title: Loss of free fatty acid receptor 2 enhances colonic adenoma development and reduces the chemopreventive effects of black raspberries in ApcMin/+ mice.
abstract: We previously showed that black raspberries (BRBs) have beneficial effects in human colorectal cancer and a mouse model of colorectal cancer (ApcMin/+). The current study investigated the role of free fatty acid receptor 2 (FFAR2) in colon carcinogenesis and whether the FFAR2 signaling pathway contributes to BRB-mediated chemoprevention in mice. FFAR2 (also named GPR43) is a member of the G-protein-coupled receptor family that is expressed in leukocytes and colon. ApcMin/+and ApcMin/+-FFAR2-/-mice were given a control diet or the control diet supplemented with 5% BRBs for 8 weeks. FFAR2 deficiency promoted colonic polyp development, with 100% incidence and increased polyp number and size. The ApcMin/+mice developed colonic tubular adenoma, whereas the ApcMin/+-FFAR2-/-mice developed colonic tubular adenoma with high-grade dysplasia. FFAR2 deficiency also enhanced the cAMP-PKA-CREB-HDAC pathway, downstream of FFAR2 signaling, and increased activation of the Wnt pathway, and raised the percentage of GR-1+neutrophils in colonic lamina propria (LP) and increased infiltration of GR-1+neutrophils into colonic polyps. BRBs suppressed colonic polyp development and inhibited the cAMP-PKA-CREB-HDAC and Wnt pathways in the ApcMin/+mice but not the ApcMin/+-FFAR2-/-mice. They also increased the percentage of GR-1+neutrophils and cytokine secretion in colonic LP and decreased the infiltration of GR-1+neutrophils and IL-1β expression in colon polyps of ApcMin/+mice but not ApcMin/+-FFAR2-/-mice. These results suggest that loss of FFAR2 drives colon tumorigenesis and that BRBs require functional FFAR2 to be chemopreventive. BRBs have the potential to modulate the host immune system, thereby enhancing the antitumor immune microenvironment.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine.
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.forename: Chad
authors.initials: C
authors.lastname: W Skaer
authors.forename: Hsin-Tzu
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Department of Pathology and.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Center for Biostatistics and.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: M Yearsley
authors.forename: Kimberle
authors.initials: K
authors.lastname: A Agle
authors.forename: William
authors.initials: W
authors.lastname: R Drobyski
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Li-Shu
authors.initials: LS
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D063646:Carcinogenesis; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005638:Fruit / Q000737:chemistry; D017491:Genes, APC / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D065856:Rubus / Q000737:chemistry*
chemical_list: D016588:Anticarcinogenic Agents; C506481:Ffar2 protein, mouse; D010936:Plant Extracts; D043562:Receptors, G-Protein-Coupled