title: A New Model to Study the Role of Arachidonic Acid in Colon Cancer Pathophysiology.
abstract: A significant increase in cyclooxygenase 2 (COX2) gene expression has been shown to promote cylcooxygenase-dependent colon cancer development. Controversy associated with the role of COX2 inhibitors indicates that additional work is needed to elucidate the effects of arachidonic acid (AA)-derived (cyclooxygenase and lipoxygenase) eicosanoids in cancer initiation, progression, and metastasis. We have recently developed a novel Fads1 knockout mouse model that allows for the investigation of AA-dependent eicosanoid deficiency without the complication of essential fatty acid deficiency. Interestingly, the survival rate of Fads1-null mice is severely compromised after 2 months on a semi-purified AA-free diet, which precludes long-term chemoprevention studies. Therefore, in this study, dietary AA levels were titrated to determine the minimal level required for survival, while maintaining a distinct AA-deficient phenotype. Null mice supplemented with AA (0.1%, 0.4%, 0.6%, 2.0%, w/w) in the diet exhibited a dose-dependent increase (P < 0.05) in AA, PGE2, 6-keto PGF1α, TXB2, and EdU-positive proliferative cells in the colon. In subsequent experiments, null mice supplemented with 0.6% AA diet were injected with a colon-specific carcinogen (azoxymethane) in order to assess cancer susceptibility. Null mice exhibited significantly (P < 0.05) reduced levels/multiplicity of aberrant crypt foci (ACF) as compared with wild-type sibling littermate control mice. These data indicate that (i) basal/minimal dietary AA supplementation (0.6%) expands the utility of the Fads1-null mouse model for long-term cancer prevention studies and (ii) that AA content in the colonic epithelium modulates colon cancer risk. Cancer Prev Res; 9(9); 750-7. ©2016 AACR.
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Yang-Yi
authors.initials: YY
authors.lastname: Fan
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Callaway
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Jennifer
authors.initials: J
authors.lastname: M Monk
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Jennifer
authors.initials: J
authors.lastname: S Goldsby
authors.affiliation: Department of Palliative, Rehabilitation and Integrative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Peiying
authors.initials: P
authors.lastname: Yang
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas.
authors.forename: Logan
authors.initials: L
authors.lastname: Vincent
authors.affiliation: Program in Integrative Nutrition and Complex Diseases, Department of Nutrition and Food Science, Texas A&M University, College Station, Texas. Center for Translational Environmental Health Research, College Station, Texas. r-chapkin@tamu.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: S Chapkin
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D044943:Fatty Acid Desaturases / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016718:Arachidonic Acid; D044943:Fatty Acid Desaturases; C000623295:FADS1 protein, mouse