-3-ethoxycarbonyl propionic acid

IgG:

Immunoglobulin

IL:

Interleukin

JNK:

c-Jun N-terminal kinase

LDH:

Lactate dehydrogenase

MAP:

Mitogen-activated protein

MCT:

Monocarboxylate transporters

MRS:

Magnetic resonance spectroscopy

MS:

Multiple sclerosis

mTOR:

Mammalian target of rapamycin

NAA:

N-acetylaspartate

NADH:

Reduced form of nicotinamide adenine dinucleotide

NaTFA:

Sodium trifluoroacetate

NDP:

Nucleoside diphosphate

NMR:

Nuclear magnetic resonance

NTP:

Nucleoside triphosphate

OCTN:

Organic cation/carnitine transporters

PA:

Phosphatidic acid

PC:

Phosphocholine

PCA:

Perchloric acid

PCr:

Phosphocreatine

PDE:

Phosphodiester

PEMT:

Phosphatidylethanolamine N-methyltransferase

pHe:

pH extracellular

pHi:

PH intracellular

Pi:

Pnorganic phosphate

PI3K:

Phosphatidylinositol 3-kinases

PLA:

Phospholipase A

PME:

Phosphomonoester

PPM:

Parts per million

PtdCho:

Phosphatidylcholine

PtdEth:

Phosphatidylethanolamine

RF:

Radio frequency

RIF:

Radiation-induced fibrosarcoma

RINEPT:

Refocused insensitive nuclei enhanced by polarization transfer

RTK:

Receptor tyrosine kinase

SelMQC:

Selective multiple-quantum coherence filter

TCA:

Tricarboxylic acid

tCho:

Total choline

tCr:

Total creatine

TP53:

Tumor protein 53

TRAMP:

Transgenic adenocarcinomas of mouse prostate

VHL:

Von Hippel–Lindau

Yb-DO3A-oAA:

Ytterbium-1,4,7,10-tetraazacyclododecane-1,4,7-tetraacetic acid

References

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    PubMed  CAS  Google Scholar 

  2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    PubMed  CAS  Google Scholar 

  3. Siegel R, et al. Cancer statistics, 2012. CA Cancer J Clin. 2012;62(1):10–29.

    PubMed  Google Scholar 

  4. Dang CV, et al. Therapeutic targeting of cancer cell metabolism. J Mol Med (Berl). 2011;89(3):205–12.

    CAS  Google Scholar 

  5. Vander Heiden MG. Targeting cancer metabolism: a therapeutic window opens. Nat Rev Drug Discov. 2011;10(9):671–84.

    PubMed  CAS  Google Scholar 

  6. He Q, et al. Magnetic resonance spectroscopic imaging of tumor metabolic markers for cancer diagnosis, metabolic phenotyping, and characterization of tumor microenvironment. Dis Markers. 2003;19(2–3):69–94.

    PubMed  CAS  Google Scholar 

  7. Glunde K, Bhujwalla ZM. Metabolic tumor imaging using magnetic resonance spectroscopy. Semin Oncol. 2011;38(1):26–41.

    PubMed  PubMed Central  Google Scholar 

  8. Vander Heiden MG, et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.

    PubMed  CAS  PubMed Central  Google Scholar 

  9. Deberardinis RJ, et al. Brick by brick: metabolism and tumor cell growth. Curr Opin Genet Dev. 2008;18(1):54–61.

    PubMed  CAS  PubMed Central  Google Scholar 

  10. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721–32.

    PubMed  CAS  Google Scholar 

  11. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.

    PubMed  CAS  Google Scholar 

  12. Daye D, Wellen KE. Metabolic reprogramming in cancer: unraveling the role of glutamine in tumorigenesis. Semin Cell Dev Biol. 2012;23(4):362–9.

    PubMed  CAS  Google Scholar 

  13. DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2009;29(3):313–24.

    PubMed  PubMed Central  Google Scholar 

  14. Ackerstaff E, et al. Choline phospholipid metabolism: a target in cancer cells? J Cell Biochem. 2003;90(3):525–33.

    PubMed  CAS  Google Scholar 

  15. Glunde K, et al. Choline metabolism in malignant transformation. Nat Rev Cancer. 2011;11(12):835–48.

    PubMed  CAS  Google Scholar 

  16. Glunde K, et al. Molecular causes of the aberrant choline phospholipid metabolism in breast cancer. Cancer Res. 2004;64(12):4270–6.

    PubMed  CAS  Google Scholar 

  17. Stehelin D, et al. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature. 1976;260(5547):170–3.

    PubMed  CAS  Google Scholar 

  18. Harris H, et al. Suppression of malignancy by cell fusion. Nature. 1969;223(5204):363–8.

    PubMed  CAS  Google Scholar 

  19. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev. 2009;23(5):537–48.

    PubMed  CAS  PubMed Central  Google Scholar 

  20. Levine AJ, Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science. 2010;330(6009):1340–4.

    PubMed  CAS  Google Scholar 

  21. Rabi II, et al. The molecular beam resonance method for measuring nuclear magnetic moments. Phys Rev. 1939;55(6):526.

    CAS  Google Scholar 

  22. Bloch F, et al. Nuclear induction. Phys Rev. 1946;70(7–8):460–74.

    CAS  Google Scholar 

  23. Bloembergen N, et al. Relaxation effects in nuclear magnetic resonance absorption. Phys Rev. 1948;73(7):679.

    CAS  Google Scholar 

  24. Damadian R, et al. Field focusing nuclear magnetic resonance (FONAR): visualization of a tumor in a live animal. Science. 1976;194(4272):1430–2.

    PubMed  CAS  Google Scholar 

  25. Bloembergen N, et al. Nuclear magnetic relaxation. Nature. 1947;160(4066):475.

    PubMed  CAS  Google Scholar 

  26. Ernst RR, Anderson WA. Application of Fourier transform spectroscopy to magnetic resonance. Rev Sci Instrum. 1966;37(1):93–102.

    CAS  Google Scholar 

  27. McIntyre DJ, et al. Magnetic resonance spectroscopy of cancer metabolism and response to therapy. Radiat Res. 2012;177(4):398–435.

    PubMed  CAS  Google Scholar 

  28. Pople JA, et al. High resolution NMR spectroscopy. New York: McGraw-Hill; 1959.

    Google Scholar 

  29. Le Belle JE, et al. A comparison of cell and tissue extraction techniques using high-resolution 1H-NMR spectroscopy. NMR Biomed. 2002;15(1):37–44.

    PubMed  Google Scholar 

  30. Gillies RJ, Morse DL. In vivo magnetic resonance spectroscopy in cancer. Annu Rev Biomed Eng. 2005;7:287–326.

    PubMed  CAS  Google Scholar 

  31. Gillies RJ, et al. pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag. 2004;23(5):57–64.

    PubMed  Google Scholar 

  32. Aboagye EO, et al. Intratumoral conversion of 5-fluorocytosine to 5-fluorouracil by monoclonal antibody-cytosine deaminase conjugates: noninvasive detection of prodrug activation by magnetic resonance spectroscopy and spectroscopic imaging. Cancer Res. 1998;58(18):4075–8.

    PubMed  CAS  Google Scholar 

  33. Ruiz-Cabello J, et al. Fluorine (19F) MRS and MRI in biomedicine. NMR Biomed. 2010;24(2):114–29.

    PubMed  PubMed Central  Google Scholar 

  34. Gerig JT. Fluorine NMR of proteins. Prog Nucl Magn Reson Spectrosc. 1994;26:293–370.

    CAS  Google Scholar 

  35. Klomp DW, et al. Optimization of localized 19F magnetic resonance spectroscopy for the detection of fluorinated drugs in the human liver. Magn Reson Med. 2003;50(2):303–8.

    PubMed  CAS  Google Scholar 

  36. Martino R, et al. Fluorine nuclear magnetic resonance, a privileged tool for metabolic studies of fluoropyrimidine drugs. Curr Drug Metab. 2000;1(3):271–303.

    PubMed  CAS  Google Scholar 

  37. Yu JX, et al. 19F: a versatile reporter for non-invasive physiology and pharmacology using magnetic resonance. Curr Med Chem. 2005;12(7):819–48.

    PubMed  CAS  Google Scholar 

  38. Bhujwalla ZM, et al. Metabolic heterogeneity in RIF-1 tumours detected in vivo by 31P NMR spectroscopy. NMR Biomed. 1990;3(5):233–8.

    PubMed  CAS  Google Scholar 

  39. Daly PF, et al. Phospholipid metabolism in cancer cells monitored by 31P NMR spectroscopy. J Biol Chem. 1987;262(31):14875–8.

    PubMed  CAS  Google Scholar 

  40. Street JC, et al. 13C and 31P NMR investigation of effect of 6-aminonicotinamide on metabolism of RIF-1 tumor cells in vitro. J Biol Chem. 1996;271(8):4113–9.

    PubMed  CAS  Google Scholar 

  41. Vaupel P, et al. Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma. Radiat Res. 1989;120(3):477–93.

    PubMed  CAS  Google Scholar 

  42. Cohen SM, et al. Effects of ethanol on alanine metabolism in perfused mouse liver studied by 13C NMR. Proc Natl Acad Sci U S A. 1979;76(10):4808–12.

    PubMed  CAS  PubMed Central  Google Scholar 

  43. Fung BM. Carbon-13 and proton magnetic resonance of mouse muscle. Biophys J. 1977;19(3):315–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  44. Shen J, et al. Determination of the rate of the glutamate/glutamine cycle in the human brain by in vivo 13C NMR. Proc Natl Acad Sci U S A. 1999;96(14):8235–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  45. Horowitz BL, et al. MR of intracranial epidermoid tumors: correlation of in vivo imaging with in vitro 13C spectroscopy. AJNR Am J Neuroradiol. 1990;11(2):299–302.

    PubMed  CAS  Google Scholar 

  46. Ardenkjaer-Larsen JH, et al. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc Natl Acad Sci U S A. 2003;100(18):10158–63.

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Chaumeil MM, et al. Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma. Neuroimage. 2011;59(1):193–201.

    PubMed  PubMed Central  Google Scholar 

  48. Dafni H, et al. Hyperpolarized 13C spectroscopic imaging informs on hypoxia-inducible factor-1 and myc activity downstream of platelet-derived growth factor receptor. Cancer Res. 2010;70(19):7400–10.

    PubMed  CAS  PubMed Central  Google Scholar 

  49. Harrison C, et al. Comparison of kinetic models for analysis of pyruvate-to-lactate exchange by hyperpolarized 13 C NMR. NMR Biomed. 2012;25(11):1286–94.

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Merritt ME, et al. Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc Natl Acad Sci U S A. 2007;104(50):19773–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  51. Ouwerkerk R, et al. Tissue sodium concentration in human brain tumors as measured with 23Na MR imaging. Radiology. 2003;227(2):529–37.

    PubMed  Google Scholar 

  52. Ward CS, et al. Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy. Cancer Res. 2010;70(4):1296–305.

    PubMed  CAS  PubMed Central  Google Scholar 

  53. Burney IA, et al. Effect of vasoactive drugs on tumour blood flow as determined by 2H nuclear magnetic resonance spectroscopy. Acta Oncol. 1995;34(3):367–71.

    PubMed  CAS  Google Scholar 

  54. Zeisel SH, da Costa KA. Choline: an essential nutrient for public health. Nutr Rev. 2009;67(11):615–23.

    PubMed  PubMed Central  Google Scholar 

  55. Resseguie M, et al. Phosphatidylethanolamine N-methyltransferase (PEMT) gene expression is induced by estrogen in human and mouse primary hepatocytes. FASEB J. 2007;21(10):2622–32.

    PubMed  CAS  PubMed Central  Google Scholar 

  56. Zeisel SH. Choline: critical role during fetal development and dietary requirements in adults. Annu Rev Nutr. 2006;26:229–50.

    PubMed  CAS  PubMed Central  Google Scholar 

  57. Zeisel SH, Blusztajn JK. Choline and human nutrition. Annu Rev Nutr. 1994;14:269–96.

    PubMed  CAS  Google Scholar 

  58. Negendank W. Studies of human tumors by MRS: a review. NMR Biomed. 1992;5(5):303–24.

    PubMed  CAS  Google Scholar 

  59. Podo F. Tumour phospholipid metabolism. NMR Biomed. 1999;12(7):413–39.

    PubMed  CAS  Google Scholar 

  60. Ronen SM, Leach MO. Imaging biochemistry: applications to breast cancer. Breast Cancer Res. 2001;3(1):36–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  61. Glunde K, Serkova NJ. Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism. Pharmacogenomics. 2006;7(7):1109–23.

    PubMed  CAS  Google Scholar 

  62. Ramirez de Molina A, et al. Expression of choline kinase alpha to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study. Lancet Oncol. 2007;8(10):889–97.

    PubMed  CAS  Google Scholar 

  63. Aboagye EO, Bhujwalla ZM. Malignant transformation alters membrane choline phospholipid metabolism of human mammary epithelial cells. Cancer Res. 1999;59(1):80–4.

    PubMed  CAS  Google Scholar 

  64. Hara T, et al. Choline transporter as a novel target for molecular imaging of cancer. Mol Imaging. 2006;5(4):498–509.

    PubMed  Google Scholar 

  65. Koepsell H, et al. Organic cation transporters. Rev Physiol Biochem Pharmacol. 2003;150:36–90.

    PubMed  CAS  Google Scholar 

  66. Okuda T, et al. Identification and characterization of the high-affinity choline transporter. Nat Neurosci. 2000;3(2):120–5.

    PubMed  CAS  Google Scholar 

  67. O’Regan S, et al. An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins. Proc Natl Acad Sci U S A. 2000;97(4):1835–40.

    PubMed  PubMed Central  Google Scholar 

  68. Eliyahu G, et al. Phosphocholine as a biomarker of breast cancer: molecular and biochemical studies. Int J Cancer. 2007;120(8):1721–30.

    PubMed  CAS  Google Scholar 

  69. Katz-Brull R, Degani H. Kinetics of choline transport and phosphorylation in human breast cancer cells; NMR application of the zero trans method. Anticancer Res. 1996;16(3B):1375–80.

    PubMed  CAS  Google Scholar 

  70. Kouji H, et al. Molecular and functional characterization of choline transporter in human colon carcinoma HT-29 cells. Arch Biochem Biophys. 2009;483(1):90–8.

    PubMed  CAS  Google Scholar 

  71. Wittenberg J, Kornberg A. Choline phosphokinase. J Biol Chem. 1953;202(1):431–44.

    PubMed  CAS  Google Scholar 

  72. Marchan R, et al. Choline-releasing glycerophosphodiesterase EDI3 links the tumor metabolome to signaling network activities. Cell Cycle. 2012;11(24):4499–506.

    PubMed  CAS  PubMed Central  Google Scholar 

  73. Stewart JD, et al. Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis. Proc Natl Acad Sci U S A. 2012;109(21):8155–60.

    PubMed  CAS  PubMed Central  Google Scholar 

  74. Zhong M, et al. Phospholipase D prevents apoptosis in v-Src-transformed rat fibroblasts and MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun. 2003;302(3):615–9.

    PubMed  CAS  Google Scholar 

  75. Uchida N, et al. Phospholipase D activity in human gastric carcinoma. Anticancer Res. 1999;19(1B):671–5.

    PubMed  CAS  Google Scholar 

  76. Iorio E, et al. Alterations of choline phospholipid metabolism in ovarian tumor progression. Cancer Res. 2005;65(20):9369–76.

    PubMed  CAS  Google Scholar 

  77. Oka M, et al. Protein kinase C alpha associates with phospholipase D1 and enhances basal phospholipase D activity in a protein phosphorylation-independent manner in human melanoma cells. J Invest Dermatol. 2003;121(1):69–76.

    PubMed  CAS  Google Scholar 

  78. Foster DA, Xu L. Phospholipase D in cell proliferation and cancer. Mol Cancer Res. 2003;1(11):789–800.

    PubMed  CAS  Google Scholar 

  79. Yamashita S, et al. Overexpression of group II phospholipase A2 in human breast cancer tissues is closely associated with their malignant potency. Br J Cancer. 1994;69(6):1166–70.

    PubMed  CAS  PubMed Central  Google Scholar 

  80. Ramirez de Molina A, et al. Choline kinase is a novel oncogene that potentiates RhoA-induced carcinogenesis. Cancer Res. 2005;65(13):5647–53.

    PubMed  CAS  Google Scholar 

  81. Warden CH, et al. Acid-soluble precursors and derivatives of phospholipids increase after stimulation of quiescent Swiss 3T3 mouse fibroblasts with serum. Biochem Biophys Res Commun. 1980;94(2):690–6.

    PubMed  CAS  Google Scholar 

  82. Lacal JC, et al. Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. Nature. 1987;330(6145):269–72.

    PubMed  CAS  Google Scholar 

  83. Macara IG. Elevated phosphocholine concentration in ras-transformed NIH 3T3 cells arises from increased choline kinase activity, not from phosphatidylcholine breakdown. Mol Cell Biol. 1989;9(1):325–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  84. Ramirez de Molina A, et al. Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K. Oncogene. 2002;21(6):937–46.

    PubMed  CAS  Google Scholar 

  85. Warden CH, Friedkin M. Regulation of choline kinase activity and phosphatidylcholine biosynthesis by mitogenic growth factors in 3T3 fibroblasts. J Biol Chem. 1985;260(10):6006–11.

    PubMed  CAS  Google Scholar 

  86. Wang T, et al. Choline transporters in human lung adenocarcinoma: expression and functional implications. Acta Biochim Biophys Sin (Shanghai). 2007;39(9):668–74.

    CAS  Google Scholar 

  87. Ryan AJ, et al. c-Jun N-terminal kinase regulates CTP:phosphocholine cytidylyltransferase. Arch Biochem Biophys. 2006;447(1):23–33.

    PubMed  CAS  Google Scholar 

  88. Ackerstaff E, et al. Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res. 2001;61(9):3599–603.

    PubMed  CAS  Google Scholar 

  89. Malet-Martino M, Holzgrabe U. NMR techniques in biomedical and pharmaceutical analysis. J Pharm Biomed Anal. 2011;55(1):1–15.

    PubMed  CAS  Google Scholar 

  90. Sato N. Central role of mitochondria in metabolic regulation of liver pathophysiology. J Gastroenterol Hepatol. 2007;22 Suppl 1:S1–6.

    PubMed  CAS  Google Scholar 

  91. Zhu M, et al. Reproducibility of total choline/water ratios in mouse U87MG xenograft tumors by 1H-MRS. J Magn Reson Imaging. 2012;36(2):459–67.

    PubMed  Google Scholar 

  92. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891–9.

    PubMed  CAS  Google Scholar 

  93. Costello LC, Franklin RB. ‘Why do tumour cells glycolyse?’: from glycolysis through citrate to lipogenesis. Mol Cell Biochem. 2005;280(1–2):1–8.

    PubMed  CAS  Google Scholar 

  94. Samudio I, et al. Mitochondrial uncoupling and the Warburg effect: molecular basis for the reprogramming of cancer cell metabolism. Cancer Res. 2009;69(6):2163–6.

    PubMed  CAS  Google Scholar 

  95. Stambaugh R, Post D. Substrate and product inhibition of rabbit muscle lactic dehydrogenase heart (H4) and muscle (M4) isozymes. J Biol Chem. 1966;241(7):1462–7.

    PubMed  CAS  Google Scholar 

  96. Serganova I, et al. Metabolic imaging: a link between lactate dehydrogenase a, lactate, and tumor phenotype. Clin Cancer Res. 2011;17(19):6250–61.

    PubMed  CAS  Google Scholar 

  97. Granchi C, et al. Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials. Curr Med Chem. 2010;17(7):672–97.

    PubMed  CAS  Google Scholar 

  98. Fantin VR, et al. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006;9(6):425–34.

    PubMed  CAS  Google Scholar 

  99. Le A, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A. 2010;107(5):2037–42.

    PubMed  CAS  PubMed Central  Google Scholar 

  100. Seth P, et al. On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate. Neoplasia. 2011;13(1):60–71.

    PubMed  CAS  PubMed Central  Google Scholar 

  101. Walenta S, et al. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 2000;60(4):916–21.

    PubMed  CAS  Google Scholar 

  102. Brizel DM, et al. Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51(2):349–53.

    PubMed  CAS  Google Scholar 

  103. Albers MJ, et al. Hyperpolarized 13C lactate, pyruvate, and alanine: noninvasive biomarkers for prostate cancer detection and grading. Cancer Res. 2008;68(20):8607–15.

    PubMed  CAS  PubMed Central  Google Scholar 

  104. Gatza ML, et al. Analysis of tumor environmental response and oncogenic pathway activation identifies distinct basal and luminal features in HER2-related breast tumor subtypes. Breast Cancer Res. 2011;13(3):R62.

    PubMed  PubMed Central  Google Scholar 

  105. Walenta S, et al. Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? J Cancer Res Clin Oncol. 2003;129(6):321–6.

    PubMed  Google Scholar 

  106. Fraisl P, et al. Regulation of angiogenesis by oxygen and metabolism. Dev Cell. 2009;16(2):167–79.

    PubMed  CAS  Google Scholar 

  107. Green H, Goldberg B. Collagen and cell protein synthesis by an established mammalian fibroblast line. Nature. 1964;204:347–9.

    PubMed  CAS  Google Scholar 

  108. Hunt TK, et al. Aerobically derived lactate stimulates revascularization and tissue repair via redox mechanisms. Antioxid Redox Signal. 2007;9(8):1115–24.

    PubMed  CAS  PubMed Central  Google Scholar 

  109. Constant JS, et al. Lactate elicits vascular endothelial growth factor from macrophages: a possible alternative to hypoxia. Wound Repair Regen. 2000;8(5):353–60.

    PubMed  CAS  Google Scholar 

  110. Xiong M, et al. Production of vascular endothelial growth factor by murine macrophages: regulation by hypoxia, lactate, and the inducible nitric oxide synthase pathway. Am J Pathol. 1998;153(2):587–98.

    PubMed  CAS  PubMed Central  Google Scholar 

  111. Vegran F, et al. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 2011;71(7):2550–60.

    PubMed  CAS  Google Scholar 

  112. De Saedeleer CJ, et al. Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One. 2012;7(10):e46571.

    PubMed  PubMed Central  Google Scholar 

  113. Bottomley PA. Spatial localization in NMR spectroscopy in vivo. Ann N Y Acad Sci. 1987;508:333–48.

    PubMed  CAS  Google Scholar 

  114. Frahm J, et al. Localized high-resolution proton NMR spectroscopy using stimulated echoes: initial applications to human brain in vivo. Magn Reson Med. 1989;9(1):79–93.

    PubMed  CAS  Google Scholar 

  115. Rothman DL, et al. Homonuclear 1H double-resonance difference spectroscopy of the rat brain in vivo. Proc Natl Acad Sci U S A. 1984;81(20):6330–4.

    PubMed  CAS  PubMed Central  Google Scholar 

  116. He Q, et al. Proton detection of choline and lactate in EMT6 tumors by spin-echo-enhanced selective multiple-quantum-coherence transfer. J Magn Reson B. 1996;112(1):18–25.

    PubMed  CAS  Google Scholar 

  117. He Q, et al. Single-scan in vivo lactate editing with complete lipid and water suppression by selective multiple-quantum-coherence transfer (Sel-MQC) with application to tumors. J Magn Reson B. 1995;106(3):203–11.

    PubMed  CAS  Google Scholar 

  118. Freeman DM, et al. A double quantum coherence transfer proton NMR spectroscopy technique for monitoring steady-state tumor lactic acid levels in vivo. Magn Reson Med. 1990;14(2):321–9.

    PubMed  CAS  Google Scholar 

  119. Thakur SB, et al. In vivo lactate signal enhancement using binomial spectral-selective pulses in selective MQ coherence (SS-SelMQC) spectroscopy. Magn Reson Med. 2009;62(3):591–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  120. Mellon EA, et al. Detection of lactate with a hadamard slice selected, selective multiple quantum coherence, chemical shift imaging sequence (HDMD-SelMQC-CSI) on a clinical MRI scanner: application to tumors and muscle ischemia. Magn Reson Med. 2009;62(6):1404–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  121. Pickup S, et al. Lactate imaging with Hadamard-encoded slice-selective multiple quantum coherence chemical-shift imaging. Magn Reson Med. 2008;60(2):299–305.

    PubMed  CAS  PubMed Central  Google Scholar 

  122. Yaligar J, et al. Lactate MRSI and DCE MRI as surrogate markers of prostate tumor aggressiveness. NMR Biomed. 2011;25(1):113–22.

    PubMed  Google Scholar 

  123. Plathow C, Weber WA. Tumor cell metabolism imaging. J Nucl Med. 2008;49 Suppl 2:43S–63.

    PubMed  CAS  Google Scholar 

  124. Poptani H, et al. Detecting early response to cyclophosphamide treatment of RIF-1 tumors using selective multiple quantum spectroscopy (SelMQC) and dynamic contrast enhanced imaging. NMR Biomed. 2003;16(2):102–11.

    PubMed  CAS  Google Scholar 

  125. Aboagye EO, et al. Detection of tumor response to chemotherapy by 1H nuclear magnetic resonance spectroscopy: effect of 5-fluorouracil on lactate levels in radiation-induced fibrosarcoma 1 tumors. Cancer Res. 1998;58(5):1063–7.

    PubMed  CAS  Google Scholar 

  126. Hakumaki JM, Kauppinen RA. 1H NMR visible lipids in the life and death of cells. Trends Biochem Sci. 2000;25(8):357–62.

    PubMed  CAS  Google Scholar 

  127. Delikatny EJ, et al. MR-visible lipids and the tumor microenvironment. NMR Biomed. 2011;24(6):592–611.

    PubMed  CAS  PubMed Central  Google Scholar 

  128. Mannechez A, et al. Proton NMR visible mobile lipid signals in sensitive and multidrug-resistant K562 cells are modulated by rafts. Cancer Cell Int. 2005;5(1):2.

    PubMed  PubMed Central  Google Scholar 

  129. Hakumaki JM, et al. 1H MRS detects polyunsaturated fatty acid accumulation during gene therapy of glioma: implications for the in vivo detection of apoptosis. Nat Med. 1999;5(11):1323–7.

    PubMed  CAS  Google Scholar 

  130. Ferretti A, et al. Biophysical and structural characterization of 1H-NMR-detectable mobile lipid domains in NIH-3T3 fibroblasts. Biochim Biophys Acta. 1999;1438(3):329–48.

    PubMed  CAS  Google Scholar 

  131. Melkus G, et al. Short-echo spectroscopic imaging combined with lactate editing in a single scan. NMR Biomed. 2008;21(10):1076–86.

    PubMed  CAS  Google Scholar 

  132. Rosi A, et al. (1H) MRS studies of signals from mobile lipids and from lipid metabolites: comparison of the behavior in cultured tumor cells and in spheroids. NMR Biomed. 2004;17(2):76–91.

    PubMed  CAS  Google Scholar 

  133. Mylonis I, et al. Hypoxia causes triglyceride accumulation by HIF-1-mediated stimulation of lipin 1 expression. J Cell Sci. 2012;125(Pt 14):3485–93.

    PubMed  CAS  PubMed Central  Google Scholar 

  134. Heerdt BG, et al. Initiation of growth arrest and apoptosis of MCF-7 mammary carcinoma cells by tributyrin, a triglyceride analogue of the short-chain fatty acid butyrate, is associated with mitochondrial activity. Cancer Res. 1999;59(7):1584–91.

    PubMed  CAS  Google Scholar 

  135. Namiot Z, et al. Gastric cancer with special references to WHO and Lauren’s classifications: glycogen and triacylglycerol concentrations in the tumor. Neoplasma. 1989;36(3):363–8.

    PubMed  CAS  Google Scholar 

  136. Calabrese C, et al. Biochemical alterations from normal mucosa to gastric cancer by ex vivo magnetic resonance spectroscopy. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1386–95.

    PubMed  CAS  Google Scholar 

  137. Le Moyec L, et al. Proton nuclear magnetic resonance spectroscopy reveals cellular lipids involved in resistance to adriamycin and taxol by the K562 leukemia cell line. Cancer Res. 1996;56(15):3461–7.

    PubMed  Google Scholar 

  138. Santini MT, et al. The relationship between 1H-NMR mobile lipid intensity and cholesterol in two human tumor multidrug resistant cell lines (MCF-7 and LoVo). Biochim Biophys Acta. 2001;1531(1–2):111–31.

    PubMed  CAS  Google Scholar 

  139. Tallan HH, et al. N-acetyl-L-aspartic acid in brain. J Biol Chem. 1956;219(1):257–64.

    PubMed  CAS  Google Scholar 

  140. Baslow MH. N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res. 2003;28(6):941–53.

    PubMed  CAS  Google Scholar 

  141. Goldstein FB. Biosynthesis of N-acetyl-L-aspartic acid. Biochim Biophys Acta. 1959;33(2):583–4.

    PubMed  CAS  Google Scholar 

  142. Benuck M, D’Adamo Jr AF. Acetyl transport mechanisms. Metabolism of N-acetyl-L-aspartic acid in the non-nervous tissues of the rat. Biochim Biophys Acta. 1968;152(3):611–8.

    PubMed  CAS  Google Scholar 

  143. Clark JF, et al. N-acetylaspartate as a reservoir for glutamate. Med Hypotheses. 2006;67(3):506–12.

    PubMed  CAS  Google Scholar 

  144. Rigotti DJ, et al. Whole-brain N-acetylaspartate as a surrogate marker of neuronal damage in diffuse neurologic disorders. AJNR Am J Neuroradiol. 2007;28(10):1843–9.

    PubMed  CAS  Google Scholar 

  145. Law M, et al. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. AJNR Am J Neuroradiol. 2003;24(10):1989–98.

    PubMed  Google Scholar 

  146. Mehta V, Namboodiri MA. N-acetylaspartate as an acetyl source in the nervous system. Brain Res Mol Brain Res. 1995;31(1–2):151–7.

    PubMed  CAS  Google Scholar 

  147. Ishimaru H, et al. Differentiation between high-grade glioma and metastatic brain tumor using single-voxel proton MR spectroscopy. Eur Radiol. 2001;11(9):1784–91.

    PubMed  CAS  Google Scholar 

  148. Bulik M, et al. Potential of MR spectroscopy for assessment of glioma grading. Clin Neurol Neurosurg. 2012;115(2):146–53.

    PubMed  Google Scholar 

  149. Gyngell ML, et al. Proton MR spectroscopy of experimental brain tumors in vivo. Acta Neurochir Suppl (Wien). 1994;60:350–2.

    CAS  Google Scholar 

  150. Wallimann T, et al. Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J. 1992;281(Pt 1):21–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  151. Prabhakar G, et al. Phosphocreatine restores high-energy phosphates in ischemic myocardium: implication for off-pump cardiac revascularization. J Am Coll Surg. 2003;197(5):786–91.

    PubMed  Google Scholar 

  152. da Silva RP, et al. Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am J Physiol Endocrinol Metab. 2009;296(2):E256–61.

    PubMed  PubMed Central  Google Scholar 

  153. Ohtsuki S, et al. The blood–brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J Cereb Blood Flow Metab. 2002;22(11):1327–35.

    PubMed  CAS  Google Scholar 

  154. Murphy R, et al. Creatine transporter protein content, localization, and gene expression in rat skeletal muscle. Am J Physiol Cell Physiol. 2001;280(3):C415–22.

    PubMed  CAS  Google Scholar 

  155. Baird MF, et al. Creatine-kinase- and exercise-related muscle damage implications for muscle performance and recovery. J Nutr Metabol. 2012;2012:960363.

    Google Scholar 

  156. Shatton JB, et al. Creatine kinase activity and isozyme composition in normal tissues and neoplasms of rats and mice. Cancer Res. 1979;39(2 Pt 1):492–501.

    PubMed  CAS  Google Scholar 

  157. Lowry OH, et al. Diversity of metabolic patterns in human brain tumors–I. High energy phosphate compounds and basic composition. J Neurochem. 1977;29(6):959–77.

    PubMed  CAS  Google Scholar 

  158. Sartorius A, et al. Proton magnetic resonance spectroscopic creatine correlates with creatine transporter protein density in rat brain. J Neurosci Methods. 2008;172(2):215–9.

    PubMed  CAS  Google Scholar 

  159. Meyerand ME, et al. Classification of biopsy-confirmed brain tumors using single-voxel MR spectroscopy. AJNR Am J Neuroradiol. 1999;20(1):117–23.

    PubMed  CAS  Google Scholar 

  160. Weybright P, et al. Differentiation between brain tumor recurrence and radiation injury using MR spectroscopy. AJR Am J Roentgenol. 2005;185(6):1471–6.

    PubMed  Google Scholar 

  161. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr. 2003;133(6 Suppl 1):2068S–72.

    PubMed  CAS  Google Scholar 

  162. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev. 1990;48(8):297–309.

    PubMed  CAS  Google Scholar 

  163. Li X, et al. Composition of amino acids in feed ingredients for animal diets. Amino Acids. 2011;40(4):1159–68.

    PubMed  CAS  Google Scholar 

  164. Rajagopalan KN, DeBerardinis RJ. Role of glutamine in cancer: therapeutic and imaging implications. J Nucl Med. 2011;52(7):1005–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  165. Reitzer LJ, et al. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem. 1979;254(8):2669–76.

    PubMed  CAS  Google Scholar 

  166. Choi C, et al. Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T. NMR Biomed. 2010;23(9):1044–52.

    PubMed  CAS  Google Scholar 

  167. Zhao Y, et al. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4:e532.

    PubMed  CAS  PubMed Central  Google Scholar 

  168. McKnight TR. Proton magnetic resonance spectroscopic evaluation of brain tumor metabolism. Semin Oncol. 2004;31(5):605–17.

    PubMed  CAS  Google Scholar 

  169. Canese R, et al. Characterisation of in vivo ovarian cancer models by quantitative 1H magnetic resonance spectroscopy and diffusion-weighted imaging. NMR Biomed. 2011;25(4):632–42.

    PubMed  Google Scholar 

  170. Xu W, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19(1):17–30.

    PubMed  CAS  PubMed Central  Google Scholar 

  171. Losman JA, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–5.

    PubMed  CAS  Google Scholar 

  172. Koivunen P, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  173. Choi C, et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med. 2012;18(4):624–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  174. Andronesi OC, et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med. 2012;4(116):116ra4.

    PubMed  PubMed Central  Google Scholar 

  175. Zhang X, et al. Tumor pH and its measurement. J Nucl Med. 2010;51(8):1167–70.

    PubMed  CAS  Google Scholar 

  176. Paradise RK, et al. Acidic extracellular pH promotes activation of integrin alpha(v)beta(3). PLoS One. 2011;6(1):e15746.

    PubMed  CAS  PubMed Central  Google Scholar 

  177. Song CW, et al. Influence of tumor pH on therapeutic response. In: Cancer drug resistance. New Jersey: Humana Press; 2006. p. 21–42.

    Google Scholar 

  178. Gerweck LE, Seetharaman K. Cellular pH gradient in tumor versus normal tissue: potential exploitation for the treatment of cancer. Cancer Res. 1996;56(6):1194–8.

    PubMed  CAS  Google Scholar 

  179. McCarty MF, Whitaker J. Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev. 2010;15(3):264–72.

    PubMed  Google Scholar 

  180. Robey IF, Martin NK. Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer. BMC Cancer. 2011;11:235.

    PubMed  CAS  PubMed Central  Google Scholar 

  181. Zetter BR. Angiogenesis and tumor metastasis. Annu Rev Med. 1998;49:407–24.

    PubMed  CAS  Google Scholar 

  182. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    PubMed  CAS  Google Scholar 

  183. Folkman J, et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med. 1971;133(2):275–88.

    PubMed  CAS  PubMed Central  Google Scholar 

  184. Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002;282(5):C947–70.

    PubMed  CAS  Google Scholar 

  185. Griffin JL, Shockcor JP. Metabolic profiles of cancer cells. Nat Rev Cancer. 2004;4(7):551–61.

    PubMed  CAS  Google Scholar 

  186. Griffiths JR. Are cancer cells acidic? Br J Cancer. 1991;64(3):425–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  187. Halestrap AP, Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 2004;447(5):619–28.

    PubMed  CAS  Google Scholar 

  188. Chiche J, et al. Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH. Cancer Res. 2009;69(1):358–68.

    PubMed  CAS  Google Scholar 

  189. Cheng X-F, Wu R-H. MR-based methods for pH measurement in brain tumors: current status and clinical potential. In: Abujamra AL, editor. Diagnostic techniques and surgical management of brain tumors. Intech; New York: 2011. p 287–302.

    Google Scholar 

  190. Raghunand N. Tissue pH measurement by magnetic resonance spectroscopy and imaging. Methods Mol Med. 2006;124:347–64.

    PubMed  Google Scholar 

  191. Garcia-Martin ML, et al. Mapping extracellular pH in rat brain gliomas in vivo by 1H magnetic resonance spectroscopic imaging: comparison with maps of metabolites. Cancer Res. 2001;61(17):6524–31.

    PubMed  CAS  Google Scholar 

  192. van Sluis R, et al. In vivo imaging of extracellular pH using 1H MRSI. Magn Reson Med. 1999;41(4):743–50.

    PubMed  Google Scholar 

  193. Gil S, et al. Imidazol-1-ylalkanoic acids as extrinsic 1H NMR probes for the determination of intracellular pH, extracellular pH and cell volume. Bioorg Med Chem. 1994;2(5):305–14.

    PubMed  CAS  Google Scholar 

  194. Vermathen P, et al. Administration and (1)H MRS detection of histidine in human brain: application to in vivo pH measurement. Magn Reson Med. 2000;43(5):665–75.

    PubMed  CAS  Google Scholar 

  195. Martinez GV, et al. Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents. NMR Biomed. 2011;24(10):1380–91.

    PubMed  CAS  PubMed Central  Google Scholar 

  196. Ward KM, Balaban RS. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med. 2000;44(5):799–802.

    PubMed  CAS  Google Scholar 

  197. Ward KM, et al. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J Magn Reson. 2000;143(1):79–87.

    PubMed  CAS  Google Scholar 

  198. van Zijl PC, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t? Magn Reson Med. 2011;65(4):927–48.

    PubMed  PubMed Central  Google Scholar 

  199. Liu G, et al. Imaging in vivo extracellular pH with a single paramagnetic chemical exchange saturation transfer magnetic resonance imaging contrast agent. Mol Imaging. 2012;11(1):47–57.

    PubMed  Google Scholar 

  200. Stubbs M, et al. An assessment of 31P MRS as a method of measuring pH in rat tumours. NMR Biomed. 1992;5(6):351–9.

    PubMed  CAS  Google Scholar 

  201. Gillies RJ, et al. 31P-MRS measurements of extracellular pH of tumors using 3-aminopropylphosphonate. Am J Physiol. 1994;267(1 Pt 1):C195–203.

    PubMed  CAS  Google Scholar 

  202. Raghunand N, et al. Plasmalemmal pH-gradients in drug-sensitive and drug-resistant MCF-7 human breast carcinoma xenografts measured by 31P magnetic resonance spectroscopy. Biochem Pharmacol. 1999;57(3):309–12.

    PubMed  CAS  Google Scholar 

  203. Ojugo AS, et al. Measurement of the extracellular pH of solid tumours in mice by magnetic resonance spectroscopy: a comparison of exogenous (19)F and (31)P probes. NMR Biomed. 1999;12(8):495–504.

    PubMed  CAS  Google Scholar 

  204. Klomp DW, et al. 31P MRSI and 1H MRS at 7 T: initial results in human breast cancer. NMR Biomed. 2011;24(10):1337–42.

    PubMed  Google Scholar 

  205. Klomp DW, et al. Efficient 1H to 31P polarization transfer on a clinical 3T MR system. Magn Reson Med. 2008;60(6):1298–305.

    PubMed  CAS  Google Scholar 

  206. Gibellini F, Smith TK. The Kennedy pathway–De novo synthesis of phosphatidylethanolamine and phosphatidylcholine. IUBMB Life. 2010;62(6):414–28.

    PubMed  CAS  Google Scholar 

  207. Kennedy EP, Weiss SB. The function of cytidine coenzymes in the biosynthesis of phospholipides. J Biol Chem. 1956;222(1):193–214.

    PubMed  CAS  Google Scholar 

  208. Henneberry AL, McMaster CR. Cloning and expression of a human choline/ethanolaminephosphotransferase: synthesis of phosphatidylcholine and phosphatidylethanolamine. Biochem J. 1999;339(Pt 2):291–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  209. Lykidis A. Comparative genomics and evolution of eukaryotic phospholipid biosynthesis. Prog Lipid Res. 2007;46(3–4):171–99.

    PubMed  CAS  Google Scholar 

  210. Gallego-Ortega D, et al. Differential role of human choline kinase alpha and beta enzymes in lipid metabolism: implications in cancer onset and treatment. PLoS One. 2009;4(11):e7819.

    PubMed  PubMed Central  Google Scholar 

  211. Kent C. Eukaryotic phospholipid biosynthesis. Annu Rev Biochem. 1995;64:315–43.

    PubMed  CAS  Google Scholar 

  212. Dixon RM, Tian M. Phospholipid synthesis in the lymphomatous mouse liver studied by 31P nuclear magnetic resonance spectroscopy in vitro and by administration of 14C-radiolabelled compounds in vivo. Biochim Biophys Acta. 1993;1181(2):111–21.

    PubMed  CAS  Google Scholar 

  213. Zhu L, Bakovic M. Breast cancer cells adapt to metabolic stress by increasing ethanolamine phospholipid synthesis and CTP:ethanolaminephosphate cytidylyltransferase-Pcyt2 activity. Biochem Cell Biol. 2012;90(2):188–99.

    PubMed  CAS  Google Scholar 

  214. Swanson MG, et al. Quantification of choline- and ethanolamine-containing metabolites in human prostate tissues using 1H HR-MAS total correlation spectroscopy. Magn Reson Med. 2008;60(1):33–40.

    PubMed  CAS  PubMed Central  Google Scholar 

  215. Albert DH, Anderson CE. Fatty acid composition at the 2-position of ether-linked and diacyl ethanolamine and choline phosphoglycerides of human brain tumors. Lipids. 1977;12(9):722–8.

    PubMed  CAS  Google Scholar 

  216. Al-Saffar NM, et al. Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models. Cancer Res. 2006;66(1):427–34.

    PubMed  CAS  Google Scholar 

  217. Krishnamachary B, et al. Noninvasive detection of lentiviral-mediated choline kinase targeting in a human breast cancer xenograft. Cancer Res. 2009;69(8):3464–71.

    PubMed  CAS  Google Scholar 

  218. Kristeleit R, et al. Histone modification enzymes: novel targets for cancer drugs. Expert Opin Emerg Drugs. 2004;9(1):135–54.

    PubMed  CAS  Google Scholar 

  219. Legube G, Trouche D. Regulating histone acetyltransferases and deacetylases. EMBO Rep. 2003;4(10):944–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  220. Chung YL, et al. Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of a novel histone deacetylase inhibitor, LAQ824, in human colon carcinoma cells and xenografts. Neoplasia. 2008;10(4):303–13.

    PubMed  CAS  PubMed Central  Google Scholar 

  221. Fang M, et al. The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell. 2010;143(5):711–24.

    PubMed  CAS  Google Scholar 

  222. Nieminen AI, et al. Myc-induced AMPK-phospho p53 pathway activates Bak to sensitize mitochondrial apoptosis. Proc Natl Acad Sci U S A. 2013;110(20):E1839–48.

    PubMed  CAS  PubMed Central  Google Scholar 

  223. Pavlov E, et al. Inorganic polyphosphate and energy metabolism in mammalian cells. J Biol Chem. 2010;285(13):9420–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  224. Okunieff PG, et al. Tumor size dependent changes in a murine fibrosarcoma: use of in vivo 31P NMR for non-invasive evaluation of tumor metabolic status. Int J Radiat Oncol Biol Phys. 1986;12(5):793–9.

    PubMed  CAS  Google Scholar 

  225. Gadian DG, Radda GK. NMR studies of tissue metabolism. Annu Rev Biochem. 1981;50:69–83.

    PubMed  CAS  Google Scholar 

  226. Deutsch CJ, Taylor JS. Intracellular pH as measured by 19F NMR. Ann N Y Acad Sci. 1987;508:33–47.

    PubMed  CAS  Google Scholar 

  227. Longley DB, et al. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.

    PubMed  CAS  Google Scholar 

  228. Wolf W, et al. 19F-MRS studies of fluorinated drugs in humans. Adv Drug Deliv Rev. 2000;41(1):55–74.

    PubMed  CAS  Google Scholar 

  229. Harada M, et al. In-vivo 19F-MRS study of 5-fluorouracil (5-FU) metabolism on tumors. Gan To Kagaku Ryoho. 1991;18(1):75–80.

    PubMed  CAS  Google Scholar 

  230. van Laarhoven HW, et al. Carbogen breathing differentially enhances blood plasma volume and 5-fluorouracil uptake in two murine colon tumor models with a distinct vascular structure. Neoplasia. 2006;8(6):477–87.

    PubMed  PubMed Central  Google Scholar 

  231. McSheehy PM, et al. Enhanced 5-fluorouracil cytotoxicity and elevated 5-fluoronucleotides in the rat Walker carcinosarcoma following methotrexate pre-treatment: a 19F-MRS study in vivo. Br J Cancer. 1992;65(3):369–75.

    PubMed  CAS  PubMed Central  Google Scholar 

  232. Mehta VD, et al. Fluorinated proteins as potential 19F magnetic resonance imaging and spectroscopy agents. Bioconjug Chem. 1994;5(3):257–61.

    PubMed  CAS  Google Scholar 

  233. Dresselaers T, et al. Non-invasive 19F MR spectroscopy of 5-fluorocytosine to 5-fluorouracil conversion by recombinant Salmonella in tumours. Br J Cancer. 2003;89(9):1796–801.

    PubMed  CAS  PubMed Central  Google Scholar 

  234. Li C, et al. Conjugation of poly-L-lysine to bacterial cytosine deaminase improves the efficacy of enzyme/prodrug cancer therapy. J Med Chem. 2008;51(12):3572–82.

    PubMed  CAS  Google Scholar 

  235. Papadopoulou MV, et al. Novel non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS). Studies in the SCCVII/C3H murine model. Anticancer Res. 2006;26(5A):3259–63.

    PubMed  CAS  Google Scholar 

  236. Papadopoulou MV, et al. Novel fluorinated hypoxia-targeted compounds as Non-invasive probes for measuring tumor-hypoxia by 19F-magnetic resonance spectroscopy (19F-MRS). Anticancer Res. 2006;26(5A):3253–8.

    PubMed  CAS  Google Scholar 

  237. Cline JM, et al. Distribution of the hypoxia marker CCI-103F in canine tumors. Int J Radiat Oncol Biol Phys. 1994;28(4):921–33.

    PubMed  CAS  Google Scholar 

  238. Ljungkvist AS, et al. Changes in tumor hypoxia measured with a double hypoxic marker technique. Int J Radiat Oncol Biol Phys. 2000;48(5):1529–38.

    PubMed  CAS  Google Scholar 

  239. Raleigh JA, et al. Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. Br J Cancer. 1987;56(4):395–400.

    PubMed  CAS  PubMed Central  Google Scholar 

  240. Aboagye EO, et al. The novel fluorinated 2-nitroimidazole hypoxia probe SR-4554: reductive metabolism and semiquantitative localisation in human ovarian cancer multicellular spheroids as measured by electron energy loss spectroscopic analysis. Br J Cancer. 1995;72(2):312–8.

    PubMed  CAS  PubMed Central  Google Scholar 

  241. Aboagye EO, et al. Bioreductive metabolism of the novel fluorinated 2-nitroimidazole hypoxia probe N-(2-hydroxy-3,3,3-trifluoropropyl)-2-(2-nitroimidazolyl) acetamide (SR-4554). Biochem Pharmacol. 1997;54(11):1217–24.

    PubMed  CAS  Google Scholar 

  242. Kwock L, et al. Evaluation of a fluorinated 2-nitroimidazole binding to hypoxic cells in tumor-bearing rats by 19F magnetic resonance spectroscopy and immunohistochemistry. Radiat Res. 1992;129(1):71–8.

    PubMed  CAS  Google Scholar 

  243. Mason RP. Transmembrane pH gradients in vivo: measurements using fluorinated vitamin B6 derivatives. Curr Med Chem. 1999;6(6):481–99.

    PubMed  CAS  Google Scholar 

  244. Maher EA, et al. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed. 2012;25(11):1234–44.

    PubMed  CAS  PubMed Central  Google Scholar 

  245. 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. 2012;25(10):1177–86.

    PubMed  CAS  PubMed Central  Google Scholar 

  246. Kurhanewicz J, et al. Current and potential applications of clinical 13C MR spectroscopy. J Nucl Med. 2008;49(3):341–4.

    PubMed  CAS  PubMed Central  Google Scholar 

  247. Gaglio D, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523.

    PubMed  PubMed Central  Google Scholar 

  248. Post JF, et al. 13C NMR studies of glucose metabolism in human leukemic CEM-C7 and CEM-C1 cells. Magn Reson Med. 1992;23(2):356–66.

    PubMed  CAS  Google Scholar 

  249. Rothman DL, et al. In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos Trans R Soc Lond B Biol Sci. 1999;354(1387):1165–77.

    PubMed  CAS  PubMed Central  Google Scholar 

  250. Rivenzon-Segal D, et al. Glycolysis as a metabolic marker in orthotopic breast cancer, monitored by in vivo (13)C MRS. Am J Physiol Endocrinol Metab. 2002;283(4):E623–30.

    PubMed  CAS  Google Scholar 

  251. Poptani H, et al. Cyclophosphamide treatment modifies tumor oxygenation and glycolytic rates of RIF-1 tumors: 13C magnetic resonance spectroscopy, Eppendorf electrode, and redox scanning. Cancer Res. 2003;63(24):8813–20.

    PubMed  CAS  Google Scholar 

  252. Constantinidis I, et al. In vivo 13CNMR spectroscopy of glucose metabolism of RIF-1 tumors. Magn Reson Med. 1991;20(1):17–26.

    PubMed  CAS  Google Scholar 

  253. Nielsen FU, et al. Effect of changing tumor oxygenation on glycolytic metabolism in a murine C3H mammary carcinoma assessed by in vivo nuclear magnetic resonance spectroscopy. Cancer Res. 2001;61(13):5318–25.

    PubMed  CAS  Google Scholar 

  254. Locasale JW, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43(9):869–74.

    PubMed  CAS  PubMed Central  Google Scholar 

  255. Gillies RJ, et al. In vitro and in vivo 13C and 31P NMR analyses of phosphocholine metabolism in rat glioma cells. Magn Reson Med. 1994;32(3):310–8.

    PubMed  CAS  Google Scholar 

  256. Ronen SM, Degani H. The application of 13C NMR to the characterization of phospholipid metabolism in cells. Magn Reson Med. 1992;25(2):384–9.

    PubMed  CAS  Google Scholar 

  257. Katz-Brull R, et al. Choline metabolism in breast cancer; 2H-, 13C- and 31P-NMR studies of cells and tumors. MAGMA. 1998;6(1):44–52.

    PubMed  CAS  Google Scholar 

  258. Katz-Brull R, et al. Metabolic markers of breast cancer: enhanced choline metabolism and reduced choline-ether-phospholipid synthesis. Cancer Res. 2002;62(7):1966–70.

    PubMed  CAS  Google Scholar 

  259. Golman K, et al. Molecular imaging using hyperpolarized 13C. Br J Radiol. 2003;76(Spec No 2):S118–27.

    PubMed  CAS  Google Scholar 

  260. Day SE, et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat Med. 2007;13(11):1382–7.

    PubMed  CAS  Google Scholar 

  261. Ross BD, et al. Hyperpolarized MR imaging: neurologic applications of hyperpolarized metabolism. AJNR Am J Neuroradiol. 2009;31(1):24–33.

    PubMed  Google Scholar 

  262. Rizi RR. A new direction for polarized carbon-13 MRI. Proc Natl Acad Sci U S A. 2009;106(14):5453–4.

    PubMed  CAS  PubMed Central  Google Scholar 

  263. Bowers CR, Weitekamp DP. Transformation of symmetrization order to nuclear-spin magnetization by chemical reaction and nuclear magnetic resonance. Phys Rev Lett. 1986;57(21):2645–8.

    PubMed  CAS  Google Scholar 

  264. Goodson BM. Nuclear magnetic resonance of laser-polarized noble gases in molecules, materials, and organisms. J Magn Reson. 2002;155(2):157–216.

    PubMed  CAS  Google Scholar 

  265. Abragam A, Goldman M. Principles of dynamic nuclear polarisation. Rep Prog Phys. 2001;41(3):395.

    Google Scholar 

  266. Frossati G. Polarization of 3He, D2 (and possibly129Xe) using cryogenic techniques. Nucl Instrum Meth A. 1998;402(2):479–83.

    Google Scholar 

  267. Schroeder MA, et al. Hyperpolarized magnetic resonance: a novel technique for the in vivo assessment of cardiovascular disease. Circulation. 2011;124(14):1580–94.

    PubMed  PubMed Central  Google Scholar 

  268. Kurhanewicz J, et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia. 2011;13(2):81–97.

    PubMed  PubMed Central  Google Scholar 

  269. Bunney TD, Katan M. Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nat Rev Cancer. 2010;10(5):342–52.

    PubMed  CAS  Google Scholar 

  270. Morgensztern D, McLeod HL. PI3K/Akt/mTOR pathway as a target for cancer therapy. Anticancer Drugs. 2005;16(8):797–803.

    PubMed  CAS  Google Scholar 

  271. Day SE, et al. Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1–13C]pyruvate and 13C magnetic resonance spectroscopic imaging. Magn Reson Med. 2011;65(2):557–63.

    PubMed  CAS  PubMed Central  Google Scholar 

  272. Gallagher FA, et al. Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors. Proc Natl Acad Sci U S A. 2009;106(47):19801–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  273. Keshari KR, et al. Hyperpolarized [2-13C]-fructose: a hemiketal DNP substrate for in vivo metabolic imaging. J Am Chem Soc. 2009;131(48):17591–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  274. Allouche-Arnon H, et al. A hyperpolarized choline molecular probe for monitoring acetylcholine synthesis. Contrast Media Mol Imaging. 2011;6(3):139–47.

    PubMed  CAS  Google Scholar 

  275. Chen AP, et al. Feasibility of using hyperpolarized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies. Magn Reson Imaging. 2008;26(6):721–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  276. Wang JB, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18(3):207–19.

    PubMed  CAS  PubMed Central  Google Scholar 

  277. Gallagher FA, et al. 13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C-labeled glutamine. Magn Reson Med. 2008;60(2):253–7.

    PubMed  CAS  Google Scholar 

  278. Qu W, et al. Facile synthesis [5-(13)C-4-(2)H(2)]-L-glutamine for hyperpolarized MRS imaging of cancer cell metabolism. Acad Radiol. 2011;18(8):932–9.

    PubMed  Google Scholar 

  279. Gallagher FA, et al. Magnetic resonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonate. Nature. 2008;453(7197):940–3.

    PubMed  CAS  Google Scholar 

  280. Meldrum NU, Roughton FJ. Carbonic anhydrase. Its preparation and properties. J Physiol. 1933;80(2):113–42.

    PubMed  CAS  PubMed Central  Google Scholar 

  281. Rutledge AC, Adeli K. Fructose and the metabolic syndrome: pathophysiology and molecular mechanisms. Nutr Rev. 2007;65(6 Pt 2):S13–23.

    PubMed  Google Scholar 

  282. Engel FL. The influence of the endocrine glands on fatty acid and ketone body metabolism. AMA Arch Intern Med. 1957;100(1):18–33.

    PubMed  CAS  Google Scholar 

  283. Modica-Napolitano JS, et al. Mitochondria and human cancer. Curr Mol Med. 2007;7(1):121–31.

    PubMed  CAS  Google Scholar 

  284. Modica-Napolitano JS, Singh KK. Mitochondria as targets for detection and treatment of cancer. Expert Rev Mol Med. 2002;4(9):1–19.

    PubMed  Google Scholar 

  285. Lodi A, Ronen SM. Magnetic resonance spectroscopy detectable metabolomic fingerprint of response to antineoplastic treatment. PLoS One. 2011;6(10):e26155.

    PubMed  CAS  PubMed Central  Google Scholar 

  286. Bottomley PA, et al. Human in vivo phosphate metabolite imaging with 31P NMR. Magn Reson Med. 1988;7(3):319–36.

    PubMed  CAS  Google Scholar 

  287. Griffiths JR, et al. 31P-NMR studies of a human tumour in situ. Lancet. 1983;1(8339):1435–6.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Traylor Building, Room 310A, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Asif Rizwan

  2. Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Traylor Building, Room 212, 720 Rutland Avenue, Baltimore, MD, 21205, USA

    Kristine Glunde

  3. Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, 21231, USA

    Kristine Glunde

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  1. Asif Rizwan
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  2. Kristine Glunde
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Correspondence to Asif Rizwan .

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Editors and Affiliations

  1. Health Time Group, Jaén, Spain

    Antonio Luna

  2. Dept. of MRI, Clínica Girona, Girona, Spain

    Joan C. Vilanova

  3. Botafogo - Rio de Janeiro/RJ, Brazil

    L. Celso Hygino da Cruz Jr.

  4. Centro de Diagnóstico Dr. Enrique Rossi, Buenos Aires, Argentina

    Santiago E. Rossi

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Rizwan, A., Glunde, K. (2014). Imaging of Tumor Metabolism: MR Spectroscopy. In: Luna, A., Vilanova, J., Hygino da Cruz Jr., L., Rossi, S. (eds) Functional Imaging in Oncology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40412-2_8

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