Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis‐associated colorectal cancer acting on Notch signaling and gut microbiota

• Published in: International journal of cancer Vol. 135; no. 9; pp. 2004 - 2013
• Main Authors: Piazzi, Giulia, D'Argenio, Giuseppe, Prossomariti, Anna, Lembo, Vincenzo, Mazzone, Giovanna, Candela, Marco, Biagi, Elena, Brigidi, Patrizia, Vitaglione, Paola, Fogliano, Vincenzo, D'Angelo, Leonarda, Fazio, Chiara, Munarini, Alessandra, Belluzzi, Andrea, Ceccarelli, Claudio, Chieco, Pasquale, Balbi, Tiziana, Loadman, Paul M., Hull, Mark A., Romano, Marco, Bazzoli, Franco, Ricciardiello, Luigi
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01.11.2014; Wiley Subscription Services, Inc
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cancer; Cell Proliferation; cells; chemoprevention; Colitis - chemically induced; Colitis - complications; Colitis - pathology; Colon - microbiology; Colon - pathology; colon cancer; Colorectal cancer; Colorectal Neoplasms - etiology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; dietary fish-oil; differentiation; docosahexaenoic acid; Eicosapentaenoic Acid - administration & dosage; Fatty acids; Fatty Acids, Nonesterified - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - microbiology; Immunoenzyme Techniques; inflammation; Inflammation - etiology; Inflammation - pathology; Inflammation - prevention & control; Inflammatory bowel disease; intestinal microbiota; Lactobacillus; Male; Medical research; Medical sciences; Mice; Mice, Inbred C57BL; microbiota; Microbiota - drug effects; Microbiota - physiology; mouse model; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Notch; omega 3; Real-Time Polymerase Chain Reaction; Receptors, Notch - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Rodents; sodium; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; microbiota; Notch receptor; Rectal disease; Digestive system; Colorectal cancer; Gut; Notch; omega 3; Lipids; Inflammation; Free fatty acid; Malignant tumor; n-3 fatty acid; Colonic disease; Prevention; Signal transduction; Colon cancer; Cancerology; Digestive diseases; Intestinal disease; Colitis; Colon; Eicosapentaenoic acid; Cancer; inflammation; colon cancer
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.28853

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. 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.