title: Restoring Retinoic Acid Attenuates Intestinal Inflammation and Tumorigenesis in APCMin/+ Mice.
abstract: Chronic intestinal inflammation accompanies familial adenomatous polyposis (FAP) and is a major risk factor for colorectal cancer in patients with this disease, but the cause of such inflammation is unknown. Because retinoic acid (RA) plays a critical role in maintaining immune homeostasis in the intestine, we hypothesized that altered RA metabolism contributes to inflammation and tumorigenesis in FAP. To assess this hypothesis, we analyzed RA metabolism in the intestines of patients with FAP as well as APCMin/+mice, a model that recapitulates FAP in most respects. We also investigated the impact of intestinal RA repletion and depletion on tumorigenesis and inflammation in APCMin/+mice. Tumors from both FAP patients and APCMin/+mice displayed striking alterations in RA metabolism that resulted in reduced intestinal RA. APCMin/+mice placed on a vitamin A-deficient diet exhibited further reductions in intestinal RA with concomitant increases in inflammation and tumor burden. Conversely, restoration of RA by pharmacologic blockade of the RA-catabolizing enzyme CYP26A1 attenuated inflammation and diminished tumor burden. To investigate the effect of RA deficiency on the gut immune system, we studied lamina propria dendritic cells (LPDC) because these cells play a central role in promoting tolerance. APCMin/+LPDCs preferentially induced Th17 cells, but reverted to inducing Tregs following restoration of intestinal RA in vivo or direct treatment of LPDCs with RA in vitro These findings demonstrate the importance of intestinal RA deficiency in tumorigenesis and suggest that pharmacologic repletion of RA could reduce tumorigenesis in FAP patients. Cancer Immunol Res; 4(11); 917-26. ©2016 AACR.
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Hweixian Leong
authors.initials: HL
authors.lastname: Penny
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Tyler R
authors.initials: TR
authors.lastname: Prestwood
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Nupur
authors.initials: N
authors.lastname: Bhattacharya
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Fionna
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Kenkel
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Davidson
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Immunology, Veterans Administration Hospital, Palo Alto, California.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Zuniga
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Seeley
authors.affiliation: Department of Pathology, Stanford University, Stanford, California.
authors.forename: Reetesh
authors.initials: R
authors.lastname: Pai
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Okmi
authors.initials: O
authors.lastname: Choi
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California.
authors.forename: Lorna
authors.initials: L
authors.lastname: Tolentino
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Nutritional Science and Toxicology, University of California, Berkeley, Berkeley, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.affiliation: Department of Pathology, Stanford University School of Medicine (Blood Center), Palo Alto, California. edengleman@stanford.edu.
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004760:Enterocolitis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017491:Genes, APC; D006801:Humans; D051379:Mice; D010641:Phenotype; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D047368:Tumor Burden; D014801:Vitamin A / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014801:Vitamin A; D014212:Tretinoin