Skip to main content
SpringerLink
Log in

LC–MS/MS-based metabolome analysis detected changes in the metabolic profiles of small and large intestinal adenomatous polyps in Apc Min/+ mice

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Introduction

The adenomatous polyposis coli (APC) gene is a tumor suppressor gene that is inactivated in the initiation of colorectal neoplasia. Apc Min/+ mice, which possess a heterozygous APC mutation, develop numerous adenomatous polyps, which are similar to those observed in familial adenomatous polyposis (FAP) in humans. However, unlike FAP patients, Apc Min/+ mice predominantly develop adenomatous polyps in the small intestine. The metabolic changes associated with the development of polyps in the small and large intestine remain to be investigated.

Objectives

The objective of this study was to elucidate the metabolic changes associated with intestinal polyp formation.

Methods

We compared the metabolite levels of pairs of polyp and non-polyp tissues obtained from the small intestines (n = 12) or large intestines (n = 7) of Apc Min/+ mice. To do this, we analyzed the tissue samples using two methods, liquid chromatography-tandem mass spectrometry (1) with a pentafluorophenylpropyl column for cation analysis, and (2) with a C18 reversed phase column coupled to an ion-pair reagent for anion analysis.

Results

Pathway mapping of the metabolites whose levels were significantly altered revealed that the polyp tissue of the small intestine contained significantly higher levels of intermediates involved in glycolysis, the pentose phosphate pathway, nucleotide metabolism, or glutathione biosynthesis than in the equivalent non-polyp tissue. In addition, significantly higher levels of methionine cycle intermediates were detected in the polyp tissues of both the large and small intestines. Organ-dependent (small vs. large intestine) differences were also detected in the levels of most amino acids and urea cycle intermediates.

Conclusion

Our results indicate that various metabolic changes are associated with polyp development, and understanding these alterations could make it possible to evaluate the treatment response of colorectal cancer earlier.

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

References

  • Alonso-Aperte, E., González, M. P., Póo-Prieto, R., & Varela-Moreiras, G. (2008). Folate status and S-adenosylmethionine/S-adenosylhomocysteine ratio in colorectal adenocarcinoma in humans. European Journal of Clinical Nutrition, 62, 295–298.

    Article  CAS  PubMed  Google Scholar 

  • Ames, B. N., Shigenaga, M. K., & Hagen, T. M. (1993). Oxidants, antioxidants, and the degenerative diseases of aging. Proceedings of the National Academy of Sciences of the United States of America, 90, 7915–7922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chowdhury, S. K. R., Gemin, A., & Singh, G. (2005). High activity of mitochondrial glycerophosphate dehydrogenase and glycerophosphate-dependent ROS production in prostate cancer cell lines. Biochemical and Biophysical Research Communications, 333, 1139–1145.

    Article  CAS  PubMed  Google Scholar 

  • Corpet, D. E., & Pierre, F. (2003). Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiology Biomarkers and Prevention, 12, 391–400.

    Google Scholar 

  • Cumbiner, B. M. (1995). Signal transduction by β-catenin. Current Opinion in Cell Biology, 7, 634–640.

    Article  Google Scholar 

  • Ellis, D. I., & Goodacre, R. (2006). Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy. The Analyst, 131, 875–885.

    Article  CAS  PubMed  Google Scholar 

  • Finkelstein, J. D. (1990). Methionine metabolism in mammals. The Journal of Nutritional Biochemistry, 1, 228–237.

    Article  CAS  PubMed  Google Scholar 

  • Frederiks, W. M., Vizan, P., Bosch, K. S., Vreeling-Sindelárová, H., Boren, J., & Cascante, M. (2008). Elevated activity of the oxidative and non-oxidative pentose phosphate pathway in (pre)neoplastic lesions in rat liver. International Journal of Experimental Pathology, 89, 232–240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerner, E. W., & Meyskens, F. L. (2004). Polyamines and cancer: old molecules, new understanding. Nature Reviews Cancer, 4, 781–792.

    Article  CAS  PubMed  Google Scholar 

  • Hirayama, A., Kami, K., Sugimoto, M., et al. (2009). Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Research, 69, 4918–4925.

    Article  CAS  PubMed  Google Scholar 

  • Ikeda, K., Mutoh, M., Teraoka, N., Nakanishi, H., Wakabayashi, K., & Taguchi, R. (2011). Increase of oxidant-related triglycerides and phosphatidylcholines in serum and small intestinal mucosa during development of intestinal polyp formation in Min mice. Cancer Science, 102, 79–87.

    Article  CAS  PubMed  Google Scholar 

  • Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., & Tanabe, M. (2012). KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Research, 40, 109–114.

    Article  Google Scholar 

  • Linder, N., Martelin, E., Lundin, M., et al. (2009). Xanthine oxidoreductase—Clinical significance in colorectal cancer and in vitro expression of the protein in human colon cancer cells. European Journal of Cancer, 45, 648–655.

    Article  CAS  PubMed  Google Scholar 

  • Lu, S. C. (2012). Glutathione synthesis. Biochimica et Biophysica Acta, 1830, 3143–3153.

    Article  PubMed  PubMed Central  Google Scholar 

  • MacDonald, M. J., Warner, T. F., & Mertz, R. J. (1990). High activity of mitochondrial glycerol phosphate dehydrogenase in insulinomas and carcinoid and other tumors of the amine precursor uptake decarboxylation system. Cancer Research, 50, 7203–7205.

    CAS  PubMed  Google Scholar 

  • Mashego, M. R., Rumbold, K., De Mey, M., Vandamme, E., Soetaert, W., & Heijnen, J. J. (2007). Microbial metabolomics: Past, present and future methodologies. Biotechnology Letters, 29, 1–16.

    Article  CAS  PubMed  Google Scholar 

  • Miller, D. M., Thomas, S. D., Islam, A., Muench, D., & Sedoris, K. (2012). c-Myc and cancer metabolism. Clinical Cancer Research, 18, 5546–5553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mráček, T., Drahota, Z., & Houštěk, J. (2013). The function and the role of the mitochondrial glycerol-3-phosphate dehydrogenase in mammalian tissues. Biochimica et Biophysica Acta, 1827, 401–410.

    Article  PubMed  Google Scholar 

  • Nicholson, J. K., Lindon, J. C., & Holmes, E. (1999). “Metabonomics”: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica, 29, 1181–1189.

    Article  CAS  PubMed  Google Scholar 

  • Pasikanti, K. K., Ho, P. C., & Chan, E. C. Y. (2008). Gas chromatography/mass spectrometry in metabolic profiling of biological fluids. Journal of Chromatography B, 871, 202–211.

    Article  CAS  Google Scholar 

  • Phan, L. M., Yeung, S. C. J., & Lee, M. H. (2014). Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies. Cancer Biology and Medicine, 11, 1–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saito, K. (2013). Phytochemical genomics-a new trend. Current Opinion in Plant Biology, 16, 373–380.

    Article  CAS  PubMed  Google Scholar 

  • Sansom, O. J., Meniel, V. S., Muncan, V., et al. (2007). Myc deletion rescues Apc deficiency in the small intestine. Nature, 446, 676–679.

    Article  CAS  PubMed  Google Scholar 

  • Sato, K., Tsuchihara, K., Fujii, S., et al. (2007). Autophagy is activated in colorectal cancer cells and contributes to the tolerance to nutrient deprivation. Cancer Research, 67, 9677–9684.

    Article  CAS  PubMed  Google Scholar 

  • Soga, T., Ohashi, Y., Ueno, Y., Naraoka, H., Tomita, M., & Nishioka, T. (2003). Quantitative metabolome analysis using capillary electrophoresis mass spectrometry. Journal of Proteome Research, 2, 488–494.

    Article  CAS  PubMed  Google Scholar 

  • Spratlin, J. L., Serkova, N. J., & Eckhardt, S. G. (2009). Clinical applications of metabolomics in oncology: A review. Clinical Cancer Research, 15, 431–440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Steward, W. P., & Brown, K. (2013). Cancer chemoprevention: a rapidly evolving field. British Journal of Cancer, 109, 1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taketo, M. M., & Edelmann, W. (2009). Mouse models of colon cancer. Gastroenterology, 136, 780–798.

    Article  CAS  PubMed  Google Scholar 

  • Theodoridis, G., Gika, H. G., & Wilson, I. D. (2008). LC-MS-based methodology for global metabolite profiling in metabonomics/metabolomics. Trends in Analytical Chemistry, 27, 251–260.

    Article  CAS  Google Scholar 

  • Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-tieulent, J., & Jemal, A. (2015). Global Cancer Statistics, 2012. Cancer Journal for Clinicians, 65, 87–108.

    Article  Google Scholar 

  • Urakami, K., Zangiacomi, V., Yamaguchi, K., & Kusuhara, M. (2013). Impact of 2-deoxy-d-glucose on the target metabolome profile of a human endometrial cancer cell line. Biomedical Research, 34, 221–229.

    Article  CAS  PubMed  Google Scholar 

  • Winawer, S., Fletcher, R., Rex, D., et al. (2003). Colorectal cancer screening and surveillance: Clinical guidelines and rationale—Update based on new evidence. Gastroenterology, 124, 544–560.

    Article  PubMed  Google Scholar 

  • Wishart, D. S. (2008). Metabolomics: applications to food science and nutrition research. Trends in Food Science and Technology, 19, 482–493.

    Article  CAS  Google Scholar 

  • Yoshie, T., Nishiumi, S., Izumi, Y., et al. (2012). Regulation of the metabolite profile by an APC gene mutation in colorectal cancer. Cancer Science, 103, 1010–1021.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [M.Y.]; a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan [S.N.]; and AMED-CREST from the Agency for Medical Research and Development [M.Y.].

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Makoto Suzuki, Shin Nishiumi, Takashi Kobayashi, Takeshi Azuma & Masaru Yoshida

  2. Division of Metabolomics Research, Department of Internal Related, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

  3. AMED-CREST, AMED, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan

    Masaru Yoshida

Authors
  1. Makoto Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin Nishiumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masaru Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Shin Nishiumi or Masaru Yoshida.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest in the submission of this manuscript.

Ethical statement

All institutional, national, and international ethical guidelines for the care and use of laboratory animals were followed.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suzuki, M., Nishiumi, S., Kobayashi, T. et al. LC–MS/MS-based metabolome analysis detected changes in the metabolic profiles of small and large intestinal adenomatous polyps in Apc Min/+ mice. Metabolomics 12, 68 (2016). https://doi.org/10.1007/s11306-016-0988-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11306-016-0988-7

Keywords

Search

Navigation