Received: 16 November 2022 Revised: 15 January 2023 Accepted: 10 February 2023

DOI: 10.1002/cnr2.1795

REVIEW

Metabolomics in oncology

Gurparsad Singh Suri 1 | Gurleen Kaur 1 | Giuseppina M. Carbone 2 |

Dheeraj Shinde 2

1
Department of Biological Sciences, California
Baptist University, Riverside, California, USA Abstract
2
Institute of Oncology Research (IOR), Background: Oncogenic transformation alters intracellular metabolism and contrib-
Universita’ della Svizzera Italiana (USI),
Bellinzona, Switzerland utes to the growth of malignant cells. Metabolomics, or the study of small molecules,
can reveal insight about cancer progression that other biomarker studies cannot.
Correspondence
Dheeraj Shinde, Institute of Oncology Number of metabolites involved in this process have been in spotlight for cancer
Research (IOR), Università della Svizzera detection, monitoring, and therapy.
italiana (USI), Bellinzona, 6500 Switzerland.
Email: [email protected]
Recent Findings: In this review, the “Metabolomics” is defined in terms of current
technology having both clinical and translational applications. Researchers have
shown metabolomics can be used to discern metabolic indicators non-invasively
using different analytical methods like positron emission tomography, magnetic reso-
nance spectroscopic imaging etc. Metabolomic profiling is a powerful and technically
feasible way to track changes in tumor metabolism and gauge treatment response
across time. Recent studies have shown metabolomics can also predict individual
metabolic changes in response to cancer treatment, measure medication efficacy,
and monitor drug resistance. Its significance in cancer development and treatment is
summarized in this review.
Conclusion: Although in infancy, metabolomics can be used to identify treatment
options and/or predict responsiveness to cancer treatments. Technical challenges like
database management, cost and methodical knowhow still persist. Overcoming these
challenges in near further can help in designing new treatment régimes with
increased sensitivity and specificity.

KEYWORDS
biomarker, cancer, metabolic reprogramming, metabolism, metabolomics

1 | I N T RO DU CT I O N WHO estimates for 2019, cancer is the main cause of death for adults
aged below 70 in most countries.2 Cancer cells have a faulty metabo-
Metabolomics includes the systematic identification and quantifica- lism causing uncontrolled proliferation. This altered metabolism gener-
tion of metabolic products from the human body. In this review, we ates unique metabolic characteristics that can be used to aid in early
emphasize its relevance and potential applications in the oncology cancer detection, personalized treatment, and/or gauge therapeutic
field. response.3,4
Cancer is one of the leading causes of mortality worldwide and a Metabolic changes in cancer patient due to treatment, nutrition,
key deterrent to increasing global life expectancy.1 According to and exercise can influence cancer outcomes and patient quality of

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.

Cancer Reports. 2023;6:e1795. wileyonlinelibrary.com/journal/cnr2 1 of 13

https://doi.org/10.1002/cnr2.1795
2 of 13 SURI ET AL.

life.5,6 Metabolites can be evaluated in several body fluids such as

blood, plasma and urine and therefore represent a potential non-
invasive tool for the management of cancer patients, eventually pro-
viding a novel set of diagnostic biomarkers for tumor status and pro-
gression. Moreover, its study can support the management of the
anticancer treatment response at an individualized level and also
predict failures.7
Biochemical processes and metabolic pathways can be described
in details using metabolomics rather than standard clinical laboratory
procedures.8 In metabolomics, metabolites such as monosaccharides,
amino acids, small lipids, co-factors, vitamin B complexes, energy cycle
intermediates, nucleotides, exogenous xenobiotics and more are mea- F I G U R E 1 Schematics showing reprogrammed cancer cell
9,10 metabolism. Extrinsic factors include hypoxic microenvironments,
sured and studied comprehensively. Biomass, energy and redox
acidic conditions, altered nutrients while Intrinsic factors include gene
balance all play a key role in cell metabolism, which is essential for life.
mutations, oncogene deregulations. Tricarboxylic acid (TCA)
There have been numerous studies demonstrating the importance of
metabolic reprogramming in a variety of disorders, including cancer,
diabetes, cardiovascular disease, and neurological disease.11,12 In growth. (C) Lastly, when cancer cells colonize other organs, they must
order to uncover the underlying causes of disease and devise new adapt to a completely new metabolic environments compared to pri-
treatments, understanding metabolism is a necessity. mary sites in order to grow.14,15 Understanding the mechanisms
The objective of this article is to give a general overview on the underlying this metabolic reprogramming can help in identification of
current and future prospects on metabolomics and its role in cancer new therapeutic targets for cancer.
detection, monitoring and treatment. Here, we discuss recent devel-
opments in metabolomics and then emphasize on the clinical applica-
tions of metabolomics. 2.1 | Metabolic reprogramming and tumor
microenvironment

2 | R E P R O G R A M M I N G OF CA NC E R C E LL Tumor microenvironments have altered metabolic mechanism com-

METABOLISM pared to normal tissues. This metabolism is influenced by number of
intrinsic and extrinsic factors (Figure 1). The classic example of cell-
Metabolic reprogramming helps cancer cells to survive and proliferate intrinsic factor is altered glycolysis (also known as Warburg effect),16
during the course of cancer development. The enhanced growth and a fast glycolysis event due to the necessity of malignant proliferation.
proliferation in malignant cells require an increased amount of energy Lack of oxygen in the local tumor microenvironment is frequently
in the form of ATP and other co-factors. This increased demand for caused by tumor cells high proliferative capacity and high energy
resources is fulfilled through alteration of flux via multiple metabolic requirement. However, despite the fact that glycolysis does not give
pathways. Altered Glycolysis and glucose metabolism (Warburg as much energy as aerobic respiration, it is 100 times faster and pro-
effect) is the most well-known and studied pathways in cancer metab- duces the amino acids and pentose phosphates required by rapidly
olism. Over time multiple other pathways have been found to be proliferating cancer cells.17,18 Similarly, another most frequently
altered in cancer cells for example lipid metabolism pathway, gluta- altered signaling pathway in human cancer is phosphatidylinositol-
mine metabolism pathway, amino acid metabolism, citric acid cycle, 3-kinase (PI3K)/Akt signaling pathway19 which along with mTOR
13
fatty acid oxidation, one-carbon metabolism etc. The reprogram- (mammalian target of rapamycin) controls the uptake of glucose, lipids,
ming in theses pathways is complex and involves multiple factors. Also nucleotides and amino acids.20,21 Aberrant activation of this pathway
depending on the cancer type the reprogramming occurs in various through mutation is dominant in many tumor progressions. Other
degrees and in contexts with the microenvironmental conditions, pro- intrinsic factors include altered glutaminolysis,22 activated mitochon-
viding required plasticity to cancer cell. drial electron transport chain (ETC) function23,24 altered tricarboxylic
In this review we have tried to differentiate the metabolic state acid (TCA) cycle in many cancer types,25 mutations in enzymes such
of cancer cells depending on the stages of cancer progression. For as isocitrate dehydrogenases 1 and 2 (IDH1, IDH2),26 succinate dehy-
cancer cells to proliferate, invade, and metastasize they need to drogenase (SDH) and (fumarate hydratase) FH.27,28 On the other
acquire a different metabolic state. It can broadly be classified into hand, extrinsic factors like transformed nutrient microenvironment
3 stages. (A) Tumor micro-environments are typically acidic and hyp- due to heterogenous density of blood and lymphatic vessels force
oxic with a distinct nutrient composition compared to normal tissues, cancer cells for metabolic reprogramming in order to survive.29,30
forcing cancer cells to adapt to such conditions in order to survive. Other extrinsic factors for example hypoxia and acidification also play
(B) During invasion, for survival in blood vessels, cancer cells must a critical role in metabolic reprogramming31,32 (Figure 1). Hypoxic
reprogram their metabolic state, allowing for anchorage-independent microenvironments lead to upregulation and stabilization of hypoxia-
SURI ET AL. 3 of 13

inducible factors (HIFs), which are known to regulate expression of through upregulation of asparagine synthetase (ASNS) an enzyme
several genes (for example SNAIL, ZEB1, TWIST, matrix metalloprotei- responsible to synthesize asparagine from aspartate.51 Multiple other
nases, lactate dehydrogenase A and pyruvate dehydrogenase kinase proteins are known to be deregulated in many cancer types that sup-
133–38) that contribute to cancer progression, including many involved port metastases for example deregulation of phosphoglycerate dehy-
in cell survival, angiogenesis, glycolysis, cancer invasion, and metasta- drogenase (PHGDH),52 α-ketoglutarate,53 monocarboxylate
sis. Understanding these metabolic switches and their role in meta- transporter 1 (MCT1),54 pentose phosphate pathway,55 acetyl-CoA
bolic reprogramming can provide critical insights in designing effective carboxylase (ACC)56 etc. Decoding these metabolic pathways and
treatment regimens. their role in metastatic can be beneficial in designing new targeted
therapies against metastatic cancer types.

2.2 | Metabolic reprograming for anchorage-

independent growth 4 | DR U G S T A RG E T I N G C A N C E R
METABOLI SM
For cancer cells to metastasise anchorage independent growth is a
requirement, wherein cancer cells must detach from extra cellular Increased understanding of cancer metabolism has led to develop-
matrix, enter blood/lymphatic vessel and survive in anchorage- ment of new drugs targeting tumor metabolism. These metabolism-
independent manner. Interestingly a very small portion of circulating based therapies are designed to target specific metabolic pathways
cancer cells are capable of doing this.39,40 Primarily because anchor- that are involved in tumor growth and progression. Such drugs work
age independent growth requires metabolic reprogramming, which by either blocking the target enzyme involved in the pathway or pro-
induce oxidative stress on the cells.41 A classic example of this meta- viding a metabolic product that alters tumor metabolism. Table 1 pro-
bolic reprogramming is reductive carboxylation of glutamine that vides a brief list of metabolism-based anti-cancer drugs along with
reduces excessive reactive oxygen species (ROS) in mitochondria.42 their targets.
This process converts glutamine derived α-ketoglutarate (αKG) to cit-
rate through cytosolic IDH1 enzyme. Another enzyme fatty acid
synthase (FASN) is essential in maintaining the IDH1 activity44 thus 5 | METABOLITE-BASED BIOMARKERS
indirectly regulating reductive carboxylation. Bueno et al., have FOR DIAGNOSIS, PROGNOSIS AND
recently showed pharmacological inhibition of FASN can prevent P ER S O N A LI Z E D C A N C E R T R E A T M E N T
tumor progression.43 Similarly, this reductive carboxylation pathway
was also found to be essential in maintaining cell proliferation under It is projected by 2030 around 17 million people would die per year
hypoxic conditions in renal cell carcinoma (RCC).44,45 Also, pentose from cancer.125 Discovery of sensitive biomarkers for cancer using a
46
phosphate pathway upregulation is observed in multiple cancer tailored strategy is now a focus in cancer research and can be utilized
types and is associated with anchorage independent growth, invasion as a detection tool for therapeutic targeting of metabolic enzymes.
and metastasis47 mainly observed in KRAS-induced anchorage- Early intervention in cancer treatment could lead to better outcomes
independent growth.48 Amino acid metabolism also play an important if these tactics are successfully applied. In future, diagnostic and prog-
role in Anchorage-Independent cell survival, it works by altering nostic biomarkers of disease will play an important role in individual-
sphingolipid diversity through deregulation of serine, alanine, and ized treatment and precision medicine. Analyzing metabolic
pyruvate.49 In conclusion decrypting this metabolic network involved phenotypes will allow for the categorization of patients by their meta-
in anchorage-independent growth can provide helpful insights in bolic profiles.
designing therapeutic strategies to prevent cancer metastasis. For example, larkin et al.,126 recently showed metabolomic bio-
markers in blood samples can be used to identify cancer with nonspe-
cific symptoms.126 A similar study by shi et al., identified
3 | METABOLIC REPROGRAMMING TO 61 differential metabolites in the plasma of children with medulloblas-
FORM METASTATIC TUMOR toma.127 Another study by Oshashi et al.,128 showed through meta-
bolic profiling, metabolite levels differ between head and neck
One of the leading causes of death in cancer patients is metastasis. squamous cell carcinoma (HNSCC) and normal tissues.128 Such
After extravasation, in order to survive cancer cells must reprogramme metabolite insights can significantly enhance diagnostic and prognos-
their metabolic status as per the new site which is distinct from that tic outcomes in cancer patients.
of the primary site. Thus, to adapt to this new microenvironment mul- Similar screening used for a large metabolomics investigation
tiple enzymes and pathways are deregulated. For example, in meta- identified 15 metabolites that differed between colorectal cancer
static breast cancer increased proline catabolism is observed via (CRC) tissue and normal tissue near the tumor.129 In addition to the
proline dehydrogenase (PRODH) upregulation compared to primary elevation of lactate, glycerol, and glutamate linked to the Warburg
breast cancer cases,50 Similarly asparagine is known to increase the effect, they found high levels of alanine, aspartate, palmitoleic acid,
metastatic and invasive capabilities in breast cancer cells. It works kynurenine, and uracil, as well as high levels of putrescine, cysteine,
4 of 13 SURI ET AL.

TABLE 1 List of metabolism-based anti-cancer drugs along with their targets

Drug Target Reference

α-Cyano-4-hydroxycinnamic acid Lactate dehydrogenase 57

58
Cinnamate Monocarboxylate transporters
59
Oxamate Lactate dehydrogenase
60
FX11 Lactate dehydrogenase
61
BPTES Glutaminase
62
JHU-083 Glutaminase
63
Cerulenin Fatty acid synthase
64
Orlistat Fatty acid synthase
65
GSK2194069 Fatty acid synthase
66
6-aminonicotinamide 6-phosphogluconate dehydrogenase
67
Polydatin Glucose-6-phosphate dehydrogenase
68
A939572 Stearoyl-CoA desaturase
69
Fatostatin Sterol regulatory element-binding protein
70
Soraphen A Acetyl-CoA carboxylase
71
BZ36 Stearoyl-CoA desaturase
72
Fasnall Fatty acid synthase
73
SB-204990 ATP-citrate lyase
74
Betulin Sterol regulatory element-binding protein
75
Triacscin C Acetyl-CoA synthase
76
Carolacton Methylene tetrahydrofolate dehydrogenase 1 & 2
77
AGF347 Serine hydroxymethyltransferase 1/2
78
LY345899 Methylene tetrahydrofolate dehydrogenase 2
79
Genistein-27 Hexokinase 2
80
Astragalin Hexokinase 2
81
Chrysin Hexokinase 2
82
Fasentin Glucose transporters
83
STF-31 Glucose transporters
84
Cytochalasin B Glucose transporters
85
Phloretin Glucose transporters
86
WZB117 Glucose transporters
87
Ritonavir Glucose transporters
88
Koningic acid Glyceraldehyde-3-phosphate dehydrogenase
89
Iodoacetate Glyceraldehyde-3-phosphate dehydrogenase
90
BAY1436032 Mutant IDH1/2
91
Uprosertib PI3K/Akt
91
Afuresertib PI3K/Akt
92,93
Dehydroepiandrosterone Glucose-6-phosphate dehydrogenase
91
Ipatasertib PI3K/Akt
94
AZD3965 Monocarboxylate transporters
95
Mitaplatin Pyruvate dehydrogenase kinase
96,97
Dichloroacetate Pyruvate dehydrogenase kinase
98
Silybin Glucose transporters
99,100
Resveratrol Hexokinase 2
101,102
3-bromopyruvate Hexokinase 2
103,104
2-deoxyglucose Hexokinase 2
105
Lonidamine Hexokinase 2
SURI ET AL. 5 of 13

TABLE 1 (Continued)

Drug Target Reference

106
Sorafenib PI3K/Akt
107
Lonidamine Complex II (OXPHOS)
108,109
CB-839 Glutaminase
110
TVB-2640 Fatty acid synthase
111
IDH305 Mutant IDH2
112
FT-2102 Mutant IDH1/2
113
6-Mercaptopurine Phosphoribosyl pyrophosphate amidotransferase
114
6-Thioguanine Phosphoribosyl pyrophosphate amidotransferase
115
5-Fluorouracil Thymidylate synthase
116
AG-221 (enasidenib) Mutant IDH1/2
117
AG-881 Mutant IDH1/2
118
AG-120 (ivosidenib) IDH1
119
Arsenic trioxide Complex IV (OXPHOS)
120
CPI-613 Pyruvate dehydrogenase /α-ketoglutarate dehydrogenase
121,122
Pemetrexed Thymidylate synthase, Dihydrofolate reductase, Glycinamide ribonucleotide formyltransferase
123
Capecitabine Thymidylate synthase
124
Methotrexate Thymidylate synthase, Dihydrofolate reductase

Abbreviation: IDH1, Isocitrate dehydrogenases 1; IDH2, Isocitrate dehydrogenases 2; OXPHOS, oxidative phosphorylation; PI3K, phosphatidylinositol
3-kinase; Akt, serine/threonine-specific protein kinases.

hypoxanthine and 2-aminobutyrate, and low levels of myo-inositol. In positive metastatic breast malignancies. Its overexpression can be
this study, four distinct CRC cohorts from Hangzhou, Shanghai, Bei- suppressed by the anti-HER2 drugs. Women with metastatic breast
jing, and United States were evaluated, therefore it was believed that cancer treated with paclitaxel and either anti-HER2 medication (lapati-
this panel could identify CRC in patients from different genetic ori- nib) or a placebo, had their serum samples examined for metabolic
gins, mutations, clinical stages, and geographic backgrounds. More- profiles. Comparing the paclitaxel plus lapatinib group, researchers
over, CRC with a recurrence time frame of 52.9 months and better observed patients with HER2 positive illness were more likely to
5-year survival rates could be distinguished from those with a shorter respond favorably to treatment compared to control group.133
time frame (25.9 months) cases. From this metabolomics study, a pos- Metabolomics can also be used to guide oncological surgery.
sible predictive metabolic signature for human colorectal cancer Recent advances in cancer surgery have been made possible by the
emerged. Another study by Cacciatore et al., profiled plasma samples introduction of the biomarker-based iKnife technology. This technol-
from 41 South African men with prostate cancer using nuclear mag- ogy involves the intra-operative, Rapid Evaporative Ionization Mass
netic resonance (NMR) spectroscopy.130 The inflammatory NMR Spectrometry (REIMS) coupled to electrosurgical tools to allow for
markers, GlycA (glycoproteins containing N-acetylglucosamine and N- near real-time characterization of margins during cautery-led tumor
acetylgalactosamine portion), and GlycB (glycoproteins containing N- dissection. Upon clinical validation of the metabolomics profiling
acetylneuraminic acid portion), were quantified along with several method, surgeons may immediately be able to determine if tissue is
other markers. They found the plasma of patients with aggressive and healthy or cancerous based on the “smoke-based” metabolomics pro-
metastatic prostate cancer have extremely high levels of GlycA and filing of healthy and diseased cells.134
GlycB supporting the use of plasma metabolome to improve the strat-
ification of patients with prostate cancer.
In an additional study, proton magnetic resonance spectroscopy 5.1 | Metabolic markers in the progression of
(MRS) was used to quantify 2-hydroxyglutarate (2HG) levels in the cancer
tumors of 30 patients. Researchers observed 2HG expression corre-
lated with IDH1 or IDH2 mutations, a common mutation in grade For early detection and screening of malignant tumors, numerous
2 and grade 3 gliomas.131 Gliomas with IDH-1 and IDH-2 gene muta- new tumor markers have emerged as a result of comprehensive
tions are more likely to have 2HG buildup.132 Such information could development in modern molecular biology techniques; nonetheless,
be exploited in designing more selective therapies. An example of the current conventional tumor indicators lack sensitivity and specificity
successful integration between clinical application and metabolomics for the early detection of malignancies. As an alternative metabolo-
is the study by Tenori et al.,133 Human epidermal growth factor recep- mics can be used to analyze and validate metabolites as biomarkers
tor 2 (HER2) is used as a biomarker for precision medicine in HER2 for early detection of malignancies or to correctly and sensitively
6 of 13 SURI ET AL.

TABLE 2 List of metabolites identified in pathological samples of cancer patients

Tumor types Special metabolites Metabolic pathways References

135
Lung and liver cancer Polyamine Metabolites Profiling in human plasma Polyamine metabolome pathways
and urine distinguish liver from lung cancer
136
Papillary thyroid micro Increased plasma concentrations of mannose, Glycolysis and amino acid synthesis
carcinoma glucose, pyruvate, and 3-hydroxybutyrate
130
Prostate Cancer NMR spectroscopy in plasma revealed high Carbohydrate portions of glycoproteins
levels of GlycA and GlycB associated with
aggressive prostate cancer subtypes.
137
Prostate cancer Urine metabolomic profile of prostate cancer Branched-chain amino acids Glucose metabolism
patients revealed increase in glutamate and in the TCA cycle
pseudouridine, and decrease in glycine,
dimethylglycine, fumarate and 4-imidazole-
acetate compared with benign disease.
138
Bladder cancer Urine metabolomics revealed high quantities of Metabolism of fatty acids and carnitine
acetyl carnitine and adipate in cancer patients.
139
Pancreatic cancer High level of Lycocholic acid; melatonin; hippuric Glycine and serine metabolism; sphingolipid and
acid; agmatine; sphinganine; beta-sitosterol; bile metabolism; purine and glycine
hypoxanthine; and spermidine; inosine and metabolism
creatine
140
Kidney cancer Urine metabolomics revealed high quantities of Acylcarnitines
acylcarnitines in cancer patients
141
Oral squamous cell Glycerol and leucine production are boosted Fatty acid, amino acid, and glycolysis
carcinoma along with the production of fatty acids and
steroid hormones
142
Malignant gliomas Metabolomics of human cerebrospinal fluid The citric acid cycle, gluconeogenesis, and
revealed high concentration of citric acid cycle pyrimidine metabolism, urea cycle
components in MG
143
Lung cancer Metabolomic in bronchoalveolar lavage fluid Glucose and fatty acid metabolism
revealed lower level of Inositol, phosphoric
acid, and palmitic acids in cancer patients
compared to healthy individuals.
144
Epithelial Ovarian cancer Urinary metabolomics profiling revealed increase Metabolism of nucleotides, histidine, tryptophan,
in (pseudouridine, N4-acetylcytidine), (L- and mucin
histidine, imidazol-5-yl-pyruvate),
(3-indolelactic acid), (3’-sialyllactose and
3-sialyl-N-acetyllactosamine) in EOC vs Benign
lesions.
145
Medullo- blastoma (MB) Multiomic analysis in Cerebrospinal Fluid Amino acid and lipid metabolism
revealed parallel increase in genes / protein
and metabolites induced by hypoxia in
recurrent MB compared to benign lesions.
The metabolites increased were: tryptophan,
methionine, serine and lysine, (known to be
induced upon hypoxia in CSF).

Abbreviation: NMR, Nuclear magnetic resonance; GlycA, glycoproteins containing N-acetylglucosamine and N-acetylgalactosamine portion;
GlycB, glycoproteins containing N-acetylneuraminic acid portion; TCA, tricarboxylic acid cycle; MG, Malignant gliomas; EOC, Epithelial Ovarian cancer;
MB, Medullo- blastoma; CSF, Cerebrospinal Fluid.

determine tumor progression in clinical context. An overview of (MS), metabolic flux analysis (MFA) etc. These techniques can be
metabolome investigations in different types of tumors is provided used alone or in combination to identify and quantify the levels of
in Table 2. various metabolites in biological samples. Currently metabolic profil-
ing is performed mainly by exploiting 2 principal techniques: NMR
and MS. Both these techniques require small amount of sample and
6 | D E T E C T I O N M E T H O DS can identify and quantify wide range of molecules simultaneously.146
NMR spectroscopy is a powerful tool for the detection of
There are several methods used for detection in metabolomics, metabolites in cancer. In this technique magnetic field and radio fre-
including nuclear magnetic resonance (NMR), mass spectrometry quency pulses are applied on the molecules to characterize the
SURI ET AL. 7 of 13

F I G U R E 2 Brief classification of detection methods used in metabolomics. (NMR: nuclear magnetic resonance, 1D-NMR: one-dimensional
nuclear magnetic resonance, 2D-NMR: two-dimensional nuclear magnetic resonance, 3D-NMR: three-dimensional nuclear magnetic resonance,
MS: mass spectrometry, IM-MS: ion mobility mass spectrometry, DI-MS: direct injection mass spectrometry, LC–MS: liquid chromatography mass
spectrometry, CE-MS: capillary electrophoresis mass spectrometry, GC–MS: gas chromatography mass spectrometry)

resonant frequency of that atomic nucleus. Thus, providing informa- advantages of using MS for metabolomics in cancer is its high sensi-
tion about the molecular structure, motion, and chemical environ- tivity and specificity, which allows for the detection of very small
ment of the molecules. Hydrogen is most commonly targeted amounts of a wide range of metabolites.153 MS analysis has been
147
nucleus in biological samples. NMR spectroscopy can be used to used to study a variety of cancer types, and also in identification of
identify and quantify a wide range of metabolites, including small different biomarkers in cancer.154 For example, Han et al., recently
molecules, lipids, and amino acids, in cancer cells and tissues. One of showed four lipid-based biomarkers that may be used for early diag-
the advantages of using NMR for metabolomics in cancer is its ability nosis in lung cancer.155 MS can be coupled with other analytical
to provide metabolic fingerprints that can be used to distinguish techniques. Based on this coupling MS can be further classified into
between normal and cancerous tissue.148 NMR spectroscopy (a) ion mobility-MS (IM-MS), (b) direct injection-MS (DI-MS),
can also be used to monitor changes in metabolite levels during (c) liquid chromatography-MS (LC–MS), (d) capillary electrophoresis-
cancer progression and treatment. It has also been used to study a MS (CE-MS) and (e) gas chromatography-MS (GC–MS). Such cou-
variety of cancer types, including colon,149 lung,150 colorectal,151 pling provides a more inclusive understanding of the metabolic vari-
endocrine,152 etc. NMR spectroscopy can also be used in conjunc- ations related with cancer.
tion with other techniques, such as mass spectrometry (MS), to pro- Apart from these 2 principal techniques other techniques like
vide a more comprehensive understanding of the metabolic changes metabolic flux analysis (MFA) are gaining popularity in cancer
associated with cancer. NMR Spectroscopy can further be broadly research. In this technique concurrent identification and quantification
classified into (a) one-dimensional, (b) two-dimensional, and of metabolic fluxes are interpreted numerically using stoichiometric
(c) three-dimensional NMR methods (1D-NMR, 2D-NMR, and 3D- models. This permits study on huge set of reactions (e.g., transport of
NMR) (Figure 2). Limitations for NMR include initial high start-up metabolites, anabolic reactions, catabolic reactions etc.) that define
cost and requirement of high user skills. the make-up and metabolism in malignant cells.156,157 Figure 2
On the other hand, MS is a destructive method that relies upon broadly classifies these detection methods. Overall, choosing and
the generation of gas phase ions. These ions are then separated using the right techniques in detection of metabolites in cancer can
depending on their mass-to-charge ratio and the amount of ioniza- provide valuable insights into the metabolic changes associated with
tion at each point in time is detected. This data can be analyzed to cancer progression and treatment, and may aid in the development of
determine the chemical composition of the samples. One of the new diagnostic and therapeutic strategies for cancer.
8 of 13 SURI ET AL.

7 | T H E F U T U R E O F M E T A B O LO M I C S I N cycles. Overcoming these hurdles can greatly benefit clinical applica-

ONCOLOGY tion of metabolomics in the long run.
Metabolomics can make cancer precision medicine more feasible.
Metabolomics, encompasses a wide range of metabolite analysis, pat- Prior to moving into in vivo testing, in-silico models can be employed
tern identification, and statistical analysis. For prognostic or predictive to understand the effects of medicines on metabolic characteristics.
interpretation of illness status, metabolic biomarkers can be widely Metabolomics has opened new avenues for cancer research and is
employed in the clinical setting. Multivariate biomarkers, such as can- already influencing cancer diagnosis and treatment in number of dif-
cer fingerprint, profile or signature, should be identified using metabo- ferent ways.161
158
lomics as a biomarker discovery tool. Oncologists may soon be able
to detect cancer earlier, when it is still treatable, evaluate the aggres-
siveness of cancer for better prognosis and treatment, and forecast 8 | CONC LU SION
therapeutic effectiveness with the use of this technology. Despite the
fact that advanced analytic procedures are required, these signatures Although in infancy metabolomics can make a substantial impact on per-
are practical and accurate. Metabolomics has been shown to be a reli- sonalized cancer medicine. Using metabolomics, many cancer pheno-
159
able diagnostic tool for leukemia and breast cancer, respectively. types can be accurately described with individualized metabolic markers.
Genome microarrays and serum protein profiles have been used in This can be used to identified treatment options and/or predict respon-
the past to diagnose colon and ovarian cancers, respectively. Metabo- siveness to treatments. Also, it will be vital to combine the outcomes of
lomics can be helpful in malignancies that are difficult to diagnose. metabolomic assessments with other omics techniques to characterized
Ovarian cancer has already been diagnosed using metabolomic pro- the entire spectrum of the malignant phenotypes. Technical challenges
files from serum.160 like database management, cost and methodical knowhow still persist.
Ascitic fluid, pancreatic secretions, and bronchoalveolar or pleural Overcoming these challenges in near further can help in designing new
fluid may all be useful in the diagnosis of cancers in future. When no treatment régimes with increased sensitivity and specificity.
other test can provide a conclusive response, metabolomics may save
time, money and effort by identifying pathognomonic patterns in
these fluids and validating them. Even more promising is the prospect ETHICAL STATEMENT
of screening cancers through conveniently accessible bodily fluid.
Development and application of metabolite spectrum databases, Ethical Approval and Consent to participate is not required for such
cross-validation between NMR and MS metabolites, and correlation type of studies. Also, the review has been done in accordance to ethi-
with other quantitative assays will all play a role in the future of cal guidelines and that is has been performed in a responsible way,
metabolite research. Finally, the results of metabolomic analyses must with no misconduct.
be integrated with results from other omics technologies in order to
characterize the whole malignant phenotypic range. CONFLIC T OF INTER E ST STATEMENT
Misdiagnosis, recurrence of symptoms, and undesirable side The authors have stated explicitly that there are no conflicts of inter-
effects can restrict the clinical efficacy of current clinical practice in ill- est in connection with this article.
ness control. Biomarkers associated with disease-specific alterations
can be examined to establish a tailored method for treating and moni- AUTHOR CONTRIBU TIONS
toring disease development by comparing the metabolomic profiles of Gurparsad Singh Suri: Conceptualization (equal); investigation (equal);
two or more disease phenotypes. methodology (supporting); project administration (equal); resources
To date, metabolomics implementation in clinic is still not com- (equal); supervision (equal); validation (equal); visualization (equal);
mon. There are still open problems to be solved including the scalabil- writing – original draft (equal); writing – review and editing (equal).
ity of data interpretation and standardization of sample handling Gurleen Kaur: Conceptualization (supporting); investigation (support-
practice. The successful transition from research tool to a clinically ing); resources (supporting); visualization (supporting). giuseppina car-
implemented tool requires cooperation between several disciplines. bone: Conceptualization (equal); investigation (equal); project
To date the major problems to be solved are related to equipment administration (equal); supervision (lead); writing – review and editing
design, experimental validation, standardization of methods, and data (equal). Dheeraj Shinde: Conceptualization (equal); data curation
interpretability in a reproducible fashion. Strict protocols are needed (equal); formal analysis (equal); investigation (equal); methodology
to eliminate any potential biases that may arise from using metabolo- (equal); project administration (equal); resources (equal); writing –
mics on a variety of biological fluids, including cerebrospinal fluid original draft (lead); writing – review and editing (lead).
(CSF), urine, plasma, sweat etc. The metabolomics profile can be
highly variable if the time interval between sample collection and pro- DATA AVAILABILITY STAT EMEN T
cessing is not strictly regulated. Furthermore, the quality of the data Data sharing is not applicable to this article as no new data were cre-
obtained is harmed by incorrect storage and repeated freeze–thaw ated or analyzed in this study.
SURI ET AL. 9 of 13

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