[en] Oxylipins derived from dietary polyunsaturated fatty acids (PUFAs) are key determinants of intestinal health, homeostasis, and inflammatory disorders, such as colitis-associated colorectal cancer. Previous research has independently linked a high dietary omega (ω)-6:ω-3 PUFA ratio, or intestinal helminth infection, to an increased risk of colitis-associated colorectal cancer. However, whether these two factors interact to exacerbate disease risk and whether oxylipins contribute to this is unknown. In this study, we report that infection with the helminth Heligmosomoides polygyrus bakeri (Hpb) exacerbates tumor formation when combined with a high ω-6:ω-3 PUFA ratio diet. Dietary increases in tumor burden correlated with heightened levels of arachidonic acid (AA) and AA-derived lipoxygenase (LOX) oxylipins in the colon, including the 12/15-LOX product 12-hydroxyeicosatetraenoic acid, prior to disease onset. Although helminth infection further increased the production of 12/15-LOX oxylipins and increased expression of Alox15, responsible for producing these metabolites, inhibition of cyclooxygenase-dependent prostaglandin production with aspirin prevented helminth-exacerbation of disease. Helminth-infected mice exhibited increased phosphorylation of β-catenin in the colon, which was inhibited by EP2 and 4 antagonists. Moreover, administration of an EP agonist increased tumor burden in naive mice fed a high ω-6:ω-3 PUFA ratio diet, to the levels seen in helminth-exacerbation of disease. These data suggest that dietary changes in fatty acid composition coordinate with helminth-induced activation of EP signaling to exacerbate tumor development.
Disciplines :
Immunology & infectious disease
Author, co-author :
Smith, Katherine A ; Cardiff University, School of Biosciences, Cardiff, UK. Electronic address: smithk28@cardiff.ac.uk
Reed, Ella K ; Cardiff University, School of Biosciences, Cardiff, UK
Guschina, Irina ; Cardiff University, School of Biosciences, Cardiff, UK
Tyrrell, Victoria J; Cardiff University, School of Medicine, Cardiff, UK
Butters, Claire ; University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa
Darby, Matthew G ; University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa
Katsandegwaza, Brunette ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Chetty, Alisha; University of Cape Town, Institute of Infectious Disease and Molecular Medicine, Cape Town, South Africa
Horsnell, William G C; University of Exeter, Medical Research Council Centre for Medical Mycology, Exeter, UK
O'Donnell, Valerie B; Cardiff University, School of Medicine, Cardiff, UK
Gallimore, Awen; Cardiff University, School of Medicine, Cardiff, UK
Language :
English
Title :
Helminth-induced prostaglandin signaling and dietary shifts in PUFA metabolism promote colitis-associated cancer.
Ferlay, J. L. M., Ervik, M., Lam, F., Colombet, M., Mery, L., Piñeros, M., et al. (2024) Global Cancer Observatory: Cancer Tomorrow (version 1.1). International Agency for Research on Cancer, Lyon, France
Clevers, H. (2004) At the crossroads of inflammation and cancer. Cell. 118, 671–674
Kim, E. R., and Chang, D. K. (2014) Colorectal cancer in inflammatory bowel disease: the risk, pathogenesis, prevention and diagnosis. World J. Gastroenterol. 20, 9872–9881
Lakatos, P. L., and Lakatos, L. (2008) Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J. Gastroenterol. 14, 3937–3947
McMichael, A. J., McCall, M. G., Hartshorne, J. M., and Woodings, T. L. (1980) Patterns of gastro-intestinal cancer in European migrants to Australia: the role of dietary change. Int. J. Cancer. 25, 431–437
Le Marchand, L., Wilkens, L. R., Kolonel, L. N., Hankin, J. H., and Lyu, L. C. (1997) Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res. 57, 4787–4794
Casari, S., Di Paola, M., Banci, E., Diallo, S., Scarallo, L., Renzo, S., et al. (2022) Changing dietary habits: the impact of urbanization and rising socio-economic status in families from Burkina Faso in sub-Saharan Africa. Nutrients. 14, 1782
Parkin, D. M., Nambooze, S., Wabwire-Mangen, F., and Wabinga, H. R. (2010) Changing cancer incidence in Kampala, Uganda, 1991-2006. Int. J. Cancer. 126, 1187–1195
Mariamenatu, A. H., and Abdu, E. M. (2021) Overconsumption of omega-6 polyunsaturated fatty acids (PUFAs) versus deficiency of omega-3 PUFAs in modern-day diets: the disturbing factor for their "balanced antagonistic metabolic functions" in the human body. J. Lipids. 2021, 8848161
Tjonneland, A., Overvad, K., Bergmann, M. M., Nagel, G., Linseisen, J., Hallmans, G., et al. (2009) Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut. 58, 1606–1611
Lu, Y., Li, D., Wang, L., Zhang, H., Jiang, F., Zhang, R., et al. (2023) Comprehensive investigation on associations between dietary intake and blood levels of fatty acids and colorectal cancer risk. Nutrients. 15, 730
Hudert, C. A., Weylandt, K. H., Lu, Y., Wang, J., Hong, S., Dignass, A., et al. (2006) Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc. Natl. Acad. Sci. U. S. A. 103, 11276–11281
Whelan, J., and McEntee, M. F. (2004) Dietary (n-6) PUFA and intestinal tumorigenesis. J. Nutr. 134 (12 Suppl), 3421S–3426S
Nowak, J., Weylandt, K. H., Habbel, P., Wang, J., Dignass, A., Glickman, J. N., et al. (2007) Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis. 28, 1991–1995
Rohwer, N., Kuhl, A. A., Ostermann, A. I., Hartung, N. M., Schebb, N. H., Zopf, D., et al. (2020) Effects of chronic low-dose aspirin treatment on tumor prevention in three mouse models of intestinal tumorigenesis. Cancer Med. 9, 2535–2550
Figueiredo, J. C., Jacobs, E. J., Newton, C. C., Guinter, M. A., Cance, W. G., and Campbell, P. T. (2021) Associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs with colorectal cancer mortality after diagnosis. J. Natl. Cancer Inst. 113, 833–840
Schmocker, C., Gottschall, H., Rund, K. M., Kutzner, L., Nolte, F., Ostermann, A. I., et al. (2021) Oxylipin patterns in human colon adenomas. Prostaglandins Leukot. Essent. Fatty Acids. 167, 102269
Nguyen, C. H., Stadler, S., Brenner, S., Huttary, N., Krieger, S., Jager, W., et al. (2016) Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching. Br. J. Cancer. 115, 364–370
Chang, J., Jiang, L., Wang, Y., Yao, B., Yang, S., Zhang, B., et al. (2015) 12/15 Lipoxygenase regulation of colorectal tumorigenesis is determined by the relative tumor levels of its metabolite 12-HETE and 13-HODE in animal models. Oncotarget. 6, 2879–2888
Stadler, S., Nguyen, C. H., Schachner, H., Milovanovic, D., Holzner, S., Brenner, S., et al. (2017) Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca(2+) signalling. Cell Mol. Life Sci. 74, 1907–1921
Kroschwald, S., Chiu, C. Y., Heydeck, D., Rohwer, N., Gehring, T., Seifert, U., et al. (2018) Female mice carrying a defective Alox15 gene are protected from experimental colitis via sustained maintenance of the intestinal epithelial barrier function. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 1863, 866–880
Madbouly, K. M., Senagore, A. J., Mukerjee, A., Hussien, A. M., Shehata, M. A., Navine, P., et al. (2007) Colorectal cancer in a population with endemic Schistosoma mansoni: is this an at-risk population? Int. J. Colorectal Dis. 22, 175–181
Hayes, K. S., Cliffe, L. J., Bancroft, A. J., Forman, S. P., Thompson, S., Booth, C., et al. (2017) Chronic Trichuris muris infection causes neoplastic change in the intestine and exacerbates tumor formation in APC min/+ mice. PLoS Negl. Trop. Dis. 11, e0005708
Pastille, E., Frede, A., McSorley, H. J., Grab, J., Adamczyk, A., Kollenda, S., et al. (2017) Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer. PLoS Pathog. 13, e1006649
Katsidzira, L., Gangaidzo, I. T., Makunike-Mutasa, R., Manyanga, T., Matsena-Zingoni, Z., Thomson, S., et al. (2019) A case-control study of risk factors for colorectal cancer in an African population. Eur. J. Cancer Prev. 28, 145–150
Pullan, R. L., Smith, J. L., Jasrasaria, R., and Brooker, S. J. (2014) Global numbers of infection and disease burden of soil transmitted helminth infections in 2010. Parasit Vectors. 7, 37
Henkel, F. D. R., Friedl, A., Haid, M., Thomas, D., Bouchery, T., Haimerl, P., et al. (2019) House dust mite drives proinflammatory eicosanoid reprogramming and macrophage effector functions. Allergy. 74, 1090–1101
de Los Reyes Jimenez, M., Lechner, A., Alessandrini, F., Bohnacker, S., Schindela, S., Trompette, A., et al. (2020) An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products. Sci. Transl. Med. 12, eaay0605
Prodjinotho, U. F., Gres, V., Henkel, F., Lacorcia, M., Dandl, R., Haslbeck, M., et al. (2022) Helminthic dehydrogenase drives PGE(2) and IL-10 production in monocytes to potentiate Treg induction. EMBO Rep. 23, e54096
Imamura, F., Micha, R., Khatibzadeh, S., Fahimi, S., Shi, P., Powles, J., et al. (2015) Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. Lancet Glob. Health. 3, e132–e142
Popkin, B. M. (2006) Global nutrition dynamics: the world is shifting rapidly toward a diet linked with noncommunicable diseases. Am. J. Clin. Nutr. 84, 289–298
Enos, R. T., Velazquez, K. T., McClellan, J. L., Cranford, T. L., Nagarkatti, M., Nagarkatti, P. S., et al. (2016) High-fat diets rich in saturated fat protect against azoxymethane/dextran sulfate sodium-induced colon cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 310, G906–G919
Johnston, C. J., Robertson, E., Harcus, Y., Grainger, J. R., Coakley, G., Smyth, D. J., et al. (2015) Cultivation of Heligmosomoides polygyrus: an immunomodulatory nematode parasite and its secreted products. J. Vis. Exp. 98, e52412
Bligh, E. G., and Dyer, W. J. (1959) A rapid method of total lipid extraction and purification. Can J. Biochem. Physiol. 37, 911–917
Southam, A. D., Weber, R. J., Engel, J., Jones, M. R., and Viant, M. R. (2016) A complete workflow for high-resolution spectral-stitching nanoelectrospray direct-infusion mass-spectrometry-based metabolomics and lipidomics. Nat. Protoc. 12, 310–328
Martens, M., Ammar, A., Riutta, A., Waagmeester, A., Slenter, D. N., Hanspers, K., et al. (2021) WikiPathways: connecting communities. Nucleic Acids Res. 49, D613–D621
Kutmon, M., van Iersel, M. P., Bohler, A., Kelder, T., Nunes, N., Pico, A. R., et al. (2015) PathVisio 3: an extendable pathway analysis toolbox. PLoS Comput. Biol. 11, e1004085
Gabbs, M., Leng, S., Devassy, J. G., Monirujjaman, M., and Aukema, H. M. (2015) Advances in our understanding of oxylipins derived from dietary PUFAs. Adv. Nutr. 6, 513–540
Litwack, G. (2022) Chapter 8 - eicosanoids. In Hormones, Fourth Edition, G. Litwack, editor. Academic Press, 195–212
Jia, Q., Lupton, J. R., Smith, R., Weeks, B. R., Callaway, E., Davidson, L. A., et al. (2008) Reduced colitis-associated colon cancer in Fat-1 (n-3 fatty acid desaturase) transgenic mice. Cancer Res. 68, 3985–3991
Matsunaga, H., Hokari, R., Kurihara, C., Okada, Y., Takebayashi, K., Okudaira, K., et al. (2008) Omega-3 fatty acids exacerbate DSS-induced colitis through decreased adiponectin in colonic subepithelial myofibroblasts. Inflamm. Bowel Dis. 14, 1348–1357
Wang, W., Yang, J., Edin, M. L., Wang, Y., Luo, Y., Wan, D., et al. (2019) Targeted metabolomics identifies the cytochrome P450 monooxygenase eicosanoid pathway as a novel therapeutic target of colon tumorigenesis. Cancer Res. 79, 1822–1830
Petrik, M. B., McEntee, M. F., Johnson, B. T., Obukowicz, M. G., and Whelan, J. (2000) Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice. J. Nutr. 130, 2434–2443
Miyata, J., Yokokura, Y., Moro, K., Arai, H., Fukunaga, K., and Arita, M. (2021) 12/15-Lipoxygenase regulates IL-33-induced eosinophilic airway inflammation in mice. Front. Immunol. 12, 687192
Nusse, Y. M., Savage, A. K., Marangoni, P., Rosendahl-Huber, A. K. M., Landman, T. A., de Sauvage, F. J., et al. (2018) Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche. Nature. 559, 109–113
Drurey, C., Lindholm, H. T., Coakley, G., Poveda, M. C., Loser, S., Doolan, R., et al. (2022) Intestinal epithelial tuft cell induction is negated by a murine helminth and its secreted products. J. Exp. Med. 219, e20211140
Brys, L., Beschin, A., Raes, G., Ghassabeh, G. H., Noel, W., Brandt, J., et al. (2005) Reactive oxygen species and 12/15-lipoxygenase contribute to the antiproliferative capacity of alternatively activated myeloid cells elicited during helminth infection. J. Immunol. 174, 6095–6104
Ma, X., Aoki, T., Tsuruyama, T., and Narumiya, S. (2015) Definition of prostaglandin E2-EP2 signals in the colon tumor microenvironment that amplify inflammation and tumor growth. Cancer Res. 75, 2822–2832
Hawcroft, G., Ko, C. W., and Hull, M. A. (2007) Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells. Oncogene. 26, 3006–3019
Hsu, C. S., and Li, Y. (2002) Aspirin potently inhibits oxidative DNA strand breaks: implications for cancer chemoprevention. Biochem. Biophys. Res. Commun. 293, 705–709
Rauzi, F., Kirkby, N. S., Edin, M. L., Whiteford, J., Zeldin, D. C., Mitchell, J. A., et al. (2016) Aspirin inhibits the production of proangiogenic 15(S)-HETE by platelet cyclooxygenase-1. FASEB J. 30, 4256–4266
Lecomte, M., Laneuville, O., Ji, C., DeWitt, D. L., and Smith, W. L. (1994) Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin. J. Biol. Chem. 269, 13207–13215
Neilson, A. P., Ren, J., Hong, Y. H., Sen, A., Smith, W. L., Brenner, D. E., et al. (2012) Effect of fish oil on levels of R- and S-enantiomers of 5-, 12-, and 15-hydroxyeicosatetraenoic acids in mouse colonic mucosa. Nutr. Cancer. 64, 163–172
Yang, V. W., Liu, Y., Kim, J., Shroyer, K. R., and Bialkowska, A. B. (2019) Increased genetic instability and accelerated progression of colitis-associated colorectal cancer through intestinal epithelium-specific deletion of Klf4. Mol. Cancer Res. 17, 165–176
Brudvik, K. W., Paulsen, J. E., Aandahl, E. M., Roald, B., and Tasken, K. (2011) Protein kinase A antagonist inhibits beta-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in Apc(Min/+) mice. Mol. Cancer. 10, 149
Kabashima, K., Saji, T., Murata, T., Nagamachi, M., Matsuoka, T., Segi, E., et al. (2002) The prostaglandin receptor EP4 suppresses colitis, mucosal damage and CD4 cell activation in the gut. J. Clin. Invest. 109, 883–893
Ohno, H., Morikawa, Y., and Hirata, F. (1978) Studies on 15-hydroxyprostaglandin dehydrogenase with various prostaglandin analogues. J. Biochem. 84, 1485–1494
Kiriyama, M., Ushikubi, F., Kobayashi, T., Hirata, M., Sugimoto, Y., and Narumiya, S. (1997) Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells. Br. J. Pharmacol. 122, 217–224
Bartsch, H., Nair, J., and Owen, R. W. (1999) Dietary polyunsaturated fatty acids and cancers of the breast and colorectum: emerging evidence for their role as risk modifiers. Carcinogenesis. 20, 2209–2218
Azrad, M., Turgeon, C., and Demark-Wahnefried, W. (2013) Current evidence linking polyunsaturated Fatty acids with cancer risk and progression. Front. Oncol. 3, 224
Petrik, M. B., McEntee, M. F., Chiu, C. H., and Whelan, J. (2000) Antagonism of arachidonic acid is linked to the antitumorigenic effect of dietary eicosapentaenoic acid in Apc(Min/+) mice. J. Nutr. 130, 1153–1158
Han, Y. M., Jeong, M., Park, J. M., Kim, M. Y., Go, E. J., Cha, J. Y., et al. (2016) The omega-3 polyunsaturated fatty acids prevented colitis-associated carcinogenesis through blocking dissociation of beta-catenin complex, inhibiting COX-2 through repressing NF-kappaB, and inducing 15-prostaglandin dehydrogenase. Oncotarget. 7, 63583–63595
Simopoulos, A. P. (2002) The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed. Pharmacother. 56, 365–379
Blasbalg, T. L., Hibbeln, J. R., Ramsden, C. E., Majchrzak, S. F., and Rawlings, R. R. (2011) Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am. J. Clin. Nutr. 93, 950–962
Calder, P. C. (2006) Polyunsaturated fatty acids and inflammation. Prostaglandins Leukot. Essent. Fatty Acids. 75, 197–202
Poudyal, H., Panchal, S. K., Diwan, V., and Brown, L. (2011) Omega-3 fatty acids and metabolic syndrome: effects and emerging mechanisms of action. Prog. Lipid Res. 50, 372–387
Simopoulos, A. P. (1999) Essential fatty acids in health and chronic disease. Am. J. Clin. Nutr. 70 (3 Suppl), 560S–569S
Suzuki, R., Kohno, H., Sugie, S., Nakagama, H., and Tanaka, T. (2006) Strain differences in the susceptibility to azoxymethane and dextran sodium sulfate-induced colon carcinogenesis in mice. Carcinogenesis. 27, 162–169
Mahler, M., Bristol, I. J., Leiter, E. H., Workman, A. E., Birkenmeier, E. H., Elson, C. O., et al. (1998) Differential susceptibility of inbred mouse strains to dextran sulfate sodium-induced colitis. Am. J. Physiol. 274, G544–G551
Nambiar, P. R., Girnun, G., Lillo, N. A., Guda, K., Whiteley, H. E., and Rosenberg, D. W. (2003) Preliminary analysis of azoxymethane induced colon tumors in inbred mice commonly used as transgenic/knockout progenitors. Int. J. Oncol. 22, 145–150
Laffin, M., Fedorak, R., Zalasky, A., Park, H., Gill, A., Agrawal, A., et al. (2019) A high-sugar diet rapidly enhances susceptibility to colitis via depletion of luminal short-chain fatty acids in mice. Sci. Rep. 9, 12294
Groschel, C., Prinz-Wohlgenannt, M., Mesteri, I., Karuthedom George, S., Trawnicek, L., Heiden, D., et al. (2019) Switching to a healthy diet prevents the detrimental effects of western diet in a colitis-associated colorectal cancer model. Nutrients. 12, 45
Idborg, H., and Pawelzik, S. C. (2022) Prostanoid metabolites as biomarkers in human disease. Metabolites. 12, 721
Hamabata, T., Nakamura, T., Masuko, S., Maeda, S., and Murata, T. (2018) Production of lipid mediators across different disease stages of dextran sodium sulfate-induced colitis in mice. J. Lipid Res. 59, 586–595
Bohnacker, S., Henkel, F. D. R., Hartung, F., Geerlof, A., Riemer, S., Prodjinotho, U. F., et al. (2024) A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis. Sci. Immunol. 9, eadl1467
Amable, G., Martinez-Leon, E., Picco, M. E., Di Siervi, N., Davio, C., Rozengurt, E., et al. (2019) Metformin inhibits beta-catenin phosphorylation on Ser-552 through an AMPK/PI3K/Akt pathway in colorectal cancer cells. Int. J. Biochem. Cell Biol. 112, 88–94
Oyesola, O. O., and Tait Wojno, E. D. (2021) Prostaglandin regulation of type 2 inflammation: from basic biology to therapeutic interventions. Eur. J. Immunol. 51, 2399–2416
