Abstract: Prostate cancer (PCa) is the second most common male cancer worldwide and the fifth leading cause of death from cancer in men. Early detection and risk stratification is the most effective way to improve the survival of PCa patients. Current PCa biomarkers lack sufficient sensitivity and specificity to cancer. Metabolite biomarkers are evolving as a new diagnostic tool. This review is aimed to evaluate the potential of metabolite biomarkers for early detection, risk assessment, and monitoring of PCa. Of the 154 identified publications, 27 and 38 were original papers on urine and serum metabolomics, respectively. Nuclear magnetic resonance (NMR) is a promising method for measuring concentrations of metabolites in complex samples with good reproducibility, high sensitivity, and simple sample processing. Especially urine-based NMR metabolomics has the potential to be a cost-efficient method for the early detection of PCa, risk stratification, and monitoring treatment efficacy.

核磁共振波谱作为提高前列腺癌早期诊断和危险度分级的新方法

[1]Armitage, E.G., Barbas, C., 2014. Metabolomics in cancer biomarker discovery: current trends and future perspectives. J. Pharm. Biomed. Anal., 87:1-11.

[2]Austdal, M., Tangerås, L.H., Skråstad, R.B., et al., 2015. First trimester urine and serum metabolomics for prediction of preeclampsia and gestational hypertension: a prospective screening study. Int. J. Mol. Sci., 16(9):21520-21538.

[3]Baade, P.D., Youlden, D.R., Cramb, S.M., et al., 2013. Epidemiology of prostate cancer in the Asia-Pacific region. Prostate Int., 1(2):47-58.

[4]Bansal, N., Gupta, A., Mitash, N., et al., 2013. Low- and high-grade bladder cancer determination via human serum-based metabolomics approach. J. Proteome Res., 12(12):5839-5850.

[5]Bansal, N., Gupta, A., Sankhwar, S.N., 2015. Proteometabolomics of bladder cancer: current and future prospects. Cancer Biomark., 15(4):339-348.

[6]Beger, R.D., 2013. A review of applications of metabolomics in cancer. Metabolites, 3(3):552-574.

[7]Behr, S.C., Aggarwal, R., Seo, Y., et al., 2016. A feasibility study showing [⁶⁸Ga] citrate PET detects prostate cancer. Mol. Imaging Biol., 18(6):946-951.

[8]Bertini, I., Cacciatore, S., Jensen, B.V., et al., 2012. Metabolomic NMR fingerprinting to identify and predict survival of patients with metastatic colorectal cancer. Cancer Res., 72(1):356-364.

[9]Brawley, O.W., 2012. Prostate cancer epidemiology in the United States. World J. Urol., 30(2):195-200.

[10]Carrola, J., Rocha, C.M., Barros, A.S., et al., 2011. Metabolic signatures of lung cancer in biofluids: NMR-based metabonomics of urine. J. Proteome Res., 10(1):221-230.

[11]Center, M.M., Jemal, A., Lortet-Tieulent, J., et al., 2012. International variation in prostate cancer incidence and mortality rates. Eur. Urol., 61(6):1079-1092.

[12]Chan, A.W., Mercier, P., Schiller, D., et al., 2016. ¹H-NMR urinary metabolomic profiling for diagnosis of gastric cancer. Br. J. Cancer, 114(1):59-62.

[13]Chan, E.C., Pasikanti, K.K., Hong, Y., et al., 2015. Metabonomic profiling of bladder cancer. J. Proteome Res., 14(2):587-602.

[14]Chen, K.Y., Liu, X., Bu, P., et al., 2014. A metabolic signature of colon cancer initiating cells. The 36th Annual International Conference of the IEEE, Engineering in Medicine and Biology Society (EMBC), Chicago, IL, USA. IEEE, p.4759-4762.

[15]Chen, W., Zheng, R., Baade, P.D., et al., 2016. Cancer statistics in China, 2015. CA Cancer J. Clin., 66(2):115-132.

[16]Coffey, D.S., 2001. New insights and methodologies are needed to solve the many epidemiologic enigmas of prostate cancer. Epidemiol. Rev., 23(1):1.

[17]Davis, V.W., Schiller, D.E., Eurich, D., et al., 2013. Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature. Ann. Surg. Oncol., 20(S3):S415-S423.

[18]DeSantis, C.E., Lin, C.C., Mariotto, A.B., et al., 2014. Cancer treatment and survivorship statistics, 2014. CA Cancer J. Clin., 64(4):252-271.

[19]Dona, A.C., Jimenez, B., Schafer, H., et al., 2014. Precision high-throughput proton NMR spectroscopy of human urine, serum, and plasma for large-scale metabolic phenotyping. Anal. Chem., 86(19):9887-9894.

[20]Doskocz, M., Marchewka, Z., Jeż, M., et al., 2015. Preliminary study on J-resolved NMR method usability for toxic Kidney’s injury assessment. Adv. Clin. Exp. Med., 24(4):629-635.

[21]Drake, R.R., Elschenbroich, S., Lopez-Perez, O., et al., 2010. In-depth proteomic analyses of direct expressed prostatic secretions. J. Proteome Res., 9(5):2109-2116.

[22]Duarte, I.F., Diaz, S.O., Gil, A.M., 2014. NMR metabolomics of human blood and urine in disease research. J. Pharm. Biomed. Anal., 93:17-26.

[23]Duijvesz, D., Luider, T., Bangma, C.H., et al., 2011. Exosomes as biomarker treasure chests for prostate cancer. Eur. Urol., 59(5):823-831.

[24]Dunn, W.B., Erban, A., Weber, R.J.M., et al., 2013. Mass appeal: metabolite identification in mass spectrometry-focused untargeted metabolomics. Metabolomics, 9(S1):44-66.

[25]Edmands, W.M., Beckonert, O.P., Stella, C., et al., 2011. Identification of human urinary biomarkers of cruciferous vegetable consumption by metabonomic profiling. J. Proteome Res., 10(10):4513-4521.

[26]Ellis, J.K., Athersuch, T.J., Thzmas, L.D., et al., 2012. Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population. BMC Med., 10:61.

[27]Emwas, A.H.M., Salek, R.M., Griffin, J.L., et al., 2013. NMR-based metabolomics in human disease diagnosis: applications, limitations, and recommendations. Metabolomics, 9(5):1048-1072.

[28]Emwas, A.H., Roy, R., McKay, R.T., et al., 2016. Recommendations and standardization of biomarker quantification using NMR-based metabolomics with particular focus on urinary analysis. J. Proteome Res., 15(2):360-373.

[29]Ervik, M., Lam, F., Ferlay, J., et al., 2016. Cancer Today. International Agency for Research on Cancer, Lyon, France. http://www.iarc.fr

[30]Felgueiras, J., Silva, J.V., Fardilha, M., 2014. Prostate cancer: the need for biomarkers and new therapeutic targets. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 15(1):16-42.

[31]Ferreiro-Vera, C., Priego-Capote, F., Luque de Castro, M.D., 2012. Comparison of sample preparation approaches for phospholipids profiling in human serum by liquid chromatography-tandem mass spectrometry. J. Chromatogr. A, 1240:21-28.

[32]Frantzi, M., Latosinska, A., Merseburger, A.S., et al., 2015. Recent progress in urinary proteome analysis for prostate cancer diagnosis and management. Expert Rev. Mol. Diagn., 15(12):1539-1554.

[33]Fukuhara, K., Ohno, A., Ota, Y., et al., 2013. NMR-based metabolomics of urine in a mouse model of Alzheimer’s disease: identification of oxidative stress biomarkers. J. Clin. Biochem. Nutr., 52(2):133-138.

[34]Giskeødegård, G.F., Davies, S.K., Revell, V.L., et al., 2015a. Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation. Sci. Rep., 5:14843.

[35]Giskeødegård, G.F., Hansen, A.F., Bertilsson, H., et al., 2015b. Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia. Br. J. Cancer, 113(12):1712-1719.

[36]Gupta, A., Gupta, S., Mahdi, A.A., 2015. ¹H NMR-derived serum metabolomics of leukoplakia and squamous cell carcinoma. Clin. Chim. Acta, 441:47-55.

[37]Huang, Z., Lin, L., Gao, Y., et al., 2011. Bladder cancer determination via two urinary metabolites: a biomarker pattern approach. Mol. Cell. Proteomics, 10:M111.007922.

[38]Ibrahim, B., Marsden, P., Smith, J.A., et al., 2013. Breath metabolomic profiling by nuclear magnetic resonance spectroscopy in asthma. Allergy, 68(8):1050-1056.

[39]Issaq, H.J., Nativ, O., Waybright, T., et al., 2008. Detection of bladder cancer in human urine by metabolomic profiling using high performance liquid chromatography/mass spectrometry. J. Urol., 179(6):2422-2426.

[40]Jahn, J.L., Giovannucci, E.L., Stampfer, M.J., 2015. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the Prostate-specific Antigen-era. Int. J. Cancer, 137(12):2795-2802.

[41]James, E.L., Parkinson, E.K., 2015. Serum metabolomics in animal models and human disease. Curr. Opin. Clin. Nutr. Metab. Care, 18(5):478-483.

[42]Jemal, A., Fedewa, S.A., Ma, J., et al., 2015. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA, 314(19):2054-2061.

[43]Jiang, T., Lin, Y., Yin, H., et al., 2015. Correlation analysis of urine metabolites and clinical staging in patients with ovarian cancer. Int. J. Clin. Exp. Med., 8(10):18165-18171.

[44]Jobard, E., Blanc, E., Négrier, S., et al., 2015. A serum metabolomic fingerprint of bevacizumab and temsirolimus combination as first-line treatment of metastatic renal cell carcinoma. Br. J. Cancer, 113(8):1148-1157.

[45]Jung, J., Jung, Y., Bang, E.J., et al., 2014. Noninvasive diagnosis and evaluation of curative surgery for gastric cancer by using NMR-based metabolomic profiling. Ann. Surg. Oncol., 21(S4):S736-S742.

[46]Kim, K.B., Yang, J.Y., Kwack, S.J., et al., 2010. Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model. J. Toxicol. Environ. Health A, 73:1420-1430.

[47]Kim, K.B., Yang, J.Y., Kwack, S.J., et al., 2013. Potential metabolomic biomarkers for evaluation of adriamycin efficacy using a urinary ¹H-NMR spectroscopy. J. Appl. Toxicol., 33(11):1251-1259.

[48]Kim, Y., Ignatchenko, V., Yao, C.Q., et al., 2012. Identification of differentially expressed proteins in direct expressed prostatic secretions of men with organ-confined versus extracapsular prostate cancer. Mol. Cell. Proteomics, 11(12):1870-1884.

[49]Kline, E.E., Treat, E.G., Averna, T.A., et al., 2006. Citrate concentrations in human seminal fluid and expressed prostatic fluid determined via ¹H nuclear magnetic resonance spectroscopy outperform prostate specific antigen in prostate cancer detection. J. Urol., 176(5):2274-2279.

[50]Klotz, L., Vesprini, D., Sethukavalan, P., et al., 2015. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J. Clin. Oncol., 33(3):272-277.

[51]Kumar, D., Gupta, A., Mandhani, A., et al., 2015. Metabolomics-derived prostate cancer biomarkers: fact or fiction. J. Proteome Res., 14(3):1455-1464.

[52]Kumar, D., Gupta, A., Nath, K., 2016a. NMR-based metabolomics of prostate cancer: a protagonist in clinical diagnostics. Expert Rev. Mol. Diagn., 16(6):651-661.

[53]Kumar, D., Gupta, A., Mandhani, A., et al., 2016b. NMR spectroscopy of filtered serum of prostate cancer: a new frontier in metabolomics. Prostate, 76(12):1106-1119.

[54]Lin, P.H., Aronson, W., Freedland, S.J., 2015. Nutrition, dietary interventions and prostate cancer: the latest evidence. BMC Med., 13:3.

[55]Lodi, A., Tiziani, S., Khanim, F.L., et al., 2013. Proton NMR-based metabolite analyses of archived serial paired serum and urine samples from myeloma patients at different stages of disease activity identifies acetylcarnitine as a novel marker of active disease. PLoS ONE, 8:e56422.

[56]Mathé, E.A., Patterson, A.D., Haznadar, M., et al., 2014. Noninvasive urinary metabolomic profiling identifies diagnostic and prognostic markers in lung cancer. Cancer Res., 74(12):3259-3270.

[57]McDunn, J.E., Li, Z., Adam, K.P., et al., 2013. Metabolomic signatures of aggressive prostate cancer. Prostate, 73(14):1547-1560.

[58]Moller, H., Roswall, N., van Hemelrijck, M., et al., 2015. Prostate cancer incidence, clinical stage and survival in relation to obesity: a prospective cohort study in Denmark. Int. J. Cancer, 136(8):1940-1947.

[59]Motegi, H., Tsuboi, Y., Saga, A., et al., 2015. Identification of reliable components in multivariate curve resolution-alternating least squares (MCR-ALS):a data-driven approach across metabolic processes. Sci. Rep., 5(1):15710.

[60]Motta, A., Paris, D., Melck, D., et al., 2012. Nuclear magnetic resonance-based metabolomics of exhaled breath condensate: methodological aspects. J. Eur. Respir., 39(2):498-500.

[61]Moyer, V.A., 2012. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann. Intern. Med., 157:120-134.

[62]Nagana Gowda, G.A., Raftery, D., 2015. Can NMR solve some significant challenges in metabolomics? J. Magn. Reson., 260:144-160.

[63]Neuhaus, J., Schiffer, E., von Wilcke, P., et al., 2013. Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease. PLoS ONE, 8(6):e67514.

[64]Öman, T., Tessem, M.B., Bathen, T.F., et al., 2014. Identification of metabolites from 2D ¹H-¹³C HSQC NMR using peak correlation plots. BMC Bioinformatics, 15:413.

[65]Pasikanti, K.K., Esuvaranathan, K., Hong, Y., et al., 2013. Urinary metabotyping of bladder cancer using two-dimensional gas chromatography time-of-flight mass spectrometry. J. Proteome Res., 12(9):3865-3873.

[66]Patel, S., Ahmed, S., 2015. Emerging field of metabolomics: big promise for cancer biomarker identification and drug discovery. J. Pharm. Biomed. Anal., 107:63-74.

[67]Prensner, J.R., Rubin, M.A., Wei, J.T., et al., 2012. Beyond PSA: the next generation of prostate cancer biomarkers. Sci. Transl. Med., 4(127):127rv3.

[68]Principe, S., Jones, E.E., Kim, Y., et al., 2013. In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics, 13:1667-1671.

[69]Roberts, M.J., Schirra, H.J., Lavin, M.F., et al., 2011. Metabolomics: a novel approach to early and noninvasive prostate cancer detection. Korean J. Urol., 52(2):79-89.

[70]Roine, A., Veskimäe, E., Tuokko, A., et al., 2014. Detection of prostate cancer by an electronic nose: a proof of principle study. J. Urol., 192(1):230-234.

[71]Ronquist, G., Brody, I., 1985. The prostasome: its secretion and function in man. Biochim. Biophys. Acta, 822(2):203-218.

[72]Salagierski, M., Schalken, J.A., 2012. Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2:ERG gene fusion. J. Urol., 187(3):795-801.

[73]Salami, S.S., Schmidt, F., Laxman, B., et al., 2013. Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer. Urol. Oncol., 31(5):566-571.

[74]Schroder, F.H., Hugosson, J., Roobol, M.J., et al., 2012. Prostate-cancer mortality at 11 years of follow-up. N. Engl. J. Med., 366(11):981-990.

[75]Shipitsin, M., Small, C., Choudhury, S., et al., 2014. Identification of proteomic biomarkers predicting prostate cancer aggressiveness and lethality despite biopsy-sampling error. Br. J. Cancer, 111(6):1201-1212.

[76]Siegel, R.L., Miller, K.D., Jemal, A., 2016. Cancer statistics, 2016. CA Cancer J. Clin., 66(1):7-30.

[77]Smolinska, A., Blanchet, L., Buydens, L.M., et al., 2012. NMR and pattern recognition methods in metabolomics: from data acquisition to biomarker discovery: a review. Anal. Chem. Acta, 750:82-97.

[78]Soininen, P., Kangas, A.J., Würtz, P., et al., 2015. Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics. Circ. Cardiovasc. Genet., 8(1):192-206.

[79]Sokolenko, S., McKay, R., Blondeel, E.J.M., et al., 2013. Understanding the variability of compound quantification from targeted profiling metabolomics of 1D-¹H-NMR spectra in synthetic mixtures and urine with additional insights on choice of pulse sequences and robotic sampling. Metabolomics, 9(4):887-903.

[80]Srivastava, S., Roy, R., Singh, S., et al., 2010. Taurine—a possible fingerprint biomarker in non-muscle invasive bladder cancer: a pilot study by ¹H NMR spectroscopy. Cancer Biomark., 6(1):11-20.

[81]Stephens, N.S., Siffledeen, J., Su, X., et al., 2013. Urinary NMR metabolomic profiles discriminate inflammatory bowel disease from healthy. J. Crohn’s Colitis, 7(1):e42-e48.

[82]Struck-Lewicka, W., Kordalewska, M., Bujak, R., et al., 2015. Urine metabolic fingerprinting using LC-MS and GC-MS reveals metabolite changes in prostate cancer: a pilot study. J. Pharm. Biomed. Anal., 111:351-361.

[83]Thapar, R., Titus, M.A., 2014. Recent advances in metabolic profiling and imaging of prostate cancer. Curr. Metabolomics, 2(1):53-69.

[84]Trock, B.J., 2014. Circulating biomarkers for discriminating indolent from aggressive disease in prostate cancer active surveillance. Curr. Opin. Urol., 24(3):293-302.

[85]Trovato, F.M., Tognarelli, J.M., Crossey, M.M., et al., 2015. Challenges of liver cancer: future emerging tools in imaging and urinary biomarkers. World J. Hepatol., 7(26):2664-2675.

[86]Van, Q.N., Veenstra, T.D., Issaq, H.J., 2011. Metabolic profiling for the detection of bladder cancer. Curr. Urol. Rep., 12(1):34-40.

[87]Villaseñor, A., Kinross, J.M., Li, J.V., et al., 2014. ¹H NMR global metabolic phenotyping of acute pancreatitis in the emergency unit. J. Proteome Res., 13(12):5362-5375.

[88]Wang, X., Zhang, A., Sun, H., 2013. Power of metabolomics in diagnosis and biomarker discovery of hepatocellular carcinoma. Hepatology, 57(5):2072-2077.

[89]Warburg, O., 1956. On the origin of cancer cells. Science, 123(3191):309-314.

[90]Ward, J.L., Baker, J.M., Miller, S.J., et al., 2010. An inter-laboratory comparison demonstrates that [¹H]-NMR metabolite fingerprinting is a robust technique for collaborative plant metabolomic data collection. Metabolomics, 6(2):263-273.

[91]Wei, J.T., Feng, Z., Partin, A.W., et al., 2014. Can urinary PCA3 supplement PSA in the early detection of prostate cancer? J. Clin. Oncol., 32(36):4066-4072.

[92]Yang, M., Vousden, K.H., 2016. Serine and one-carbon metabolism in cancer. Nat. Rev. Cancer, 16(10):650-662.

[93]Yap, I.K., Angley, M., Veselkov, K.A., et al., 2010a. Urinary metabolic phenotyping differentiates children with autism from their unaffected siblings and age-matched controls. J. Proteome Res., 9(6):2996-3004.

[94]Yap, I.K., Brown, I.J., Chan, Q., et al., 2010b. Metabolome-wide association study identifies multiple biomarkers that discriminate north and south Chinese populations at differing risks of cardiovascular disease: INTERMAP study. J. Proteome Res., 9(12):6647-6654.

[95]Zhang, J., Wei, S., Liu, L., et al., 2012. NMR-based metabolomics study of canine bladder cancer. Biochim. Biophys. Acta, 1822(11):1807-1814.

[96]Zhang, X., Xu, L., Shen, J., et al., 2013. Metabolic signatures of esophageal cancer: NMR-based metabolomics and UHPLC-based focused metabolomics of blood serum. Biochim. Biophys. Acta, 1832(8):1207-1216.

[97]Zhao, W.X., Wang, B., Zhang, L.Y., et al., 2015. Analysis on the metabolite composition of serum samples from patients with papillary thyroid carcinoma using nuclear magnetic resonance. Int. J. Clin. Exp. Med., 8(10):18013-18022.

[98]Zhou, Y., Song, R., Zhang, Z., et al., 2016. The development of plasma pseudotargeted GC-MS metabolic profiling and its application in bladder cancer. Anal. Bioanal. Chem., 408(24):6741-6749.

[99]Zhu, Y., Wang, H.K., Qu, Y.Y., et al., 2015. Prostate cancer in East Asia: evolving trend over the last decade. Asian J. Androl., 17(1):48-57.

[100]Zijlstra, C., Stoorvogel, W., 2016. Prostasomes as a source of diagnostic biomarkers for prostate cancer. J. Clin. Invest., 126(4):1144-1151.

[101]Zou, X., Holmes, E., Nicholson, J.K., et al., 2016. Automatic spectroscopic data categorization by clustering analysis (ASCLAN):a data-driven approach for distinguishing discriminatory metabolites for phenotypic subclasses. Anal. Chem., 88(11):5670-5679.