Review Article Current Opportunities and Challenges of ...downloads.hindawi.com/journals/bmri/2014/625095.pdf · instrumentation to provide signal enhancements of over, -folds of

Review ArticleCurrent Opportunities and Challenges of Magnetic ResonanceSpectroscopy Positron Emission Tomography and MassSpectrometry Imaging for Mapping Cancer Metabolism In Vivo

Gigin Lin123 and Yuen-Li Chung4

1 Department of Radiology Chang Gung Memorial Hospital at Linkou Chang Gung University 5 Fuhsing Street GuishanTaoyuan 333 Taiwan

2Molecular Imaging Center Chang Gung Memorial Hospital at Linkou Chang Gung University 5 Fuhsing Street GuishanTaoyuan 333 Taiwan

3Metabolomics Core Laboratory Chang Gung Memorial Hospital at Linkou Chang Gung University 5 Fuhsing Street GuishanTaoyuan 333 Taiwan

4The Institute of Cancer Research and Royal Marsden Hospital CRUK Cancer Imaging Centre Downs Road SuttonSurrey SM2 5PT UK

Correspondence should be addressed to Yuen-Li Chung yuen-lichungicracuk

Received 19 October 2013 Revised 6 January 2014 Accepted 19 January 2014 Published 3 March 2014

Academic Editor Tzu-Chen Yen

Copyright copy 2014 G Lin and Y-L Chung This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cancer is known to have unique metabolic features such as Warburg effect Current cancer therapy has moved forward fromcytotoxic treatment to personalized targeted therapies with some that could lead to specific metabolic changes potentiallymonitored by imaging methods In this paper we addressed the important aspects to study cancer metabolism by using imagetechniques focusing on opportunities and challenges of magnetic resonance spectroscopy (MRS) dynamic nuclear polarization(DNP)-MRS positron emission tomography (PET) andmass spectrometry imaging (MSI) formapping cancermetabolism Finallywe highlighted the future possibilities of an integrated in vivo PETMR imaging systems together with an in situ MSI tissueanalytical platform may become the ultimate technologies for unraveling and understanding the molecular complexities in someaspects of cancer metabolism Such comprehensive imaging investigations might provide information on pharmacometabolomicsbiomarker discovery and disease diagnosis prognosis and treatment response monitoring for clinical medicine

1 Introduction

Cancer is known to have unique metabolic features [1]Knowledge of cancer metabolism can be applied not only forearly detection and diagnosis of cancer but also in the evalua-tion of tumor response tomedical interventions and therapies[2]Thefirst characterized phenotype observed in cancer cellsis the Warburg effect [3] which describes a shift from energygeneration through oxidative phosphorylation to energygeneration through anaerobic glycolysis even under normaloxygen concentrations Anaerobic glycolysis produces onlytwo ATPs per glucose and is less efficient than oxidativephosphorylation [4 5] Cancer cells require high-energy

demand to support cell growth and proliferation there-fore cancer cells have increased glucose uptake glycolyticactivity and lactate production and decreased mitochondrialactivity low bioenergetic status and aberrant phospholipidmetabolism [6 7] Several important oncogenes involved inthe development and progression of common human cancershave also been found to regulate glycolysis For exampleunregulated activity of the serinethreonine kinase Akt hasbeen shown to increase glucose uptake of tumor cells as wellas increase resistance to apoptosis [8ndash10] The oncogene c-myc a transcription factor controls and activates numerousglycolytic genes (eg hexokinase 2 enolase and lactate dehy-drogenase A) [11 12] Oncogenic ras is an important protein

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 625095 13 pageshttpdxdoiorg1011552014625095

2 BioMed Research International

that controls signaling pathways for cell growth regulationand malignancy transformation [13] and it has been seento increase the concentration of fructose-26-bisphosphate(F2 6BP) which is an allosteric activator of phosphofructo1-kinase and it catalyzes the phosphorylation of fructose-6-phosphate to fructose-16-bisphosphate [14] Recent advanceshave established further links between cancer metabolismand genetic alterations in p53 [15] AMPK [16] PI3K [17 18]and HIF [19]

There are growing interests in developing therapies thattarget important signaling pathways (eg PI3K [18] andMAPK [20]) and transcription factors (eg HIF-1 [21])and inhibit upregulated enzymes (eg pyruvate dehydro-genase kinase (PDK) [22] and choline kinase [23]) andmetabolite transporters (eg glucose transporter (Glut1) [24]and monocarboxylate transporter-1 (MCT-1) [25]) Thosetargeted therapies might alter cancer metabolism and thechanges in endogenous metabolites in cancer cells might bedetected even before changes in tumor sizes [26ndash28] Imagingmethods are needed to detect early metabolic changes incancer following treatment and these imaging readouts couldbe useful for monitoring the response to therapies [29 30]

Tumor heterogeneity and its adaptations to microenvi-ronment are important factors that could affect the effec-tiveness of cancer treatment hence the ability to imageand spatially map the heterogeneity of metabolism withina tumor will be very useful for planning the treatmentregime Intratumoral heterogeneity and branched evolutionare recently revealed in multiple spatially separated samplesobtained from primary renal carcinomas and associatedmetastatic sites by using genome sequencing [31] In addi-tion the metabolic heterogeneity is not only attributed togenetic alteration but is also an adaptation to hypoxic tumormicroenvironment Glycolysis confers a significant growthadvantage by producing the required metabolites for cancergrowth [27 32ndash34] as lactate can be used by oxygenatedcancer cells as oxidative fuel [35] in order to spare theglucose for the more anoxic cells in the center of the tumor[36]This cooperation between hypoxic and normoxic tumorcells optimizes energy production and allows cells to adaptefficiently to their environmental oxygen conditions [37 38]

Conventionally nuclear magnetic resonance (NMR)spectroscopy [67] and mass spectrometry (MS) [68] can beused separately or in combination to provide overlapping yetcomplementary data to evaluate cancer [69ndash72] MS havehigh sensitivity but the samples required prior separationsusing gas- or lipid-chromatography NMR has a lower sensi-tivity thanMS but it can measure all the detectable moleculesin the sample simultaneously without the need to priorseparation cancelling out the quantification errors withinthe method [69] Although analyses of biopsies with manymetabolites correlated with disease aggressiveness [73] theconventional metabolomic experiments using a single biopsyof small tumor or extracting metabolites from relativelylarge tissue areas do not provide the spatial information ofthe metabolites and multiple biopsies or biopsy of normaltissue counterpart for comparison is not feasible in routineclinical practice Hence noninvasive imaging would be auseful solution for spatial mapping of metabolites The

potential imaging techniques reviewed in this paper includebut are not limited to magnetic resonance spectroscopy(MRS) dynamic nuclear polarization (DNP) MRS positronemission tomography (PET) andmass spectrometry imaging(MSI) for tissue characterization Table 1 summarizes theadvantages disadvantages and clinical applications of eachimaging technique

2 Magnetic Resonance Spectroscopy (MRS)

Magnetic resonance spectroscopy (MRS) is a technique thatcan be used in preclinical and clinical settings to studycancer metabolism [74] It is based on nuclei such as 1H 31Pand 13C that possess the property of magnetic spin Whenthey are placed in a magnetic field these nuclei becomealigned or opposed to the external magnetic field Many ofthe nuclei are flipped into the other magnetic state whena radiofrequency pulse is applied and the differences inthe populations between these two magnetic energy statesare detected as a radio wave as the system returns toequilibrium The strength of this local field depends on theelectronic environment around the nucleus Different chem-ical structures possess different electronic environments andlead to nuclei resonating at slightly different frequenciesThese frequencies are termed as chemical shifts whichare expressed as the dimensionless units parts per million(ppm) in the spectrum and represent the metabolites of themeasured sample [75] Additional magnetic field gradientscause nuclei at different locations to precess at differentspeeds which allows spatial information to be recoveredusing Fourier analysis of themeasured signal [75] By spatiallyencoding chemical shift information one can generate MRSimaging by obtaining signals at different chemical shiftsThis can be achieved by frequency selective radiofrequencypulses as in stimulated echo acquisition mode (STEAM)[76] and point-resolved spectroscopy (PRESS) [77] in proton(1H)-MRS or by excitation and subsequent subtraction ofunwanted signals as in image selective in vivo spectroscopy(ISIS) technique [78] in phosphorus (31P)-MRS In additionmultivoxel spectroscopy such as chemical shift imaging (CSI)[79] can collect spectroscopic data from multiple adjacentvoxels in a single measurement

The clinical use of spectroscopy as an adjunct to MRIhas expanded dramatically over the past decades because oftechnical advances in hardware and pulse sequence designthat have improved the spatial and temporal resolution ofspectral data Nowadays most clinical MR scanners haveroutine sequences for 1H-MRS measurements providing awide range of metabolic and functional information inte-grated with complementary MRI localization Metabolitescommonly detected in clinical 1H-MRS include N-acetyl-aspartate (NAA) in the normal brain tissue [39] and citratein the normal prostate [40] and their levels decrease oncebeing replaced by tumor MRS detection of total cholinesignal has been used to diagnose and monitor breast [41]brain [42] and prostate cancers [44] and for monitoringthe response to anticancer therapy [23 72 80] In addition

BioMed Research International 3

Table 1 Comparison of major imaging techniques for studying cancer metabolism

Imaging techniques Advantages Disadvantages Clinicalapplications References

Magnetic resonancespectroscopy (MRS)

(i) Widely used medical imagingtechnique(ii) Ability to assess multiplemetabolites in one measurement(iii) No radiation concern

(i) It has relatively long acquisitiontime(ii) Data processing is not routine inthe clinic(iii) Lack of familiarity with clinicians

Brain head andneck prostate

breast and cervix[39ndash46]

Dynamic nuclearpolarization- (DNP-)MRS

(i) Signal enhancements of over10000-fold of magnitude for stableisotope carbon-13 (13C) enrichedcompounds(ii) Simultaneous detection of multiplehyperpolarized molecules allowedseveral metabolic pathways to beprobed at the same time(iii) No radiation concern(iv) Short acquisition time(v) Real-time observation of not onlythe uptake of the targeted molecule butalso its flux to produce downstreammetabolic products

Hyperpolarized 13C-labelledsubstrates have very short half-life (intens of seconds)

Prostate [47]

Positron emissiontomography (PET)

(i) Widely used in clinical applications(ii) High sensitivity

(i) Not all tumors show a significantincrease in metabolic activity onFDG-PET imaging(ii) Difficult to evaluate malignantlesions in tissues that physiologicallytake up FDG (such as the centralnervous system) or excrete FDG (suchas the kidneys and bladder) ordifferentiate between inflammationand cancer(iii) Radiation concern(iv) It measures perfusion andaccumulation of a tracer and does notdifferentiate between metabolitescontaining the radionuclide or tracerper se

Oral cancerlymphoma

melanoma lungcancer esophageal

cancer andcolorectal cancer

CervicalOvarianPancreasProstate

[48ndash57]

Mass spectrometryimaging (MSI)

(i) Highly sensitive(ii) It can be used to investigate bothidentified and unidentified moleculesin spatial localized areas without anyneed for labeling or contrasting agents

Analytical technique of tissue sectionnot noninvasive imaging

Brain oral lungbreast gastric

pancreatic renalovarian and

prostate cancer

[58ndash66]

in vivo 1H-MRS also detects signals from lipid metabolism-related compounds such as the methylene (ndashCH

2) signal at

13 ppm and the methyl (CH3) signal at 09 ppm [81] which

originate from the fatty acyl chains of the cytoplasmic mobilelipids and not from the membrane lipids [82] Significantlyhigher levels of lipid have been detected in high-grade humangliomas when compared to low-grade gliomas [81] andthese changes are associated with apoptosis necrosis or lipiddroplet formation [83ndash85]31P-MRS could provide information on tumor bioen-

ergetics and metabolites such as nucleoside triphosphates(NTPs) phosphocreatine (PCr) and inorganic phosphate(Pi) The production of high-energy phosphates such as NTPand PCr depends on the availability of glucose and oxygen(which are delivered to the tumors through blood vessels)

and is determined by diffusion distances and local oxygenconsumption rates Therefore in addition to blood flowparameters measured by DCE-MRI or perfusion CT 31P-MRS provides an opportunity to monitor downstream bio-chemical reactions following reduced blood flow in hypoxicregions [85] and is useful in detecting changes in tumorreoxygenation during radiation therapy [86] as well as alteredtissue pH level (measured by the Pi chemical shift changes)[87] 31P-MRS also measures phospholipid metabolites suchas phosphomonoester and phosphodiester in tumor whichin turn could inform on membrane turnover and tumorresponse following therapies [23 72 81]

MRS can also directly measure the pharmacokineticsof drugs that present at relatively high concentrations inthe tumor Most in vivo studies on MR pharmacokinetic


measurements of tumors employ fluorinated drugs such as[5-19F]-fluorouracil (5-FU) and its prodrug as detected by19F MRS [88 89] because 19F MRS provides relatively highsensitivity combined with low background signal Success-ful image-guided delivery of a prodrug enzyme bacterialcytosine deaminase (bCD) which converts nontoxic [5-19F]-fluorocytosine (5-FC) to 5-FU was recently reported inpreclinical studies [90]

Relative to conventional MRI MRS has lower sensitiv-ities and requires much longer acquisition times and morecomplex data processing and with clinicians unfamiliar withthe technique these factors continue to limit the applicationof MRS in the clinical setting Currently there are method-ologies that optimize the combined signals from multiele-ment coil arrays to improve detection of low concentrationmetabolites in MRS [91] in order to improve its sensitivityand spectral resolution In addition the availability of higherfield strength MR systems and novel techniques such asdynamic nuclear polarization hyperpolarization (DNP) canreduce some of these limitations

3 DNP-MRS

DNP is a novel imaging technique which uses specializedinstrumentation to provide signal enhancements of over10000-folds of magnitude for stable isotope carbon-13 (13C)enriched compounds [92] Simultaneous detection of multi-ple hyperpolarized molecules allow several metabolic path-ways to be probed at the same time [93 94] and this enhanced13C signal allows the distribution of hyperpolarized 13C-labeled molecules within the tumor tissue to be visualized[95] [1-13C]Pyruvate has been the most widely studied sub-strate to date because of its central role in cellularmetabolism[1-13C]Pyruvate also has relatively longer 1198791 relaxation timeand rapid transport into the cells for subsequent metabolism[96] Hyperpolarized [1-13C]pyruvate has been used to studythe real-time flux of pyruvate to lactate noninvasively follow-ing anticancer therapies in xenograft models [97ndash101] Thefirst clinical trial of DNP-MRS has recently demonstrated theuse of hyperpolarized [1-13C]pyruvate to examine prostatecancer metabolism in human [47] (Figure 1) and it paves theway to rapid translation of this exciting technology to clinicalresearch and perhaps clinical practice [96] Previously thedata analysis to obtain the apparent rate of pyruvate tolactate exchanges following the [1-13C]pyruvate DNP-MRSexperiment is quite complex as it requires the fitting ofthe data to a mathematical model [102] A much simplermethod to analyze this type of data has been developedrecently [103] which will improve the ease of use of thismethodology in studying cancer metabolism In addition topyruvate extracellular pH has been measured in lymphomaxenografts by using hyperpolarizedH13CO

3

minus and pH imageswere obtained by measuring the H13CO

3

minus13CO2ratio in

each imaging voxel [104] [1 4-13C2]Fumarate is potentially

a useful agent for detecting treatment response in tumorsbecause the production of labeled malate was shown to be anindicator of necrotic cell death [105]

4 Positron Emission Tomography (PET)

Positron emission tomography (PET) is a nuclear medicalimaging technique that produces three-dimensional imagingdata of functional processes in the body The system detectspairs of gamma rays emitted indirectly by positron-emittingradionuclide tracers to provide functional or metabolicinformation in PET imaging [107] When combined withX-ray computed tomography (CT) PETCT imaging canprovide both molecular information and anatomic local-ization 18F-fluorodeoxyglucose (FDG) PET is by far themost successfully used imaging technique to study glucoseuptake in tumors in vivo After intravenous injection 18F-FDG is transported across the cell membrane by glucosetransporters and metabolized to 18F-FDG-6-phosphate byhexokinase [108] In contrast to the complex metabolic fateof glucose-6-phosphate from glucose 18F-FDG-6-phosphatecannot be further metabolized in the glycolytic pathwaybecause the fluorine atom at the C

2position prevents 18F-

FDG-6-phosphate from downstream catabolism This leadsto steady accumulation of 18F-FDG-6-phosphate in metabol-ically active cells such as cancer [109]

Over the past decade 18F-FDG PETCT has becomea routine clinical test for staging and restaging of a vari-ety of malignant tumors including head and neck cancerlymphoma colorectal cervical cancer (Figure 2 [56]) andmany other solid organ cancers [48] with a sensitivity ofabout or above 90 [110] There is considerable evidencethat the reduction of 18F-FDG uptake is caused by a loss ofviable tumor cells following chemo- and radiotherapy [111]However the close relationship between various oncogenicsignaling pathways and tumor glucose metabolisms suggeststhat the drugs targeting these signal transduction pathwaysmay have amore direct effect on cellular glucosemetabolismFor example decreased 18F-FDG uptakes were found inpatients with gastrointestinal stromal tumors (GIST) withinhours following treatment with the c-Kit inhibitor imatinib[50 51] Rapid reduction in 18F-FDG uptakes was alsoobserved in patients with non-small cell lung cancer treatedwith EGFR kinase inhibitor gefitinib [52]

Although 18F-FDG is widely used in clinical applicationsnot all tumor types show a significant increase in metabolicactivity on 18F-FDG PET imaging for example in prostateneuroendocrine and hepatic tumors [48] Furthermore it isdifficult to evaluatemalignant lesions in organs that normallytake up (such as the central nervous system) or excrete FDG(such as the kidneys urinary bladder and prostate) or todifferentiate between inflammation and cancer Thereforeother PET tracers in addition to FDG have been developedfor oncological studies [30] either for clinical use or atdifferent stages of clinical evaluation These compoundsinclude 11C-acetate (a precursor of membrane fatty acids)in prostate cancer [112] 11C-methionine (a precursor of S-adenosylmethionine which is required for polyamine syn-thesis) in brain tumor [113] 18F-choline (a substrate ofcholine kinase in choline metabolism) in prostate cancer[114] and 18F-31015840-fluoro-31015840-deoxy-L-thymidine (18F-FLT) (asubstrate of thymidine kinase [TK-2] in DNA synthesis


LacPyr

LacPyr

13CAxial T2 image

Axial T2 image

T2 image + LacPyr

Figure 1 3D [1-13C]Pyruvate dynamic nuclear hyperpolarization magnetic resonance spectroscopy (DNP-MRS) imaging in a patientwith prostate cancer The upper panel shows an axial T2-weighted images and corresponding spectral array with the area of putativetumor highlighted by pink shading A region of tumor was observed on the T2-weighted images (red arrows) A region of relatively highhyperpolarized [1-13C]lactate was observed in the same location as the abnormalities that had been observed on the multiparametric 1Hstaging exam The lower panels show axial T2 images with and without metabolite overlays for different axial slices from the same patientThe colored regions in these overlays have a ratio of [1-13C]lactate[1-13C]pyruvatege02These demonstrated a large volume of bilateral cancerReprinted with permission from [106] Copyright 2013 American Association for the Advancement of Science

and a specific marker of cell proliferation) [115] Efforts arealso made to improve detection and measurement of lowlevel metabolized 18F tracer from the 18F-labeled pyrimidinenucleoside analogues [116]

41 Comparison of PET and DNP-MRS An advantage ofDNP-MRS is that it does not have radiation concern thatis commonly associated with PET Although both PET andDNP-MRS can measure the uptake of labeled substrates inreal-time another key advantage of DNP-MRS is that boththe injected substrate and its metabolic products can bedetected and followed in real-time allowing the observationof not only the uptake of the targeted molecule but also itsdownstream metabolic products [96] In contrast PET mea-sures perfusion and accumulation of a tracer but does not

differentiate betweenmetabolites containing the radionuclideor tracer per se

The most notable limitation of DNP-MRS imaging is thevery short half-life (in tens of seconds) of the hyperpolarized13C-substrates which is affected by the substratesrsquo 1198791 valueand the field strength of theMR scanner (lower field strengthMR scanner improves the half-life of the hyperpolarizedsubstrates) [96] The hyperpolarized state decreases to itsequilibrium value with a time constant according to thespin lattice relaxation time 1198791 1198791 relaxation times aredependent on the nucleus but are also sensitive to a host ofother factors including the applied field the location in amolecule molecular structure and motion and the chemicalenvironment

In general PET is much more sensitive than DNP-MRS[117] PET tracers can be detected in the nano- to picomolar


(a) (b)

Figure 2 An example of PETCT and MRI in the female pelvis A 43-year-old female patient with a primary well-differentiatedadenocarcinoma of the uterine cervix Primary cervical tumor is highlighted (arrow) and well correlated in (a) diffusion-weighted MRIand (b) 18F-FDG PETCT Reprinted with permission from [56] Copyright 2008 Springer-Verlag

range [118] whereas DNP-MRS sensitivity is still in themillimolar range Therefore DNP molecules are injected atconcentrations that greatly exceed physiologic levels (eg 15ndash28 mmoles of pyruvate in mouse models [97 119]) whereasPET-labeledmolecules can be administered at concentrationsthat are unlikely to perturb normal metabolism Althoughhyperpolarized [1-13C]pyruvate increases the sensitivity ofMR imaging signal-to-noise ratio constraints still exist forspatial and temporal resolution of 13C DNP-MRS especiallyrelative to PET emphasizing the need for further develop-ment of MR methodology [96]

42 Potential of Simultaneous PETMRS The integratedPETMRI system could offer potential in the managementof cancer with prostate headneck and breast cancersamong the primary indications for PETMRI [120] Thebenefit of integrating PET and MRI might not only resultin improved sensitivity and spatial resolution but alsoallow the specific sets of metabolic events to be examinedat the same time [121] In a preclinical murine gliomamodel advancing tumor proliferation caused an increasein 11C-choline uptake as measured by PET while gliosisand inflammation accounted for a high peritumoral totalcholine signal in MRS [122] A decrease in 18F-FDG PET andchanges in phosphomonoesters by 31P-MRS were associatedwith decreases in hexokinase II and Glut1 expression inHER2 expressing breast tumor xenografts and responding totrastuzumab treatment [123] These studies exemplified thatPETMRS could be used to monitor treatment response andcould provide unique information on drug biodistributiontargeting and metabolism and serve as surrogate pharma-cokineticspharmacodynamics (PKPD) markers [124]

Although clinical evidence of simultaneous PET andMRS measurement is not available at present previ-ous reports based on the correlation of PET and MRShave demonstrated the potential usefulness of integratedPETMRS A significant positive correlation was found

between tumor total choline concentration by 1H-MRS andtotal lesion glycolysis measured by 18F-FDG PET beforetreatment in head and neck cancer patients [125] For primarystaging in prostate cancer patients 1H-MRS was reported toimprove the sensitivity of 11C-choline PETCT in localizingtumor in the prostate gland and achieved up to 97 ofoverall accuracy [126] Combined 1H-MRS and DCE-MRIhave improved the sensitivity of 18F-choline PETCT from62 to 92 in identifying local prostate cancer recurrenceparticularly in patients with low biochemical progressionafter surgical treatment [127] For breast cancer patients withan invasive ductal carcinoma of 15ndash3 cm in size the totalcholine level in tumors measured by 1H-MRSwas highly cor-related with the standardized 18F-FDG uptake value obtainedby PETCT and these measurements were also supported bythe histologic prognostic parameters (nuclear grade estrogenreceptor status and triple-negative lesion status) [128] Thesensitivity and specificity of total choline level by 1H-MRS fordetecting breast cancer were 83 and 85 respectively andboth values could be as high as 92 after technical exclusions[129]

Whether the simultaneous collection of MRS datatogether with PETMRI will improve diagnosis of braintumor remained unclear However evidence shows thatby using cholinecreatine ratio gt 15 as a threshold theaddition of 1H-MRS could marginally increase the sensi-tivity of contrast-enhanced MRI from 86 to 100 (119875 =79) without altering the specificity (67) [130] In addi-tion by using cutoff points of NAACho le 061 on 1H-MRS and relative cerebral blood volume (rCBV) ge 150(corresponding to diagnosis of the tumors) a sensitivityof 72 and specificity of 91 in differentiating tumorsfrom nonneoplastic lesions have been achieved [131] Thedistinction of MRS between recurrent tumor and radia-tion necrosis in brain tumor using the ChoNAA ratiocould be made with 85 sensitivity and 69 specificity[132]


Hepatocyte-specific (gadoxetic acid) enhanced MRI is apowerful diagnostic tool for hepatocellular carcinoma (HCC)[133] with sensitivity of about 81ndash90 for lesion size lt 2 cm[134 135] For the detection of HCC 18F-FDG PETCT has asensitivity of only around 64ndash68 which can be improvedby using 11C-acetate [136] and 18F-fluorocholine [137] tracerswith reported sensitivity rising to 84 and 88 respectivelyDirect comparison of diagnostic accuracy of 11C-acetate or18F-fluorocholine PETCT versus hepatocyte-specific MRIon liver tumorswould be of great interest this area of researchis still under investigation Menzel et al recently reporteda multimodal in vivo assessment of glucose metabolism inHCC tumors using hyperpolarized [1-13C]pyruvate DNP-MRS and 18F-FDG PET [138] The increased [1-13C]lactatesignals in the tumor is correlated with correspondingenhanced 18F-FDG uptakeThis study revealed that PET and13C DNP-MRS can be used to visualize increased glycolyticflux in malignant tissue The combined 13C DNP-MRS andPET readouts will allow the quantitative dissection of sub-strate metabolism with respect to uptake and downstreammetabolic pathways Nonetheless these first imaging datasuggest the feasibility of 13C MRSI for future clinical use[138]

Integrated PETMRI measurements for neuroendocrinetumors are not yet available but efforts have been madeby using somatostatin receptor-specific tracer (68Ga-DOTATATE) to improve lesion detection by PET [139] 31P-MRShas been used to differentiate between responders andnonresponders to arterial embolization in neuroendocrinetumors with responders that exhibit increased cellmembrane renewal (higher phosphomonoester level)and energy consumption (lower NTP and higher Pi levels)[140] For renal cell carcinoma 1H-MRS can significantlydifferentiate tumor from healthy renal parenchyma bycomparing their lipid composition [141] An in vitro [1-13C]pyruvate DNP-MRS study of RCC cells showed asignificantly higher pyruvate-to-lactate flux than the normalrenal tubule cellsThesemetastatic RCC cells were also foundto have significantly higher monocarboxylate transporter4 (MCT4) expression and corresponding higher lactateefflux than the nonmetastatic cells which is essential formaintaining a high rate of glycolysis [142]

5 Mass Spectrometry Imaging (MSI)

Mass spectrometry imaging (MSI) is an analytical imagingtechnique for tissue section It can provide a very highspatial resolution (typically 10m) [143] but cannot providethe temporal information as the other noninvasive imagingtechniques such as MRS (seconds) and PET (10 secondsto minutes) For spatial mapping matrix-assisted laser des-orption ionization-time of flight (MALDI-TOF) is the mostwidely used technique to analyze intact biological tissuesections in a two-dimensional fashion [143] The matrixused in these studies is a small organic molecule withstrong absorbance at the laser wavelength They are applied

on the surface of the histological section and cocrystal-lized with the sample A laser pulse is used to ionize thechemical compounds on the sample and charged moleculesor molecule fragments are then generated MSI is basedon the measurements of the mass-to-charge ratios whichproduces spectra to determine the metabolome of the sam-ple This technique enables the investigation and spatiallocalization of both identified and unidentified moleculeswithout any need for labeling or contrasting agents whichfurther facilitates the discovery of new biomarkers andtheir validation [144] The damage on the biomedical tissuesections induced by laser irradiation during MALDI-MSIis relatively modest and the histological and biochemicalevaluations can be performed on the same tissue slice aftertheMSI measurements [145] (Figure 3)The combined use ofimaging modalities such as MSI and fluorescent microscopyand histologyimmunohistochemistry (IHC) [146] allowsmetabolic and pathological evaluations of the tissue sectionsin a highly precise and reliable way MALDI MSI-basedstudies have been used to elucidatemolecular signatures fromsamples with different tumor types and grades includingbrain [58] oral [59] lung [60] breast [61] gastric [62]pancreatic [63] renal [64] ovarian [65] and prostate cancers[66]

MALDI-MSI is useful for metabolic imaging albeit theaverage scanning time might take hours for a single massimage depending on sample size and resolution The targetfor MSI studies limits to lipid molecules of endogenousmetabolites because many kinds of matrix ion peaks areobserved in the low-mass range (119898119911 lt 700) and the strongpeaks that they generate interfere with the detection of thetarget low-molecular-weight compounds This is because the119898119911 range of most lipid molecules was more than 700 andalso lipids are abundant in tissues (eg more than 60 ofthe dry weight of brain tissue) and are easily ionized becauseof the presence of a polar head [147 148] MALDI-MSI wasemployed for imaging acylcarnitines PC lysophosphatidyl-choline (LPC) and sphingomyelin to differentiate viableand necrotic microenvironments of breast tumor xenografts[149] Recent breakthrough on the use of 9-aminoacridine (9-AA) as amatrix for low-molecular-weightmetabolite analysisand negativemodeMALDI-MS has been used to detect morethan 30 metabolites (which included nucleotides cofactorsphosphorylated sugars amino acids lipids and carboxylicacids) in ischemia-reperfused rat brain tissue [150] Hattoriet al have also reported spatiotemporal changes in energycharge adenylates and NADH during focal ischemia in amouse MCAO model [151] These findings highlight thepotential applications of MSI metabolomic imaging tech-nique to visualize spatiodynamics of some aspects of thetissue metabolome

Although the present MALDI method is highly sensitiveand well established on the MSI platform some limitationsneed to be overcome before the broad range of endogenousmetabolite imaging can be achieved To date thismethod canonly apply to ex vivo tissue sections It is generally knownthat in MALDI the detection of molecules is completelydependent on the matrix In addition the crystal size ofthe deposited matrix strongly affects both experimental


(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led

Figure 3 Correlation of histopathology and mass spectrometry imaging Serial sections of the tumor are used for histopathology (left)correlation with MSI results (right) Deconvolution of spectra is performed to separate 2H-labeled and unlabeled lipids Intensity images aregenerated to show the spatial distribution for both newly synthesized and preexisting lipids Reprinted with permission from [106] Copyright2013 Nature Publishing Group a division of Macmillan Publishers Limited

reproducibility and spatial resolution in MALDI-MSI Toaccelerate the use of MALDI-based metabolic imaging plat-form substantial progress in matrix development and itsapplication is required For tissue imaging in metabolomicsnanostructure-initiator mass spectrometry (NIMS) has beeninvestigated for spatial profiling of metabolites without theneed for matrix and with reduced fragmentation [152 153]

6 Concluding Remarks

The cancer metabolomics information provided by multi-modality imaging techniques has revolutionized our waysof cancer treatment Current oncologic therapy has movedforward from cytotoxic treatment to personalized therapysuch as targeting specific signal pathways or oncogene ormetabolic enzymes This would lead to altering metabolicsignatures in tumor tissue which could be monitored byusing MRS or PET imaging The nonradiation nature ofMRS renders its ease of transitioning from bench to bed-side Metabolic information provided by multivoxel MRSmeasurements combined with the anatomical informationprovided by MRI can significantly improve the assessmentof cancer location and extent and cancer aggressivenessBiomarkers discovered by MRS can lead to development ofnew PET tracers With the development of highly specificmolecular probes DNP-MRS andor PET will play a majorand integral role in the diagnosis prognosis and monitoringof treatment response in cancer and other diseases In com-bination with classical histologicalimmunohistochemicalmethods MSI analysis can provide new insights into thesimultaneously occurring metabolic processes in tissue sec-tion that could not be obtained otherwise

In the future a combination of in vivo noninvasiveimaging techniques (MRI anatomic imaging and functionalimaging including MRS and PET) in integrated MRPETscanners and ex vivoMSI validation with other tissue analyti-cal platformsmay become the ultimate technology for unrav-eling and understanding some of the molecular complexities

of cancermetabolismThepotential of a comprehensive studyon tumor metabolism has recently been demonstrated in aglioma model by using 11C-choline PET and choline on 1H-MRS for in vivo imaging tumors and tissue MSI for ex vivovalidation [122] Such combination might fulfill the functionfor pharmacometabolomics biomarker discovery diseasediagnosis and prognosis andmonitoring treatment responseThe development of integrated bioinformatics tools wouldhelp to handle the spatial temporal andmultiparametric datafrom cancer metabolic imaging

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

We acknowledge the support received from Chang GungMedical Foundation (Taiwan) Grants CMRPG370444 andCMRPG3B1921 also the Cancer Research UK and EPSRCCancer Imaging Centre in association with the MRC andDepartment of Health (England) Grant C1060A10334

References

[1] D Hanahan and R AWeinberg ldquoHallmarks of cancer the nextgenerationrdquo Cell vol 144 no 5 pp 646ndash674 2011

[2] R Kaddurah-Daouk B S Kristal and R M WeinshilboumldquoMetabolomics a global biochemical approach to drugresponse and diseaserdquo Annual Review of Pharmacology andToxicology vol 48 pp 653ndash683 2008

[3] OWarburg ldquoOn the origin of cancer cellsrdquo Science vol 123 no3191 pp 309ndash314 1956

[4] R A Gatenby andR J Gillies ldquoAmicroenvironmentalmodel ofcarcinogenesisrdquo Nature Reviews Cancer vol 8 no 1 pp 56ndash612008


[5] P R Rich ldquoThe molecular machinery of Keilinrsquos respiratorychainrdquo Biochemical Society Transactions vol 31 no 6 pp 1095ndash1105 2003

[6] J L Griffin and R A Kauppinen ldquoTumour metabolomics inanimal models of human cancerrdquo Journal of Proteome Researchvol 6 no 2 pp 498ndash505 2007

[7] L C Costello and R B Franklin ldquorsquoWhy do tumour cellsglycolysersquo from glycolysis through citrate to lipogenesisrdquoMolecular and Cellular Biochemistry vol 280 no 1-2 pp 1ndash82005

[8] R L Elstrom D E Bauer M Buzzai et al ldquoAkt stimulatesaerobic glycolysis in cancer cellsrdquo Cancer Research vol 64 no11 pp 3892ndash3899 2004

[9] D R Plas andC BThompson ldquoAkt-dependent transformationthere is more to growth than just survivingrdquo Oncogene vol 24no 50 pp 7435ndash7442 2005

[10] T Porstmann C R Santos B Griffiths et al ldquoSREBP activityis regulated by mTORC1 and contributes to Akt-dependent cellgrowthrdquo Cell Metabolism vol 8 no 3 pp 224ndash236 2008

[11] J-W Kim and C V Dang ldquoCancerrsquos molecular sweet tooth andthe warburg effectrdquo Cancer Research vol 66 no 18 pp 8927ndash8930 2006

[12] H Shim C Dolde B C Lewis et al ldquoc-Myc transactivationof LDH-A implications for tumor metabolism and growthrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 94 no 13 pp 6658ndash6663 1997

[13] J Downward ldquoTargeting RAS signalling pathways in cancertherapyrdquo Nature Reviews Cancer vol 3 no 1 pp 11ndash22 2003

[14] S Telang A Yalcin A L Clem et al ldquoRas transforma-tion requires metabolic control by 6-phosphofructo-2-kinaserdquoOncogene vol 25 no 55 pp 7225ndash7234 2006

[15] K H Vousden and K M Ryan ldquoP53 and metabolismrdquo NatureReviews Cancer vol 9 no 10 pp 691ndash700 2009

[16] D B Shackelford and R J Shaw ldquoThe LKB1-AMPK pathwaymetabolism and growth control in tumour suppressionrdquoNatureReviews Cancer vol 9 no 8 pp 563ndash575 2009

[17] K-K Wong J A Engelman and L C Cantley ldquoTargeting thePI3K signaling pathway in cancerrdquo Current Opinion in Geneticsand Development vol 20 no 1 pp 87ndash90 2010

[18] N M S Al-Saffar L E Jackson F I Raynaud et al ldquoThe phos-phoinositide 3-kinase inhibitor PI-103 downregulates cholinekinase 120572 leading to phosphocholine and total choline decreasedetected bymagnetic resonance spectroscopyrdquoCancer Researchvol 70 no 13 pp 5507ndash5517 2010

[19] N C Denko ldquoHypoxia HIF1 and glucose metabolism in thesolid tumourrdquoNature Reviews Cancer vol 8 no 9 pp 705ndash7132008

[20] M Beloueche-Babari L E Jackson N M S Al-Saffar PWorkman M O Leach and S M Ronen ldquoMagnetic resonancespectroscopy monitoring of mitogen-activated protein kinasesignaling inhibitionrdquo Cancer Research vol 65 no 8 pp 3356ndash3363 2005

[21] B F Jordan K Black I F Robey M Runquist G Powis andR J Gillies ldquoMetabolite changes in HT-29 xenograft tumorsfollowing HIF-1120572 inhibition with PX-478 as studied by MRspectroscopy in vivo and ex vivordquo NMR in Biomedicine vol 18no 7 pp 430ndash439 2005

[22] J-W Kim I Tchernyshyov G L Semenza and C V DangldquoHIF-1-mediated expression of pyruvate dehydrogenase kinasea metabolic switch required for cellular adaptation to hypoxiardquoCell Metabolism vol 3 no 3 pp 177ndash185 2006

[23] N M S Al-Saffar H Troy A R de Molina et al ldquoNoninvasivemagnetic resonance spectroscopic pharmacodynamic markersof the choline kinase inhibitor MN58b in human carcinomamodelsrdquo Cancer Research vol 66 no 1 pp 427ndash434 2006

[24] A Evans V Bates H Troy et al ldquoGlut-1 as a therapeutictarget increased chemoresistance and HIF-1-independent linkwith cell turnover is revealed through COMPARE analysis andmetabolomic studiesrdquo Cancer Chemotherapy and Pharmacol-ogy vol 61 no 3 pp 377ndash393 2008

[25] P Sonveaux T Copetti C J de Saedeleer et al ldquoTargeting thelactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesisrdquo PLoS ONEvol 7 no 3 Article ID e33418 2012

[26] R L Yauch and J Settleman ldquoRecent advances in pathway-targeted cancer drug therapies emerging from cancer genomeanalysisrdquo Current Opinion in Genetics and Development vol 22no 1 pp 45ndash49 2012

[27] M G Vander Heiden ldquoTargeting cancer metabolism a thera-peutic window opensrdquo Nature Reviews Drug Discovery vol 10no 9 pp 671ndash684 2011

[28] D A Tennant R V Duran and E Gottlieb ldquoTargetingmetabolic transformation for cancer therapyrdquo Nature ReviewsCancer vol 10 no 4 pp 267ndash277 2010

[29] J Evelhoch M Garwood D Vigneron et al ldquoExpanding theuse of magnetic resonance in the assessment of tumor responseto therapy workshop reportrdquo Cancer Research vol 65 no 16pp 7041ndash7044 2005

[30] P Workman E O Aboagye Y-L Chung et al ldquoMinimallyinvasive Pharmacokinetic and Pharmacodynamic Technologiesin hypothesis-testing clinical trials of innovative therapiesrdquoJournal of the National Cancer Institute vol 98 no 9 pp 580ndash598 2006

[31] M Gerlinger A J Rowan S Horswell et al ldquoIntratumorheterogeneity and branched evolution revealed by multiregionsequencingrdquoTheNew England Journal of Medicine vol 366 no10 pp 883ndash892 2012

[32] T N Seyfried and L M Shelton ldquoCancer as a metabolicdiseaserdquo Nutrition and Metabolism vol 7 article 7 2010

[33] R A Gatenby and R J Gillies ldquoWhy do cancers have highaerobic glycolysisrdquo Nature Reviews Cancer vol 4 no 11 pp891ndash899 2004

[34] M Israel and L Schwartz ldquoThe metabolic advantage of tumorcellsrdquoMolecular Cancer vol 10 article 70 2011

[35] O Feron ldquoPyruvate into lactate and back from the Warburgeffect to symbiotic energy fuel exchange in cancer cellsrdquoRadiotherapy and Oncology vol 92 no 3 pp 329ndash333 2009

[36] P Icard and H Lincet ldquoA global view of the biochemicalpathways involved in the regulation of themetabolism of cancercellsrdquo Biochimica et Biophysica Acta vol 1826 no 2 pp 423ndash433 2012

[37] G L Semenza ldquoTumor metabolism cancer cells give and takelactaterdquoThe Journal of Clinical Investigation vol 118 no 12 pp3835ndash3837 2008

[38] P Sonveaux F Vegran T Schroeder et al ldquoTargeting lactate-fueled respiration selectively kills hypoxic tumor cells in micerdquoThe Journal of Clinical Investigation vol 118 no 12 pp 3930ndash3942 2008

[39] J L Griffin and R A Kauppinen ldquoA metabolomics perspectiveof human brain tumoursrdquoThe FEBS Journal vol 274 no 5 pp1132ndash1139 2007


[40] M G Swanson A S Zektzer Z L Tabatabai et al ldquoQuanti-tative analysis of prostate metabolites using1H HR-MAS spec-troscopyrdquo Magnetic Resonance in Medicine vol 55 no 6 pp1257ndash1264 2006

[41] L Bartella and W Huang ldquoProton (1H) MR spectroscopy ofthe breastrdquo Radiographics vol 27 supplement 1 pp S241ndashS2522007

[42] C Dowling AW Bollen S M Noworolski et al ldquoPreoperativeproton MR spectroscopic imaging of brain tumors correlationwith histopathologic analysis of resection specimensrdquoAmericanJournal of Neuroradiology vol 22 no 4 pp 604ndash612 2001

[43] S K Mukherji S Schiro M Castillo L Kwock K E Mullerand W Blackstock ldquoProton MR spectroscopy of squamous cellcarcinomaof the extracranial head andneck in vitro and in vivostudiesrdquo American Journal of Neuroradiology vol 18 no 6 pp1057ndash1072 1997

[44] M Seitz A Shukla-Dave A Bjartell et al ldquoFunctionalmagneticresonance imaging in prostate cancerrdquo European Urology vol55 no 4 pp 801ndash814 2009

[45] P Alusta I Im B A Pearce et al ldquoImproving protonMR spec-troscopy of brain tissue for noninvasive diagnosticsrdquo Journal ofMagnetic Resonance Imaging vol 32 no 4 pp 818ndash829 2010

[46] M M Mahon I J Cox R Dina et al ldquo1H Magnetic resonancespectroscopy of preinvasive and invasive cervical cancer invivo-ex vivo profiles and effect of tumor loadrdquo Journal ofMagnetic Resonance Imaging vol 19 no 3 pp 356ndash364 2004

[47] S J Nelson J Kurhanewicz D B Vigneron et al ldquoMetabolicimaging of patients with prostate cancer using hyperpolarized[1-13C]pyruvaterdquo Science Translational Medicine vol 5 no 198Article ID 198ra08 2013

[48] A Zhu D Lee and H Shim ldquoMetabolic positron emissiontomography imaging in cancer detection and therapy responserdquoSeminars in Oncology vol 38 no 1 pp 55ndash69 2011

[49] S-H Ng T-C Yen C-T Liao et al ldquo18F-FDG PET andCTMRI in oral cavity squamous cell carcinoma a prospectivestudy of 124 patients with histologic correlationrdquo Journal ofNuclear Medicine vol 46 no 7 pp 1136ndash1143 2005

[50] A D van den Abbeele and R D Badawi ldquoUse of positronemission tomography in oncology and its potential role toassess response to imatinib mesylate therapy in gastrointestinalstromal tumors (GISTs)rdquo European Journal of Cancer vol 38supplement 5 pp S60ndash65 2002

[51] S Stroobants J Goeminne M Seegers et al ldquo18FDG-Positronemission tomography for the early prediction of response inadvanced soft tissue sarcoma treated with imatinib mesylate(Glivec)rdquo European Journal of Cancer vol 39 no 14 pp 2012ndash2020 2003

[52] N Sunaga N Oriuchi K Kaira et al ldquoUsefulness of FDG-PETfor early prediction of the response to gefitinib in non-small celllung cancerrdquo Lung Cancer vol 59 no 2 pp 203ndash210 2008

[53] B Simcock D Neesham M Quinn E Drummond A Milnerand R J Hicks ldquoThe impact of PETCT in the management ofrecurrent ovarian cancerrdquo Gynecologic Oncology vol 103 no 1pp 271ndash276 2006

[54] B K P Goh ldquoPositron emission tomographycomputed tomog-raphy influences on the management of resectable pancreaticcancer and its cost-effectivenessrdquoAnnals of Surgery vol 243 no5 pp 709ndash710 2006

[55] H Schoder K Herrmann M Gonen et al ldquo2-[18F]fluoro-2-deoxyglucose positron emission tomography for the detectionof disease in patients with prostate-specific antigen relapse after

radical prostatectomyrdquo Clinical Cancer Research vol 11 no 13pp 4761ndash4769 2005

[56] K-C Ho G Lin J-J Wang C-H Lai C-J Chang and T-CYen ldquoCorrelation of apparent diffusion coefficients measuredby 3T diffusion-weighted MRI and SUV from FDG PETCT inprimary cervical cancerrdquo European Journal of Nuclear Medicineand Molecular Imaging vol 36 no 2 pp 200ndash208 2009

[57] T-C Yen L-C See T-C Chang et al ldquoDefining the priorityof using 18F-FDG PET for recurrent cervical cancerrdquo Journal ofNuclear Medicine vol 45 no 10 pp 1632ndash1639 2004

[58] S A Schwartz R J Weil R C Thompson et al ldquoProteomic-based prognosis of brain tumor patients using direct-tissuematrix-assisted laser desorption ionizationmass spectrometryrdquoCancer Research vol 65 no 17 pp 7674ndash7681 2005

[59] S A Patel A Barnes N Loftus et al ldquoImaging mass spec-trometry using chemical inkjet printing reveals differentialprotein expression in human oral squamous cell carcinomardquoThe Analyst vol 134 no 2 pp 301ndash307 2009

[60] M R Groseclose P P Massion P Chaurand and R M Capri-oli ldquoHigh-throughput proteomic analysis of formalin-fixedparaffin-embedded tissue microarrays using MALDI imagingmass spectrometryrdquo Proteomics vol 8 no 18 pp 3715ndash37242008

[61] S Rauser CMarquardt B Balluff et al ldquoClassification ofHER2receptor status in breast cancer tissues byMALDI imagingmassspectrometryrdquo Journal of Proteome Research vol 9 no 4 pp1854ndash1863 2010

[62] Y Morita K Ikegami N Goto-Inoue et al ldquoImaging massspectrometry of gastric carcinoma in formalin-fixed paraffin-embedded tissue microarrayrdquo Cancer Science vol 101 no 1 pp267ndash273 2010

[63] M-C Djidja E Claude M F Snel et al ldquoMALDI-ion mobilityseparation-mass spectrometry imaging of glucose-regulatedprotein 78 kDa (Grp78) in human formalin-fixed paraffin-embedded pancreatic adenocarcinoma tissue sectionsrdquo Journalof Proteome Research vol 8 no 10 pp 4876ndash4884 2009

[64] S R Oppenheimer D Mi M E Sanders and R M CapriolildquoMolecular analysis of tumor margins by MALDI mass spec-trometry in renal carcinomardquo Journal of Proteome Research vol9 no 5 pp 2182ndash2190 2010

[65] R Lemaire S A Menguellet J Stauber et al ldquoSpecific MALDIimaging and profiling for biomarker hunting and validationfragment of the 11S proteasome activator complex reg alphafragment is a new potential ovary cancer biomarkerrdquo Journalof Proteome Research vol 6 no 11 pp 4127ndash4134 2007

[66] L H Cazares D Troyer S Mendrinos et al ldquoImaging massspectrometry of a specific fragment of mitogen-activated pro-tein kinaseextracellular signal-regulated kinase kinase kinase 2discriminates cancer from uninvolved prostate tissuerdquo ClinicalCancer Research vol 15 no 17 pp 5541ndash5551 2009

[67] J K Nicholson J C Lindon and E Holmes ldquorsquoMetabonomicsrsquounderstanding the metabolic responses of living systems topathophysiological stimuli viamultivariate statistical analysis ofbiological NMR spectroscopic datardquo Xenobiotica vol 29 no 11pp 1181ndash1189 1999

[68] O Fiehn J Kopka P Dormann T Altmann R N Tretheweyand L Willmitzer ldquoMetabolite profiling for plant functionalgenomicsrdquo Nature Biotechnology vol 18 no 11 pp 1157ndash11612000

[69] W B Dunn D I Broadhurst H J Atherton R Goodacre andJ L Griffin ldquoSystems level studies of mammalianmetabolomes


the roles of mass spectrometry and nuclear magnetic resonancespectroscopyrdquo Chemical Society Reviews vol 40 no 1 pp 387ndash426 2011

[70] E M Lenz and I D Wilson ldquoAnalytical strategies in metabo-nomicsrdquo Journal of Proteome Research vol 6 no 2 pp 443ndash4582007

[71] N Psychogios D D Hau J Peng et al ldquoThe human serummetabolomerdquo PLoS ONE vol 6 no 2 Article ID e16957 2011

[72] J R Griffiths and Y L Chung ldquoMetabolomic studies on cancerand on anticancer drugs by NMR ex vivordquo in Encyclopedia ofMagnetic Resonance R K Harris and R E Wasylishen EdsJohn Wiley amp Sons Chichester UK 2011

[73] M V Brown J E McDunn P R Gunst et al ldquoCancer detectionand biopsy classification using concurrent histopathologicaland metabolomic analysis of core biopsiesrdquo Genome Medicinevol 4 no 4 article 33 2012

[74] K Glunde and Z M Bhujwalla ldquoMetabolic tumor imagingusing magnetic resonance spectroscopyrdquo Seminars in Oncologyvol 38 no 1 pp 26ndash41 2011

[75] C P Slichter Principles of Magnetic Resonance Springer NewYork NY USA 3rd edition 1990

[76] J Frahm H Bruhn M L Gyngell K D Merboldt W Hanickeand R Sauter ldquoLocalized high-resolution proton NMR spec-troscopy using stimulated echoes initial applications to humanbrain in vivordquoMagnetic Resonance in Medicine vol 9 no 1 pp79ndash93 1989

[77] P A Bottomley ldquoSpatial localization in NMR spectroscopy invivordquo Annals of the New York Academy of Sciences vol 508 pp333ndash348 1987

[78] R J Ordidge R M Bowley and G McHale ldquoA generalapproach to selection of multiple cubic volume elements usingthe ISIS techniquerdquoMagnetic Resonance in Medicine vol 8 no3 pp 323ndash331 1988

[79] T R Brown B M Kincaid and K Ugurbil ldquoNMR chemicalshift imaging in three dimensionsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 79 no11 I pp 3523ndash3526 1982

[80] K Glunde C Jie and Z M Bhujwalla ldquoMolecalar causes oftile aberrant choline phospholipidmetabolism in breast cancerrdquoCancer Research vol 64 no 12 pp 4270ndash4276 2004

[81] R J Gillies and D L Morse ldquoIn vivo magnetic resonance spec-troscopy in cancerrdquo Annual Review of Biomedical Engineeringvol 7 pp 287ndash326 2005

[82] J M Hakumaki H Poptani A-M Sandmair S Yla-Herttualaand R A Kauppinen ldquo1H MRS detects polyunsaturated fattyacid accumulation during gene therapy of glioma implicationsfor the in vivo detection of apoptosisrdquo Nature Medicine vol 5no 11 pp 1323ndash1327 1999

[83] N M S Al-Saffar J C Titley D Robertson et al ldquoApoptosis isassociated with triacylglycerol accumulation in Jurkat T-cellsrdquoBritish Journal of Cancer vol 86 no 6 pp 963ndash970 2002

[84] J E Schmitz M I Kettunen D-E Hu and K M Brindle ldquo1HMRS-visible lipids accumulate during apoptosis of lymphomacells in vitro and in vivordquoMagnetic Resonance in Medicine vol54 no 1 pp 43ndash50 2005

[85] J L Griffin K K Lehtimaki P K Valonen et al ldquoAssignmentof 1H nuclear magnetic resonance visible polyunsaturatedfatty acids in BT4C gliomas undergoing ganciclovir-thymidinekinase gene therapy-induced programmed cell deathrdquo CancerResearch vol 63 no 12 pp 3195ndash3201 2003

[86] P G Okunieff J A Koutcher L Gerweck et al ldquoTumor sizedependent changes in a murine fibrosarcoma use of in vivo 31PNMR for non-invasive evaluation of tumor metabolic statusrdquoInternational Journal of Radiation Oncology Biology Physics vol12 no 5 pp 793ndash799 1986

[87] G M Tozer and J R Griffiths ldquoThe contribution made by celldeath and oxygenation to 31P MRS observations of tumourenergymetabolismrdquoNMR in Biomedicine vol 5 no 5 pp 279ndash289 1992

[88] W Wolf C A Presant and V Waluch ldquo19F-MRS studies offluorinated drugs in humansrdquoAdvanced Drug Delivery Reviewsvol 41 no 1 pp 55ndash74 2000

[89] Y-L Chung H Troy I R Judson et al ldquoNoninvasive mea-surements of capecitabine metabolism in bladder tumors over-expressing thymidine phosphorylase by fluorine-19 magneticresonance spectroscopyrdquo Clinical Cancer Research vol 10 no11 pp 3863ndash3870 2004

[90] C Li M-F Penet P Winnard Jr D Artemov and Z MBhujwalla ldquoImage-guided enzymeprodrug cancer therapyrdquoClinical Cancer Research vol 14 no 2 pp 515ndash522 2008

[91] E L Hall M C Stephenson D Price and P G MorrisldquoMethodology for improved detection of low concentrationmetabolites in MRS optimised combination of signals frommulti-element coil arraysrdquoNeuroImage vol 86 pp 35ndash42 2014

[92] J H Ardenkjaeligr-Larsen B Fridlund A Gram et al ldquoIncreasein signal-to-noise ratio of gt10000 times in liquid-state NMRrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 18 pp 10158ndash10163 2003

[93] D M Wilson K R Keshari P E Z Larson et al ldquoMulti-compound polarization by DNP allows simultaneous assess-ment of multiple enzymatic activities in vivordquo Journal ofMagnetic Resonance vol 205 no 1 pp 141ndash147 2010

[94] T H Witney M I Kettunen D-E Hu et al ldquo Detecting treat-ment response in a model of human breast adenocarcinomausing hyperpolarised [1-13C]pyruvate and [14-13C2]fumaraterdquoBritish Journal of Cancer vol 103 no 9 pp 1400ndash1406 2010

[95] K Golman R I Zandt M Lerche R Pehrson and J HArdenkjaer-Larsen ldquoMetabolic imaging by hyperpolarized 13Cmagnetic resonance imaging for in vivo tumor diagnosisrdquoCancer Research vol 66 no 22 pp 10855ndash10860 2006

[96] J Kurhanewicz D B Vigneron K Brindle et al ldquoAnalysis ofcancermetabolismby imaging hyperpolarized nuclei prospectsfor translation to clinical researchrdquo Neoplasia vol 13 no 2 pp81ndash97 2011

[97] S E DayM I Kettunen F AGallagher et al ldquoDetecting tumorresponse to treatment using hyperpolarized 13Cmagnetic reso-nance imaging and spectroscopyrdquo Nature Medicine vol 13 no11 pp 1382ndash1387 2007

[98] A P ChenW Chu Y P Gu and C H Cunnhingham ldquoProbingearly tumor response to radiation therapy using hyperpolarized[1-(1)(3)C]pyruvate in MDA-MB-231 xenograftsrdquo PLoS ONEvol 8 no 2 Article ID e56551 2013

[99] I Park R Bok T Ozawa et al ldquoDetection of early response totemozolomide treatment in brain tumors using hyperpolarized13C MR metabolic imagingrdquo Journal of Magnetic ResonanceImaging vol 33 no 6 pp 1284ndash1290 2011

[100] C S Ward H S Venkatesh M M Chaumeil et al ldquoNonin-vasive detection of target modulation following phosphatidyli-nositol 3-kinase inhibition using hyperpolarized 13C magneticresonance spectroscopyrdquo Cancer Research vol 70 no 4 pp1296ndash1305 2010


[101] K Golman L E Olsson O Axelsson S ManssonM Karlssonand J S Petersson ldquoMolecular imaging using hyperpolarized13Crdquo The British Journal of Radiology vol 76 no 2 pp S118ndashS127 2003

[102] D KHill Y JaminM ROrton et al ldquo(1)HNMRandhyperpo-larized (1)(3)C NMR assays of pyruvate-lactate a comparativestudyrdquo NMR in Biomedicine vol 26 no 10 pp 1321ndash1325 2013

[103] D K Hill M R Orton E Mariotti et al ldquoModel free approachto kinetic analysis of real-time hyperpolarized 13C magneticresonance spectroscopy datardquo PLoS ONE vol 8 no 9 ArticleID e71996 2013

[104] F A Gallagher M I Kettunen S E Day et al ldquoMagneticresonance imaging of pH in vivo using hyperpolarized 13C-labelled bicarbonaterdquo Nature vol 453 no 7197 pp 940ndash9432008

[105] F A Gallagher M I Kettunen D-E Hu et al ldquoProductionof hyperpolarized [14-13C2]malate from [14-13C2]fumarate isa marker of cell necrosis and treatment response in tumorsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 106 no 47 pp 19801ndash19806 2009

[106] S J Nelson J Kurhanewicz D B Vigneron et al ldquoMetabolicimaging of patients with prostate cancer using hyperpolarized[1-(1)(3)C]pyruvaterdquo Science Translational Medicine vol 5 no198 Article ID 198ra08 2013

[107] V Kapoor B M McCook and F S Torok ldquoAn introductionto PET-CT imagingrdquo Radiographics vol 24 no 2 pp 523ndash5432004

[108] M LMacheda S Rogers and J D Best ldquoMolecular and cellularregulation of glucose transporter (GLUT) proteins in cancerrdquoJournal of Cellular Physiology vol 202 no 3 pp 654ndash662 2005

[109] S Maschauer O Prante M Hoffmann J T Deichen andT Kuwert ldquoCharacterization of 18F-FDG uptake in humanendothelial cells in vitrordquo Journal of Nuclear Medicine vol 45no 3 pp 455ndash460 2004

[110] K AWood P J Hoskin andM I Saunders ldquoPositron emissiontomography in oncology a reviewrdquo Clinical Oncology vol 19no 4 pp 237ndash255 2007

[111] C Plathow andW AWeber ldquoTumor cell metabolism imagingrdquoJournal of Nuclear Medicine vol 49 supplement 2 pp 43Sndash63S2008

[112] I Grassi C Nanni V Allegri et al ldquoThe clinical use of PETwith (11)C-acetaterdquo American Journal of Nuclear Medicine andMolecular Imaging vol 2 no 1 pp 33ndash47 2012

[113] AW Glaudemans R H Enting M A Heesters et al ldquoValue of11C-methionine PET in imaging brain tumours andmetastasesrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 40 no 4 pp 615ndash635 2013

[114] D Hausmann L K Bittencourt U I Attenberger et alldquoDiagnostic accuracy of 18F choline PETCT using time-of-flight reconstruction algorithm in prostate cancer patients withbiochemical recurrencerdquo Clinical Nuclear Medicine 2013

[115] D Soloviev D Lewis D Honess and E Aboagye ldquo[18F]FLTan imaging biomarker of tumour proliferation for assessmentof tumour response to treatmentrdquo European Journal of Cancervol 48 no 4 pp 416ndash424 2012

[116] V Paolillo H H Yeh U Mukhopadhyay J G Gelovani andMM Alauddin ldquoImproved detection andmeasurement of lowlevels of [18F]fluoride metabolized from [18F]-labeled pyrim-idine nucleoside analogues in biological samplesrdquo NuclearMedicine and Biology vol 38 no 8 pp 1129ndash1134 2011

[117] F A Gallagher S E Bohndiek M I Kettunen D Y Lewis DSoloviev and KM Brindle ldquoHyperpolarized13CMRI and PETin vivo tumor biochemistryrdquo Journal of Nuclear Medicine vol52 no 9 pp 1333ndash1336 2011

[118] J Culver W Akers and S Achilefu ldquoMultimodality molecularimaging with combined optical and SPECTPET modalitiesrdquoJournal of Nuclear Medicine vol 49 no 2 pp 169ndash172 2008

[119] M J Albers R Bok A P Chen et al ldquoHyperpolarized13C lactate pyruvate and alanine noninvasive biomarkers forprostate cancer detection and gradingrdquoCancer Research vol 68no 20 pp 8607ndash8615 2008

[120] C Buchbender T A Heusner T C Lauenstein A Bockischand G Antoch ldquoOncologic PETMRI part 1 tumors of thebrain head and neck chest abdomen and pelvisrdquo Journal ofNuclear Medicine vol 53 no 6 pp 928ndash938 2012

[121] S E Bohndiek and K M Brindle ldquoImaging and rsquoomic methodsfor the molecular diagnosis of cancerrdquo Expert Review of Molec-ular Diagnostics vol 10 no 4 pp 417ndash434 2010

[122] H F Wehrl J Schwab K Hasenbach et al ldquoMultimodal eluci-dation of choline metabolism in a murine glioma model usingmagnetic resonance spectroscopy and 11C-choline positronemission tomographyrdquoCancer Research vol 73 no 5 pp 1470ndash1480 2013

[123] T A Smith M V Appleyard S Sharp I N Fleming KMurray and A M Thompson ldquoResponse to trastuzumab byHER2 expressing breast tumour xenografts is accompaniedby decreased Hexokinase II glut1 and [18F]-FDG incorpora-tion and changes in 31P-NMR-detectable phosphomonoestersrdquoCancer Chemotherapy and Pharmacology vol 71 no 2 pp 473ndash480 2013

[124] W Wolf ldquoThe unique potential for noninvasive imaging inmodernizing drug development and in transforming therapeu-tics PETMRIMRSrdquo Pharmaceutical Research vol 28 no 3pp 490ndash493 2011

[125] J F A Jansen H Schoder N Y Lee et al ldquoTumor metabolismand perfusion in head and neck squamous cell carcinomapretreatment multimodality imaging with1H magnetic res-onance spectroscopy dynamic contrast-enhanced MRI and[18F]FDG-PETrdquo International Journal of Radiation OncologyBiology Physics vol 82 no 1 pp 299ndash307 2012

[126] C Testa R Schiavina R Lodi et al ldquoProstate cancer sextantlocalization with MR imaging MR spectroscopy and 11C-choline PETCTrdquo Radiology vol 244 no 3 pp 797ndash806 2007

[127] V Panebianco A Sciarra D Lisi et al ldquoProstate cancer1HMRS-DCEMR at 3 T versus [(18)F]choline PETCT in thedetection of local prostate cancer recurrence in men withbiochemical progression after radical retropubic prostatectomy(RRP)rdquo European Journal of Radiology vol 81 no 4 pp 700ndash708 2012

[128] M Tozaki and K Hoshi ldquo1H MR spectroscopy of invasiveductal carcinoma correlations with FDG PET and histologicprognostic factorsrdquoAmerican Journal of Roentgenology vol 194no 5 pp 1384ndash1390 2010

[129] R Katz-Brull P T Lavin and R E Lenkinski ldquoClinical utilityof proton magnetic resonance spectroscopy in characterizingbreast lesionsrdquo Journal of the National Cancer Institute vol 94no 16 pp 1197ndash1203 2002

[130] A Kumiko I Reiichi N Yuki et al ldquoUsefulness of ChoCrratio in proton MR spectroscopy for differentiating resid-ualrecurrent glioma from non-neoplastic lesionsrdquoNippon ActaRadiologica vol 64 no 3 pp 121ndash126 2004


[131] R Hourani L J Brant T Rizk J D Weingart P B Barkerand A Horska ldquoCan proton MR spectroscopic and perfusionimaging differentiate between neoplastic and nonneoplasticbrain lesions in adultsrdquo American Journal of Neuroradiologyvol 29 no 2 pp 366ndash372 2008

[132] E A Smith R C Carlos L R Junck C I Tsien A Eliasand P C Sundgren ldquoDeveloping a clinical decision modelMR spectroscopy to differentiate between recurrent tumorand radiation change in patients with new contrast-enhancinglesionsrdquo American Journal of Roentgenology vol 192 no 2 ppW45ndashW52 2009

[133] S A Sung M-J Kim S L Joon H-S Hong E C Yong andJ-Y Choi ldquoAdded value of gadoxetic acid-enhanced hepato-biliary phase MR imaging in the diagnosis of hepatocellularcarcinomardquo Radiology vol 255 no 2 pp 459ndash466 2010

[134] J Hwang S H Kim M W Lee and J Y Lee ldquoSmall (le =2 cm) hepatocellular carcinoma in patients with chronic liverdisease comparison of gadoxetic acid-enhanced 30 TMRI andmultiphasic 64-multirow detector CTrdquo The The British Journalof Radiology vol 85 no 1015 pp e314ndashe322 2012

[135] M J Park Y K Kim M W Lee et al ldquoSmall hepatocellularcarcinomas improved sensitivity by combining gadoxetic acid-enhanced and diffusion-weighted MR imaging patternsrdquo Radi-ology vol 264 no 3 pp 761ndash770 2012

[136] J-W Park H K Ji K K Seok et al ldquoA prospective evaluationof18F-FDG and11C-acetate PETCT for detection of primaryand metastatic hepatocellular carcinomardquo Journal of NuclearMedicine vol 49 no 12 pp 1912ndash1921 2008

[137] J-N Talbot L Fartoux S Balogova et al ldquoDetection of hep-atocellular carcinoma with PETCT a prospective comparisonof18F-fluorocholine and18F-FDG in patients with cirrhosis orchronic liver diseaserdquo Journal of Nuclear Medicine vol 51 no11 pp 1699ndash1706 2010

[138] M I Menzel E V Farrell M A Janich et al ldquoMultimodalassessment of in vivo metabolism with hyperpolarized [1-13C]MR spectroscopy and 18F-FDG PET imaging in hepa-tocellular carcinoma tumor-bearing ratsrdquo Journal of NuclearMedicine vol 54 no 7 pp 1113ndash1119 2013

[139] R Srirajaskanthan I Kayani A M Quigley J Soh M ECaplin and J Bomanji ldquoThe role of 68Ga-DOTATATE PET inpatients with neuroendocrine tumors and negative or equivocalfindings on 111In-DTPA-octreotide scintigraphyrdquo Journal ofNuclear Medicine vol 51 no 6 pp 875ndash882 2010

[140] M Ljungberg G Westberg B Vikhoff-Baaz et al ldquo31P MRspectroscopy to evaluate the efficacy of hepatic artery emboliza-tion in the treatment of neuroendocrine liver metastasesrdquo ActaRadiologica vol 53 no 10 pp 1118ndash1126 2012

[141] F Sullentrop J Hahn and D Moka ldquoIn vitro and in vivo (1)H-MR spectroscopic examination of the renal cell carcinomardquoInternational Journal of Biomedical Science vol 8 no 2 pp 94ndash108 2012

[142] K R Keshari R Sriram B L Koelsch et al ldquoHyperpolarized13C-pyruvatemagnetic resonance reveals rapid lactate export inmetastatic renal cell carcinomasrdquo Cancer Research vol 73 no2 pp 529ndash538 2013

[143] D S Cornett J A Mobley E C Dias et al ldquoA novel histology-directed strategy for MALDI-MS tissue profiling that improvesthroughput and cellular specificity in human breast cancerrdquoMolecular and Cellular Proteomics vol 5 no 10 pp 1975ndash19832006

[144] S Nimesh S Mohottalage R Vincent and P KumarathasanldquoCurrent status and future perspectives of mass spectrometry

imagingrdquo International Journal ofMolecular Sciences vol 14 no6 pp 11277ndash11301 2013

[145] D Miura Y Fujimura and H Wariishi ldquoIn situ metabolomicmass spectrometry imaging recent advances and difficultiesrdquoJournal of Proteomics vol 75 no 16 pp 5052ndash5060 2012

[146] A C Crecelius D S Cornett R M Caprioli B Williams BM Dawant and B Bodenheimer ldquoThree-dimensional visual-ization of protein expression in mouse brain structures usingimagingmass spectrometryrdquo Journal of the American Society forMass Spectrometry vol 16 no 7 pp 1093ndash1099 2005

[147] T Harada A Yuba-Kubo Y Sugiura et al ldquoVisualization ofvolatile substances in different organelles with an atmospheric-pressure mass microscoperdquo Analytical Chemistry vol 81 no 21pp 9153ndash9157 2009

[148] G Sun K Yang Z Zhao S Guan X Han and R WGross ldquoMatrix-assisted laser desorptionionization time-of-flight mass spectrometric analysis of cellular glycerophospho-lipids enabled bymultiplexed solvent dependent analyte-matrixinteractionsrdquo Analytical Chemistry vol 80 no 19 pp 7576ndash7585 2008

[149] K Chughtai L Jiang T R Greenwood K Glunde and RM Heeren ldquoMass spectrometry images acylcarnitines phos-phatidylcholines and sphingomyelin in MDA-MB-231 breasttumor modelsrdquo Journal of Lipid Research vol 54 no 2 pp 333ndash344 2013

[150] D Miura Y Fujimura M Yamato et al ldquoUltrahighly sensitivein situ metabolomic imaging for visualizing spatiotemporalmetabolic behaviorsrdquo Analytical Chemistry vol 82 no 23 pp9789ndash9796 2010

[151] K Hattori M Kajimura T Hishiki et al ldquoParadoxical ATP ele-vation in ischemic penumbra revealed by quantitative imagingmass spectrometryrdquo Antioxidants and Redox Signaling vol 13no 8 pp 1157ndash1167 2010

[152] R Calavia F E Annanouch X Correig and O Yanes ldquoNanos-tructure Initiator Mass Spectrometry for tissue imaging inmetabolomics future prospects and perspectivesrdquo Journal ofProteomics vol 75 no 16 pp 5061ndash5068 2012

[153] T R Northen O Yanes M T Northen et al ldquoClathratenanostructures for mass spectrometryrdquo Nature vol 449 no7165 pp 1033ndash1036 2007

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


that controls signaling pathways for cell growth regulationand malignancy transformation [13] and it has been seento increase the concentration of fructose-26-bisphosphate(F2 6BP) which is an allosteric activator of phosphofructo1-kinase and it catalyzes the phosphorylation of fructose-6-phosphate to fructose-16-bisphosphate [14] Recent advanceshave established further links between cancer metabolismand genetic alterations in p53 [15] AMPK [16] PI3K [17 18]and HIF [19]

There are growing interests in developing therapies thattarget important signaling pathways (eg PI3K [18] andMAPK [20]) and transcription factors (eg HIF-1 [21])and inhibit upregulated enzymes (eg pyruvate dehydro-genase kinase (PDK) [22] and choline kinase [23]) andmetabolite transporters (eg glucose transporter (Glut1) [24]and monocarboxylate transporter-1 (MCT-1) [25]) Thosetargeted therapies might alter cancer metabolism and thechanges in endogenous metabolites in cancer cells might bedetected even before changes in tumor sizes [26ndash28] Imagingmethods are needed to detect early metabolic changes incancer following treatment and these imaging readouts couldbe useful for monitoring the response to therapies [29 30]

Tumor heterogeneity and its adaptations to microenvi-ronment are important factors that could affect the effec-tiveness of cancer treatment hence the ability to imageand spatially map the heterogeneity of metabolism withina tumor will be very useful for planning the treatmentregime Intratumoral heterogeneity and branched evolutionare recently revealed in multiple spatially separated samplesobtained from primary renal carcinomas and associatedmetastatic sites by using genome sequencing [31] In addi-tion the metabolic heterogeneity is not only attributed togenetic alteration but is also an adaptation to hypoxic tumormicroenvironment Glycolysis confers a significant growthadvantage by producing the required metabolites for cancergrowth [27 32ndash34] as lactate can be used by oxygenatedcancer cells as oxidative fuel [35] in order to spare theglucose for the more anoxic cells in the center of the tumor[36]This cooperation between hypoxic and normoxic tumorcells optimizes energy production and allows cells to adaptefficiently to their environmental oxygen conditions [37 38]

Conventionally nuclear magnetic resonance (NMR)spectroscopy [67] and mass spectrometry (MS) [68] can beused separately or in combination to provide overlapping yetcomplementary data to evaluate cancer [69ndash72] MS havehigh sensitivity but the samples required prior separationsusing gas- or lipid-chromatography NMR has a lower sensi-tivity thanMS but it can measure all the detectable moleculesin the sample simultaneously without the need to priorseparation cancelling out the quantification errors withinthe method [69] Although analyses of biopsies with manymetabolites correlated with disease aggressiveness [73] theconventional metabolomic experiments using a single biopsyof small tumor or extracting metabolites from relativelylarge tissue areas do not provide the spatial information ofthe metabolites and multiple biopsies or biopsy of normaltissue counterpart for comparison is not feasible in routineclinical practice Hence noninvasive imaging would be auseful solution for spatial mapping of metabolites The

potential imaging techniques reviewed in this paper includebut are not limited to magnetic resonance spectroscopy(MRS) dynamic nuclear polarization (DNP) MRS positronemission tomography (PET) andmass spectrometry imaging(MSI) for tissue characterization Table 1 summarizes theadvantages disadvantages and clinical applications of eachimaging technique

2 Magnetic Resonance Spectroscopy (MRS)

Magnetic resonance spectroscopy (MRS) is a technique thatcan be used in preclinical and clinical settings to studycancer metabolism [74] It is based on nuclei such as 1H 31Pand 13C that possess the property of magnetic spin Whenthey are placed in a magnetic field these nuclei becomealigned or opposed to the external magnetic field Many ofthe nuclei are flipped into the other magnetic state whena radiofrequency pulse is applied and the differences inthe populations between these two magnetic energy statesare detected as a radio wave as the system returns toequilibrium The strength of this local field depends on theelectronic environment around the nucleus Different chem-ical structures possess different electronic environments andlead to nuclei resonating at slightly different frequenciesThese frequencies are termed as chemical shifts whichare expressed as the dimensionless units parts per million(ppm) in the spectrum and represent the metabolites of themeasured sample [75] Additional magnetic field gradientscause nuclei at different locations to precess at differentspeeds which allows spatial information to be recoveredusing Fourier analysis of themeasured signal [75] By spatiallyencoding chemical shift information one can generate MRSimaging by obtaining signals at different chemical shiftsThis can be achieved by frequency selective radiofrequencypulses as in stimulated echo acquisition mode (STEAM)[76] and point-resolved spectroscopy (PRESS) [77] in proton(1H)-MRS or by excitation and subsequent subtraction ofunwanted signals as in image selective in vivo spectroscopy(ISIS) technique [78] in phosphorus (31P)-MRS In additionmultivoxel spectroscopy such as chemical shift imaging (CSI)[79] can collect spectroscopic data from multiple adjacentvoxels in a single measurement

The clinical use of spectroscopy as an adjunct to MRIhas expanded dramatically over the past decades because oftechnical advances in hardware and pulse sequence designthat have improved the spatial and temporal resolution ofspectral data Nowadays most clinical MR scanners haveroutine sequences for 1H-MRS measurements providing awide range of metabolic and functional information inte-grated with complementary MRI localization Metabolitescommonly detected in clinical 1H-MRS include N-acetyl-aspartate (NAA) in the normal brain tissue [39] and citratein the normal prostate [40] and their levels decrease oncebeing replaced by tumor MRS detection of total cholinesignal has been used to diagnose and monitor breast [41]brain [42] and prostate cancers [44] and for monitoringthe response to anticancer therapy [23 72 80] In addition












Prostate [47]




Oral cancerlymphoma




[48ndash57]






prostate cancer

[58ndash66]


2) signal at









3 DNP-MRS


3


3

minus13CO2ratio in










LacPyr

LacPyr

13CAxial T2 image

Axial T2 image

T2 image + LacPyr








(a) (b)
















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























Prostate [47]




Oral cancerlymphoma




[48ndash57]






prostate cancer

[58ndash66]


2) signal at









3 DNP-MRS


3


3

minus13CO2ratio in










LacPyr

LacPyr

13CAxial T2 image

Axial T2 image

T2 image + LacPyr








(a) (b)
















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















3 DNP-MRS


3


3

minus13CO2ratio in










LacPyr

LacPyr

13CAxial T2 image

Axial T2 image

T2 image + LacPyr








(a) (b)
















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















LacPyr

LacPyr

13CAxial T2 image

Axial T2 image

T2 image + LacPyr








(a) (b)
















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(a) (b)
















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

























(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















(new

ly sy

nthe

sized

)U

nlab

eled

(pre

exist

ing)

PC (340) PC (364)

PC (340) PC (364)

2H

-labe

led









Acknowledgments


References







































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















































































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of














































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Documents

Review Article Current Opportunities and Challenges of ...downloads.hindawi.com/journals/bmri/2014/625095.pdf · instrumentation to provide signal enhancements of over, -folds of