Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota
Giulia Piazzi
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Conflct of Interest: Luigi Ricciardiello has received an unrestricted scientific grant from SLA Pharma AG. Mark Hull has received a travel grant and an unrestricted scientific grant from SLA Pharma AG.
Search for more papers by this authorGiuseppe D'Argenio
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorAnna Prossomariti
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorVincenzo Lembo
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorGiovanna Mazzone
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorMarco Candela
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorElena Biagi
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorPatrizia Brigidi
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorPaola Vitaglione
Department of Agricultural and Food Science, University of Naples, Naples, Italy
Search for more papers by this authorVincenzo Fogliano
Food Quality Design, Wageningen University & Research Centre, Wageningen, The Netherlands
Search for more papers by this authorLeonarda D'Angelo
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorChiara Fazio
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorAlessandra Munarini
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorAndrea Belluzzi
Gastroenterology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorClaudio Ceccarelli
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Search for more papers by this authorPasquale Chieco
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorTiziana Balbi
Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorPaul M. Loadman
Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, United Kingdom
Search for more papers by this authorMark A. Hull
Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, United Kingdom
Search for more papers by this authorMarco Romano
Department of Clinical and Experimental Medicine “Magrassi-Lanzara”, Gastroenterology Unit, Second University of Naples, Naples, Italy
Search for more papers by this authorFranco Bazzoli
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorCorresponding Author
Luigi Ricciardiello
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Correspondence to: Dr. Luigi Ricciardiello, Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, PAD11, Bologna 40138, Italy, Tel.: +39-051-6363381, E-mail: [email protected]Search for more papers by this authorGiulia Piazzi
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Conflct of Interest: Luigi Ricciardiello has received an unrestricted scientific grant from SLA Pharma AG. Mark Hull has received a travel grant and an unrestricted scientific grant from SLA Pharma AG.
Search for more papers by this authorGiuseppe D'Argenio
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorAnna Prossomariti
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorVincenzo Lembo
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorGiovanna Mazzone
Gastroenterology Unit, University of Naples Federico II and Institute of Protein Biochemistry, CNR, Naples, Italy
Search for more papers by this authorMarco Candela
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorElena Biagi
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorPatrizia Brigidi
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
Search for more papers by this authorPaola Vitaglione
Department of Agricultural and Food Science, University of Naples, Naples, Italy
Search for more papers by this authorVincenzo Fogliano
Food Quality Design, Wageningen University & Research Centre, Wageningen, The Netherlands
Search for more papers by this authorLeonarda D'Angelo
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorChiara Fazio
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorAlessandra Munarini
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorAndrea Belluzzi
Gastroenterology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorClaudio Ceccarelli
Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
Search for more papers by this authorPasquale Chieco
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorTiziana Balbi
Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Search for more papers by this authorPaul M. Loadman
Yorkshire Experimental Cancer Medicine Centre, Institute of Cancer Therapeutics, University of Bradford, United Kingdom
Search for more papers by this authorMark A. Hull
Section of Molecular Gastroenterology, Leeds Institute of Biomedical & Clinical Sciences, St James's University Hospital, Leeds, United Kingdom
Search for more papers by this authorMarco Romano
Department of Clinical and Experimental Medicine “Magrassi-Lanzara”, Gastroenterology Unit, Second University of Naples, Naples, Italy
Search for more papers by this authorFranco Bazzoli
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Search for more papers by this authorCorresponding Author
Luigi Ricciardiello
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
Correspondence to: Dr. Luigi Ricciardiello, Department of Medical and Surgical Sciences, University of Bologna, Via Massarenti 9, PAD11, Bologna 40138, Italy, Tel.: +39-051-6363381, E-mail: [email protected]Search for more papers by this authorAbstract
Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA–FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA-FFA is an excellent candidate for CRC chemoprevention in CAC.
Abstract
What's new?
Recent clinical data show that, as yet, there is no agent clearly protecting against colorectal cancer (CRC) development in long-standing inflammatory bowel diseases. This study tests the effect of dietary supplementation with eicosapentaenoic acid, as free fatty acid (EPA-FFA), in a mouse model of colitis-associated CRC. The results demonstrate for the first time that EPA-FFA is an effective chemopreventive agent during both initiation and promotion of colitis-associated colorectal cancer in mice, with changes in Notch1 signaling and gut microbiota composition. Early EPA-FFA supplementation could thus be a good strategy for CRC prevention in subjects affected by inflammatory bowel diseases.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
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