Potential role of metabolomics in diagnosis and surveillance of gastric cancer

Table 1 Marker metabolites between gastric cancer and healthy controls

Ref.	Animal vs humananalytical platform	Sample typegroups	Statistically significant metabolites identified (P < 0.05)(up or down indicate levels in cancer group)
Hu et al[24], 2011	Animal (mice)Gas chromatography,Mass Spectrometry	UrineMetastasis group (n = 8)Non-metastasis group (n = 8)Normal group (n = 8)	Carbohydrates: Anaerobic respiration: lactate up TCA cycle: citric acid up, malic acid upNucleic acids: uric acid upLipids: hexadecanoic acid upOthers: butanoic acid, propanoic acid, glycerol, pyrimidine, glycerol all up
Hirayama et al[26], 2009	HumanCapillary electrophoresisMass spectrometry	Resected stomach specimens (n = 12)GC tissue Adjacent normal tissue	Carbohydrates: Anaerobic respiration: lactate up Glycolysis: glucose down TCA cycle: citric acid down, malic acid/fumarate upAmino acids: 19 elevated, except glutamine (no change)Nucleic acids: GMP up
Song et al[27], 2011	HumanGas chromatography,Mass spectrometry	Resected stomach specimens (n = 30)GC tissue Adjacent normal tissue	Carbohydrates: TCA cycle: fumarate up, alpha-ketoglutarate up Lipids: up: xylonic acid, octadecanoic acid Down: 9-hexadecanoic acid, cis-vaccenic acid, arachidonic acid, 9-octadecenamide, squaleneOthers: up: valeric acid, benzenepropanoic acid, 1-phenanthrene-carboxylic acid down: 3-hydroxybutanoic acid
Cai et al[28], 2010	HumanGas chromatography,Mass spectrometry	Resected stomach specimens (n = 65)GC tissue Adjacent normal tissue	Carbohydrates: Anaerobic respiration: lactate up Glycolysis: up: fructose, glyceraldehyde, pyruvate TCA cycle: up isocitric acid, fumarate down
Aa et al[29], 2012	HumanGas chromatography, mass spectrometry	Plasma and tissuePre-op GC (n = 17)Post-op GC (n = 15)CSG (n = 20)	Tissue samples show larger variations between GC and CSG than plasma samples (up/down show change for tissue CG compared to tissue CSG) Carbohydrates: Anaerobic respiration: lactate up Glycolysis: glucose down, fructose-6-phosphate down TCA cycle: citrate up, malate up, fumarate up Other: maltose down, ribose down, glyceric acid-2,3-diphosphate downAmino acids: cysteine upLipids: up: docosahexanoic acid, heptanoic acid, 9-Z-hexadecenoic acid, beta-hydroxybutyratedown: cholesterolNucleic acids: uracil up, uridine downOthers: up: 2-aminoadipate, monomethylphosphate down: inositol, ribitol, beta-D-methylglucopyranoside
Wu et al[31], 2010	HumanGas chromatography,Mass spectrometry	Resected stomach specimens (n = 18)GC tissue Adjacent normal tissue	Carbohydrates: up: galactofuranosidedown: L-altrose, L-mannofuranose, D-ribofuranoseAmino acids: up: L-valine, L-isoleucine, serine, L-glutamineDown: phosphoserineOthers: up: heptanedioic acid, propanoic acid, phenanthrenol, butanetriol, acetamide, butenoic acid, oxazolethione, naphthalene down: myo-inositol
Song et al[32], 2012	HumanGas chromatography,Mass spectrometry	SerumGC (n = 30)Healthy (n = 30)	Carbohydrates: down: fumarate, 2-O-mesyl arabinoseAmino acids: up: valine, sarcosine Down: glutamine, hexanedioic acidLipids: down: 9, 12-octadecadienoic acid, 9-octadecenoic acid, trans-13-octadecenoic acid, nonhexacontanoic acidCholesterol: up cholesta-3,5-diene, cholesterol, pentafluoropropionate, cholesterol, cholest-5- en-3-ol
Ikeda et al[36], 2012	HumanGas chromatography,Mass spectrometry	SerumGC (n = 11)Healthy (n = 12)	Carbohydrates: Glycolysis: down: pyruvateOthers: up: 3-hydroxypropionic acid Down: 3-hydroxyisobutyric acid, octanoic acid, phosphoric acid
Kim et al[38], 2010	Animal (mice)1H-NMR	UrineGC (n = 10)Healthy (n = 10)	Carbohydrates: TCA cycle: Citrate up, 2-oxoglutarate upOthers: up: 3-indoxylsulfate Down: taurine, trimethylamine, oxaloacetate, TMAO, hippurate
Miyagi et al[41], 2011	HumanLiquid chromato-graphy, mass spectrometryelectrospray ionization	SerumGC (n = 199)Healthy (n = 985)	Amino acids only:up: serine, glutamine, ornithine, prolinedown: asparagine, valine, methionine, tyrosine, histidine, tryptophan, phenylalanine, leucine

CSG: Chronic superficial gastritis; GC: Gastric cancer; GMP; Guanosine monophosphate;

¹H-NMR: Proton nuclear magnetic resonance spectroscopy; TCA: Tricarboxylic acid cycle; TMAO: Trimethylamine-N-oxide.

Table 2 Marker metabolites between stages of gastric cancer

Ref.	Animal vs humanplatform utilized	Sample typegroups	Statistically significant metabolites identified (P < 0.05)
Hu et al[24], 2011	Animal (mice) Gas chromatography, mass spectrometry	Urine Metastasis group (n = 8) Non-metastasis group (n = 8) Normal group (n = 8)	Up/down for metastasis group compared to non-metastasis: Amino acids: alanine, L-proline, L-threonine all down Others: butanoic acid down, glycerol down, butanedioic acid up, myo-inositol up
Song et al[27], 2011	Humans Gas chromatography, mass spectrometry	Resected stomach specimens (n = 30) Gastric Cancer tissue, Adjacent normal tissue	Did not find metabolite differences between TNM stages
Wu et al[31], 2010	Human Gas chromatography, mass spectrometry	Resected stomach specimens (n = 18) Gastric Cancer tissue -T1/T2 stage (n = 5) -T3/T4 stage (n = 13)	Up/down for T3/T4 metabolites compared to T1/T2 Amino acids: L-cysteine, L-tyrosine both up Nucleic acids: hypoxanthine up Others: butanoic acid, phenanthrenol both down
Yu et al[33], 2011	Human Gas chromatography, mass spectrometry	Plasma (n = 80) CSG (n = 19) CAG (n = 13) IM (n = 10) DYS (n = 22) Pre-op GC (n = 9 pre-op) - 4-6 wk post-op (n = 13)	Up/down for pre-op GC compared to CSG: Carbohydrates: threonate down Amino acids: up: ornithine, pyroglutamate, glutamate, asparagine Lipids: 11-eicosenoic acid up Nucleic acids: urate up Other: up: 1-monohexadecanoyl-glycerol, gamma-tocopherol, 2- hydroxybutyrate, azelaic acid
Chen et al[35], 2010	Animal (mice) Gas chromatography, mass spectrometry	GC metastasis group (n = 8) GC non-metastasis group (n = 8)	Up/down for metastasis group compared to non-metastasis: Carbohydrates: Anaerobic respiration: lactate up Glycolysis: glucose down TCA cycle: malic acid up, succinate down Amino acids: up: alanine, glycine, valine, proline, serine, leucine, dimethylglycine, aspartic acid, phosphoserine, glutamate, lysine, arginine down: isoleucine, methionine, threonine, glutamine Nucleic acids: hypoxanthine down, pyrimidine up Others: up: propanedioic acid, pyrrolidine, inositol, docosanoic acid, octadecanoic acid down: propanamide, butanedioic acid
Ikeda et al[36], 2012	Human Gas chromatography, mass spectrometry	Serum GC (n = 11) Stages I-IV	3-hydroxypropionic acid up, pyruvic acid down (statistically significant only in Stage I GC)

CAG: Chronic atrophic gastritis; CSG: Chronic superficial gastritis; DYS: Dysplasia; GC: Gastric cancer; IM: Intestinal metaplasia; T1/T2/T3/T4: Tumour stage 1/2/3/4; TCA: Tricarboxylic acid cycle; TNM: Tumour node metastasis classification.