Abstract
Introduction
Induction of tryptophan (TRP) catabolism is an adaptation mechanism to restrict excessive acute immune response in tissues. In the tumour microenvironment, TRP catabolism’s dysregulation plays an important role in local antitumour immune response suppression.
Aim
We investigated changes in the plasma concentrations of TRP and its metabolites in a cohort of colorectal cancer (CRC) patients at different tumour stages and in subjects at risk of developing CRC. TRP metabolites were assessed along kynurenine and serotonin pathways, and the activity of involved enzymes and their tissue expression were monitored.
Method
Plasmatic levels of tryptophan metabolites were quantified in 80 patients’ plasma samples by means of High-Pressure Liquid Chromatography coupled to UltraViolet/Fluorescence Detectors (HPLC-UV/FD), after a simple dilution step. Tissue IDO1 gene expression during to the adenoma-carcinoma sequence and samples were obtained from formalin-fixed and paraffin-embedded (FFPE) normal colon and tumour tissues from a subset of patients (n = 21).
Results
Altered TRP concentrations were detected in plasma samples concomitant to pre-cancerous lesion and persisted during the adenoma-carcinoma transition. Moreover, the anatomical site of cancer lesions (colon or rectum) strongly influences the TRP metabolic profiles. Colon cancer patients exhibited increased TRP catabolism with respect to those affected by rectal cancer, suggesting that TRP’s metabolism alterations play an important role in the onset and progression of colon cancer, but not in those of rectal cancer.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agostini, M., et al. (2015). An integrative approach for the identification of prognostic and predictive biomarkers in rectal cancer. Oncotarget, 6, 32561–32574. doi:10.18632/oncotarget.4935.
Caine, G. J., Stonelake, P. S., Lip, G. Y., & Kehoe, S. T. (2002). The hypercoagulable state of malignancy: Pathogenesis and current debate. Neoplasia 4, 465–473 doi:10.1038/sj.neo.7900263.
Calder, P. C., et al. (2017). Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Research Reviews, 40, 95–119. doi:10.1016/j.arr.2017.09.001.
Cascino, A., et al. (1991). Increased plasma free tryptophan levels in human cancer: A tumor related effect? Anticancer Research, 11, 1313–1316.
Cavia-Saiz, M., Rodriguez, P. M., Ayala, B., Garcia-Gonzalez, M., Coma-del Corral, M. J., & Giron, C. G. (2014). The role of plasma IDO activity as a diagnostic marker of patients with colorectal cancer. Molecular Biology Reports, 41, 2275–2279. doi:10.1007/s11033-014-3080-2.
Chai, E. Z. P., Siveen, K. S., Shanmugam, M. K., Arfuso, F., & Sethi, G. (2015). Analysis of the intricate relationship between chronic inflammation and cancer. Biochemical Journal, 468, 1–15. doi:10.1042/Bj20141337.
Clarke, G., Fitzgerald, P., Cryan, J. F., Cassidy, E. M., Quigley, E. M., & Dinan, T. G. (2009). Tryptophan degradation in irritable bowel syndrome: evidence of indoleamine 2,3-dioxygenase activation in a male cohort. BMC Gastroenterology, 9, 6–6. doi:10.1186/1471-230x-9-6.
Comai, S., et al. (2011). Effects of PEG-interferon alpha plus ribavirin on tryptophan metabolism in patients with chronic hepatitis C. Pharmacological Research, 63, 85–92. doi:10.1016/j.phrs.2010.10.009.
Deac, O. M., et al. (2015). Tryptophan catabolism and vitamin B-6 status are affected by gender and lifestyle factors in healthy young adults. The Journal of Nutrition, 145, 701–707. doi:10.3945/jn.114.203091.
Deschoolmeester, V., et al. (2010). Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunology, 11, 19. doi:10.1186/1471-2172-11-19.
Dorak, M. T., & Karpuzoglu, E. (2012). Gender differences in cancer susceptibility: an inadequately addressed issue. Frontiers in Genetics, 3, 268. doi:10.3389/fgene.2012.00268.
Ekbom, A., Helmick, C., Zack, M., & Adami, H. O. (1990). Ulcerative colitis and colorectal cancer. A population-based study. The New England Journal of Medicine, 323, 1228–1233. doi:10.1056/NEJM199011013231802.
Favennec, M., et al. (2015). The kynurenine pathway is activated in human obesity and shifted toward kynurenine monooxygenase activation. Obesity, 23, 2066–2074. doi:10.1002/oby.21199.
Ferdinande, L., et al. (2012). Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer. British Journal of Cancer, 106, 141–147. doi:10.1038/bjc.2011.513.
Fichtner-Feigl, S., Kesselring, R., & Strober, W. (2015). Chronic inflammation and the development of malignancy in the GI tract. Trends in Immunology, 36, 451–459. doi:10.1016/j.it.2015.06.007.
Forrest, C. M., Gould, S. R., Darlington, L. G., & Stone, T. W. (2003). Levels of purine, kynurenine and lipid peroxidation products in patients with inflammatory bowel disease. Advances in Experimental Medicine and Biology, 527, 395–400.
Frick, B., Schroecksnadel, K., Neurauter, G., Leblhuber, F., & Fuchs, D. (2004). Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clinical Biochemistry, 37, 684–687. doi:10.1016/j.clinbiochem.2004.02.007.
Gupta, N. K., et al. (2012). Serum analysis of tryptophan catabolism pathway: Correlation with Crohn’s disease activity. Inflammatory Bowel Diseases, 18, 1214–1220. doi:10.1002/ibd.21849.
Hewagama, A., Patel, D., Yarlagadda, S., Strickland, F. M., & Richardson, B. C. (2009). Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes and Immunity 10, 509–516. doi:10.1038/gene.2009.12.
Huang, A., Fuchs, D., Widner, B., Glover, C., Henderson, D. C., & Allen-Mersh, T. G. (2002). Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. British Journal of Cancer, 86, 1691–1696. doi:10.1038/sj.bjc.6600336.
Kim, S. E., Paik, H. Y., Yoon, H., Lee, J. E., Kim, N., & Sung, M. K. (2015). Sex- and gender-specific disparities in colorectal cancer risk. World Journal of Gastroenterology: WJG, 21, 5167–5175. doi:10.3748/wjg.v21.i17.5167.
Le Floc’h, N., Otten, W., & Merlot, E. (2011). Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41, 1195–1205. doi:10.1007/s00726-010-0752-7.
Lee, S., et al. (2017). Clinical significance of coagulation factors in operable colorectal cancer. Oncology Letters, 13, 4669–4674. doi:10.3892/ol.2017.6058.
Lima, L. G., & Monteiro, R. Q. (2013). Activation of blood coagulation in cancer: Implications for tumour progression. Bioscience Reports 33, e00064. doi:10.1042/BSR20130057.
Lob, S., et al. (2009). IDO1 and IDO2 are expressed in human tumors: Levo- but not dextro-1-methyl tryptophan inhibits tryptophan catabolism. Cancer Immunology, Immunotherapy: CII, 58, 153–157. doi:10.1007/s00262-008-0513-6.
Mandal, R., et al. (2016). The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight, 1, e89829. doi:10.1172/jci.insight.89829.
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444. doi:10.1038/nature07205.
Masaki, A., et al. (2015). Prognostic significance of tryptophan catabolism in adult T-cell leukemia/lymphoma. Rinsho Ketsueki 56, 2295–2304. doi:10.11406/rinketsu.56.2295.
McKean, K. A., & Nunney, L. (2005). Bateman’s principle and immunity: Phenotypically plastic reproductive strategies predict changes in immunological sex differences. Evolution, 59, 1510–1517.
Miyagi, Y., et al. (2011). Plasma free amino acid profiling of five types of cancer patients and its application for early detection. PLoS ONE, 6, e24143. doi:10.1371/journal.pone.0024143.
Munn, D. H., et al. (2005). GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity, 22, 633–642. doi:10.1016/j.immuni.2005.03.013.
Munn, D. H., & Mellor, A. L. (2016). IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance. Trends in Immunology, 37, 193–207. doi:10.1016/j.it.2016.01.002.
Myint, A. M., et al. (2007). Tryptophan breakdown pathway in bipolar mania. Journal of Affective Disorders, 102, 65–72. doi:10.1016/j.jad.2006.12.008.
Myint, A. M., & Kim, Y. K. (2014). Network beyond IDO in psychiatric disorders: Revisiting neurodegeneration hypothesis. Progress in Neuro-psychopharmacology & Biological Psychiatry 48, 304–313. doi:10.1016/j.pnpbp.2013.08.008.
Nishiumi, S., et al. (2012). A novel serum metabolomics-based diagnostic approach for colorectal cancer. PLoS ONE, 7, e40459. doi:10.1371/journal.pone.0040459.
Ogawa, K., et al. (2012). (-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3-dioxygenase in human colorectal cancer cells. Oncology Letters, 4, 546–550. doi:10.3892/ol.2012.761.
Opitz, C. A., et al. (2011). An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature, 478, 197–203. doi:10.1038/nature10491.
Pertovaara, M., et al. (2006). Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mechanisms of Ageing and Development, 127, 497–499. doi:10.1016/j.mad.2006.01.020.
Powell, N. D., Tarr, A. J., & Sheridan, J. F. (2013). Psychosocial stress and inflammation in cancer. Brain Behavior and Immunity, 30, S41–S47. doi:10.1016/j.bbi.2012.06.015.
Prendergast, G. C., et al. (2014). Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer. Cancer Immunology, Immunotherapy: CII, 63, 721–735. doi:10.1007/s00262-014-1549-4.
Puccetti, P., et al. (2015). Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers. PLoS ONE, 10, e0122046. doi:10.1371/journal.pone.0122046.
Sarrouilhe, D., Clarhaut, J., Defamie, N., & Mesnil, M. (2015). Serotonin and cancer: What is the link? Current Molecular Medicine, 15, 62–77.
Schmidt, S. K., et al. (2009). Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase. European Journal of Immunology, 39, 2755–2764. doi:10.1002/eji.200939535.
Schwarcz, R., Bruno, J. P., Muchowski, P. J., & Wu, H. Q. (2012). Kynurenines in the mammalian brain: When physiology meets pathology. Nature Reviews Neuroscience, 13, 465–477. doi:10.1038/nrn3257.
Siddiqui, E. J., Thompson, C. S., Mikhailidis, D. P., & Mumtaz, F. H. (2005). The role of serotonin in tumour growth (review). Oncology Reports, 14, 1593–1597.
Suzuki, Y., et al. (2010). Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer, 67, 361–365. doi:10.1016/j.lungcan.2009.05.001.
Tamas, K., et al. (2015). Rectal and colon cancer: Not just a different anatomic site. Cancer Treatment Reviews, 41, 671–679. doi:10.1016/j.ctrv.2015.06.007.
Thaker, A. I., et al. (2013). IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology, 145, 416–425.e1-4. doi:10.1053/j.gastro.2013.05.002.
Thomas, S. R., & Stocker, R. (1999). Redox reactions related to indoleamine 2,3-dioxygenase and tryptophan metabolism along the kynurenine pathway. Redox Report, 4, 199–220. doi:10.1179/135100099101534927.
Urakawa, H., Nishida, Y., Nakashima, H., Shimoyama, Y., Nakamura, S., & Ishiguro, N. (2009). Prognostic value of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clinical & Experimental Metastasis, 26, 1005–1012. doi:10.1007/s10585-009-9290-7.
van Baren, N., & van den Eynde, B. J. (2015). Tryptophan-degrading enzymes in tumoral immune resistance. Frontiers in Immunology, 6, 34. doi:10.3389/fimmu.2015.00034.
van der Goot, A. T., & Nollen, E. A. (2013). Tryptophan metabolism: Entering the field of aging and age-related pathologies. Trends in Molecular Medicine, 19, 336–344. doi:10.1016/j.molmed.2013.02.007.
Vecsei, L., Szalardy, L., Fulop, F., & Toldi, J. (2013). Kynurenines in the CNS: Recent advances and new questions. Nature Reviews Drug Discovery, 12, 64–82. http://www.nature.com/nrd/journal/v12/n1/suppinfo/nrd3793_S1.html.
Vicaut, E., Laemmel, E., & Stucker, O. (2000). Impact of serotonin on tumour growth. Annals of Medicine 32, 187–194.
Wiggins, T., Kumar, S., Markar, S. R., Antonowicz, S., & Hanna, G. B. (2015). Tyrosine, phenylalanine, and tryptophan in gastroesophageal malignancy: A systematic review. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 24, 32–38 doi:10.1158/1055-9965.EPI-14-0980.
Yu, Z., et al. (2011). Differences between human plasma and serum metabolite profiles. PLoS ONE, 6, e21230. doi:10.1371/journal.pone.0021230.
Acknowledgements
This work was supported by the Associazione Italiana Ricerca sul Cancro (AIRC), IG 2016 (Grant No. 19104).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interests.
Ethical approval
This study is conducted according to the principles expressed in the Declaration of Helsinki. Written informed consent was obtained from every individual and the protocol was approved by ethics committee of institution (Protocol Number:P448).
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Crotti, S., D’Angelo, E., Bedin, C. et al. Tryptophan metabolism along the kynurenine and serotonin pathways reveals substantial differences in colon and rectal cancer. Metabolomics 13, 148 (2017). https://doi.org/10.1007/s11306-017-1288-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11306-017-1288-6