Skip to main content
SpringerLink
Log in

Serum metabolomics analysis for early detection of colorectal cancer

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Although colorectal cancer (CRC) is one of the most common causes of cancer mortality, early-stage detection improves survival rates dramatically. Because cancer impacts important metabolic pathways, the alteration of metabolite levels as a potential biomarker of early-stage cancer has been the focus of many studies. Here, we used CE-TOFMS, a novel and promising method with small injection volume and high resolution, to separate and detect ionic compounds based on the different migration rates of charged metabolites in order to detect metabolic biomarkers in patients with CRC.

Methods

A total of 56 patients with CRC (n = 14 each of Stages I-IV), 60 healthy controls, and 59 patients with colonic adenoma were included in this study. Metabolome analysis was conducted by CE-TOFMS on serum samples of patients and controls using the Advanced Scan package (Human Metabolome Technologies).

Results

We obtained 334 metabolites in the serum, of which 139 were identified as known substances. Among these 139 known metabolites, 16 were correlated with CRC stage by upregulation and 44 by downregulation, with benzoic acid (r = −0.649, t = 11.653, p = 6.07599E−24), octanoic acid (r = 0.557, t = 9.183, p = 7.9557E−17), decanoic acid (r = 0.539, t = 8.749, p = 1.24352E−15), and histidine (r = −0.513, t = 8.194, p = 3.90224E−14) exhibiting significant correlation.

Conclusions

To the best of our knowledge, this is the first report to determine the correlation between serum metabolites and CRC stage using CE-TOFMS. Our results show that benzoic acid exhibited excellent diagnostic power and could potentially serve as a novel disease biomarker for CRC diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

CRC:

Colorectal cancer

CE-TOFMS:

Capillary electrophoresis-time-of-flight mass spectrometry

HCA:

Hierarchical cluster analysis

References

  1. Herszenyi L, Tulassay Z. Epidemiology of gastrointestinal and liver tumors. Eur Rev Med Pharmacol Sci. 2010;14(4):249–58 (epub 2010/05/26).

    PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29 (epub 2015/01/07).

    Article  PubMed  Google Scholar 

  3. Sung JJ, Lau JY, Goh KL, et al. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol. 2005;6(11):871–6 (epub 2005/11/01).

    Article  PubMed  Google Scholar 

  4. Asayama N, Oka S, Tanaka S, et al. Long-term outcomes after treatment for T1 colorectal carcinoma. Int J Colorectal Dis. 2016;31(3):571–8 (epub 2015/12/23).

    Article  PubMed  Google Scholar 

  5. Tanaka S, Saitoh Y, Matsuda T, et al. Evidence-based clinical practice guidelines for management of colorectal polyps. J Gastroenterol. 2015;50(3):252–60 (epub 2015/01/07).

    Article  PubMed  Google Scholar 

  6. Yoshida N, Hisabe T, Inada Y, et al. The ability of a novel blue laser imaging system for the diagnosis of invasion depth of colorectal neoplasms. J Gastroenterol. 2014;49(1):73–80 (epub 2013/03/16).

    Article  PubMed  Google Scholar 

  7. Asayama N, Oka S, Tanaka S, et al. Long-term outcomes after treatment for pedunculated-type T1 colorectal carcinoma: a multicenter retrospective cohort study. J Gastroenterol. 2016;51(7):702–10 (epub 2015/11/18).

    Article  CAS  PubMed  Google Scholar 

  8. Takeuchi Y, Hanafusa M, Kanzaki H, et al. An alternative option for “resect and discard” strategy, using magnifying narrow-band imaging: a prospective “proof-of-principle” study. J Gastroenterol. 2015;50(10):1017–26 (epub 2015/02/19).

    Article  PubMed  Google Scholar 

  9. Bretthauer M. Evidence for colorectal cancer screening. Best Pract Res Clin Gastroenterol. 2010;24(4):417–25 (epub 2010/09/14).

    Article  PubMed  Google Scholar 

  10. Duffy MJ, van Rossum LG, van Turenhout ST, et al. Use of faecal markers in screening for colorectal neoplasia: a European group on tumor markers position paper. Int J Cancer Journal International du Cancer. 2011;128(1):3–11 (epub 2010/09/09).

    Article  CAS  PubMed  Google Scholar 

  11. Shimwell NJ, Wei W, Wilson S, et al. Assessment of novel combinations of biomarkers for the detection of colorectal cancer. Cancer Biomark. 2010;7(3):123–32 (epub 2011/01/26).

    Article  CAS  PubMed  Google Scholar 

  12. Tanaka T, Tanaka M, Tanaka T, et al. Biomarkers for colorectal cancer. Int J Mol Sci. 2010;11(9):3209–25 (epub 2010/10/20).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fletcher RH. Carcinoembryonic antigen. Ann Intern Med. 1986;104(1):66–73 (epub 1986/01/01).

    Article  CAS  PubMed  Google Scholar 

  14. Kronborg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 1996;348(9040):1467–71 (epub 1996/11/30).

    Article  CAS  PubMed  Google Scholar 

  15. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328(19):1365–71 (epub 1993/05/13).

    Article  CAS  PubMed  Google Scholar 

  16. Tiziani S, Lopes V, Gunther UL. Early stage diagnosis of oral cancer using 1H NMR-based metabolomics. Neoplasia. 2009;11(3):269–76 (4p following epub 2009/02/27).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim K, Aronov P, Zakharkin SO, et al. Urine metabolomics analysis for kidney cancer detection and biomarker discovery. Mol Cell Proteomics MCP. 2009;8(3):558–70 (epub 2008/11/15).

    Article  CAS  PubMed  Google Scholar 

  18. Denkert C, Budczies J, Kind T, et al. Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res. 2006;66(22):10795–804 (epub 2006/11/17).

    Article  CAS  PubMed  Google Scholar 

  19. Jain M, Nilsson R, Sharma S, et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science. 2012;336(6084):1040–4 (epub 2012/05/26).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sreekumar A, Poisson LM, Rajendiran TM, et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009;457(7231):910–4 (epub 2009/02/13).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci. 2010;35(8):427–33 (epub 2010/06/24).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Munoz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 2012;3:e248 (epub 2012/01/13).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gross S, Cairns RA, Minden MD, et al. Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. J Exp Med. 2010;207(2):339–44 (epub 2010/02/10).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Patti GJ, Yanes O, Siuzdak G. Innovation: metabolomics: the apogee of the omics trilogy. Nat Rev Mol Cell Biol. 2012;13(4):263–9 (epub 2012/03/23).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gu H, Gowda GA, Raftery D. Metabolic profiling: are we en route to better diagnostic tests for cancer? Future Oncol. 2012;8(10):1207–10 (epub 2012/11/08).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gowda GA, Zhang S, Gu H, et al. Metabolomics-based methods for early disease diagnostics. Expert Rev Mol Diagn. 2008;8(5):617–33 (epub 2008/09/13).

    Article  CAS  PubMed  Google Scholar 

  27. Scalbert A, Brennan L, Fiehn O, et al. Mass-spectrometry-based metabolomics: limitations and recommendations for future progress with particular focus on nutrition research. Metabolomics. 2009;5(4):435–58 (epub 2010/01/05).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fan TW, Lane AN. NMR-based stable isotope resolved metabolomics in systems biochemistry. J Biomol NMR. 2011;49(3–4):267–80 (epub 2011/02/26).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Reaves ML, Rabinowitz JD. Metabolomics in systems microbiology. Curr Opin Biotechnol. 2011;22(1):17–25 (epub 2010/11/06).

    Article  CAS  PubMed  Google Scholar 

  30. Bain JR, Stevens RD, Wenner BR, et al. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes. 2009;58(11):2429–43 (epub 2009/10/31).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Yanes O, Tautenhahn R, Patti GJ, et al. Expanding coverage of the metabolome for global metabolite profiling. Anal Chem. 2011;83(6):2152–61 (epub 2011/02/19).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishiumi S, Kobayashi T, Ikeda A, et al. A novel serum metabolomics-based diagnostic approach for colorectal cancer. PloS one. 2012;7(7):e40459 (epub 2012/07/14).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Denkert C, Budczies J, Weichert W, et al. Metabolite profiling of human colon carcinoma–deregulation of TCA cycle and amino acid turnover. Mol Cancer. 2008;7:72 (epub 2008/09/19).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Guertin KA, Loftfield E, Boca SM, et al. Serum biomarkers of habitual coffee consumption may provide insight into the mechanism underlying the association between coffee consumption and colorectal cancer. Am J Clin Nutr. 2015;101(5):1000–11 (epub 2015/03/13).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yoshida M, Hatano N, Nishiumi S, et al. Diagnosis of gastroenterological diseases by metabolome analysis using gas chromatography-mass spectrometry. J Gastroenterol. 2012;47(1):9–20 (epub 2011/11/02).

    Article  CAS  PubMed  Google Scholar 

  36. Amiot A, Dona AC, Wijeyesekera A, et al. (1)H NMR spectroscopy of fecal extracts enables detection of advanced colorectal neoplasia. J Proteome Res. 2015;14(9):3871–81 (epub 2015/07/28).

    Article  CAS  PubMed  Google Scholar 

  37. Zamani Z, Arjmand M, Vahabi F, et al. A metabolic study on colon cancer using (1)h nuclear magnetic resonance spectroscopy. Biochem Res Int. 2014;2014:348712 (epub 2014/09/10).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhu J, Djukovic D, Deng L, et al. Colorectal cancer detection using targeted serum metabolic profiling. J Proteome Res. 2014;13(9):4120–30 (epub 2014/08/16).

    Article  CAS  PubMed  Google Scholar 

  39. Suzuki Y, Fujimori T, Kanno K, et al. Metabolome analysis of photosynthesis and the related primary metabolites in the leaves of transgenic rice plants with increased or decreased Rubisco content. Plant Cell Environ. 2012;35(8):1369–79 (epub 2012/02/11).

    Article  CAS  PubMed  Google Scholar 

  40. Soga T, Ohashi Y, Ueno Y, et al. Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. J Proteome Res. 2003;2(5):488–94 (epub 2003/10/30).

    Article  CAS  PubMed  Google Scholar 

  41. Soga T, Sugimoto M, Honma M, et al. Serum metabolomics reveals gamma-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease. J Hepatol. 2011;55(4):896–905 (epub 2011/02/22).

    Article  CAS  PubMed  Google Scholar 

  42. Hirayama A, Kami K, Sugimoto M, et al. Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 2009;69(11):4918–25 (epub 2009/05/22).

    Article  CAS  PubMed  Google Scholar 

  43. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Seoul: From the 59th World Medical Association Assembly [database on the Internet]. 2008. Available from: http://www.wma.net/en/30publications/10policies/b3/17c.pdf.

  44. Ohashi Y, Hirayama A, Ishikawa T, et al. Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS. Mol BioSyst. 2008;4(2):135–47 (epub 2008/01/24).

    Article  CAS  PubMed  Google Scholar 

  45. Ooga T, Sato H, Nagashima A, et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol BioSyst. 2011;7(4):1217–23 (epub 2011/01/25).

    Article  CAS  PubMed  Google Scholar 

  46. Sugimoto M, Wong DT, Hirayama A, et al. Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics. 2010;6(1):78–95 (epub 2010/03/20).

    Article  CAS  PubMed  Google Scholar 

  47. Junker BH, Klukas C, Schreiber F. VANTED: a system for advanced data analysis and visualization in the context of biological networks. BMC Bioinform. 2006;7:109 (epub 2006/03/08).

    Article  Google Scholar 

  48. Brusilow SW, Valle DL, Batshaw M. New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet. 1979;2(8140):452–4 (epub 1979/09/01).

    Article  CAS  PubMed  Google Scholar 

  49. Ou K, Sarnoski P, Schneider KR, et al. Microbial catabolism of procyanidins by human gut microbiota. Mol Nutr Food Res. 2014;58(11):2196–205 (epub 2014/07/22).

    Article  CAS  PubMed  Google Scholar 

  50. Chen JL, Fan J, Yan LS, Guo HQ, et al. Urine metabolite profiling of human colorectal cancer by capillary electrophoresis mass spectrometry based on MRB. Gastroenterol Res Pract. 2012;2012:125890 (epub 2012/12/18).

    PubMed  PubMed Central  Google Scholar 

  51. Qiu Y, Cai G, Su M, et al. Urinary metabonomic study on colorectal cancer. J Proteome Res. 2010;9(3):1627–34 (epub 2010/02/04).

    Article  CAS  PubMed  Google Scholar 

  52. Fukutake N, Ueno M, Hiraoka N, et al. A novel multivariate index for pancreatic cancer detection based on the plasma free amino acid profile. PloS One. 2015;10(7):e0132223 (epub 2015/07/03).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Narayanan A, Baskaran SA, Amalaradjou MA, et al. Anticarcinogenic properties of medium chain fatty acids on human colorectal, skin and breast cancer cells in vitro. Int J Mol Sci. 2015;16(3):5014–27 (epub 2015/03/10).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Murakami Y, Kubo S, Tamori A, et al. Comprehensive analysis of transcriptome and metabolome analysis in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma. Sci Rep. 2015;5:16294 (epub 2015/11/06).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kami K, Fujimori T, Sato H, et al. Metabolomic profiling of lung and prostate tumor tissues by capillary electrophoresis time-of-flight mass spectrometry. Metabolomics. 2013;9(2):444–53 (epub 2013/04/02).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Kenjiro Kami for metabolomics analysis and Editage (www.editage.jp) for English language editing. This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) (B) to Y.N. (no. 16H05289) from the Japan Society for the Promotion of Science (JSPS), and by an Adaptable and Seamless Technology Transfer Program through target-driven R&D (to Y.N.) from the Japan Agency for Medical Research and Development (AMED), a Grant-in-Aid for Scientific Research (KAKENHI) (C) to K.U. (no. 15K08313) from the Japan Society for the Promotion of Science (JSPS), and a Grant-in-Aid for Scientific Research (KAKENHI) (C) to T.T. (no. 16K09322) from the Japan Society for the Promotion of Science (JSPS).

Author information

Author notes

    Authors and Affiliations

    1. Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajiicho Hirokoji Kawaramachi Kamigyo-ku, Kyoto, 602-8566, Japan

      Kazuhiko Uchiyama, Nobuaki Yagi, Katsura Mizushima, Yasuki Higashimura, Yasuko Hirai, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Katada, Kazuhiro Kamada, Osamu Handa, Takeshi Ishikawa, Tomohisa Takagi, Hideyuki Konishi, Yoshito Itoh & Yuji Naito

    2. Department of Endoscopy and Ultrasound Medicine, Kyoto Prefectural University of Medicine, 465 Kajiicho Hirokoji Kawaramachi Kamigyo-ku, Kyoto, 602-8566, Japan

      Yuji Naito

    3. Department of Gastroenterology, Murakami Memorial Hospital, Asahi University, 3-23 Hashimotocho Gifu-city, Gifu, 500-8523, Japan

      Nobuaki Yagi

    4. Department of Surgery, Division of Digestive Surgery, Kyoto Prefectural University of Medicine, 465 Kajiicho Hirokoji Kawaramachi Kamigyo-ku, Kyoto, 602-8566, Japan

      Yoshiaki Kuriu, Masayoshi Nakanishi & Eigo Otsuji

    Authors
    1. Kazuhiko Uchiyama
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Nobuaki Yagi
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Katsura Mizushima
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yasuki Higashimura
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Yasuko Hirai
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Tetsuya Okayama
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Naohisa Yoshida
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Kazuhiro Katada
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Kazuhiro Kamada
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Osamu Handa
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Takeshi Ishikawa
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Tomohisa Takagi
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Hideyuki Konishi
      View author publications

      You can also search for this author in PubMed Google Scholar

    14. Yoshiaki Kuriu
      View author publications

      You can also search for this author in PubMed Google Scholar

    15. Masayoshi Nakanishi
      View author publications

      You can also search for this author in PubMed Google Scholar

    16. Eigo Otsuji
      View author publications

      You can also search for this author in PubMed Google Scholar

    17. Yoshito Itoh
      View author publications

      You can also search for this author in PubMed Google Scholar

    18. Yuji Naito
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Yuji Naito.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interest.

    Additional information

    Kazuhiko Uchiyama and Nobuaki Yagi are equally contributing authors.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Uchiyama, K., Yagi, N., Mizushima, K. et al. Serum metabolomics analysis for early detection of colorectal cancer. J Gastroenterol 52, 677–694 (2017). https://doi.org/10.1007/s00535-016-1261-6

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00535-016-1261-6

    Keywords

    Search

    Navigation