title: High-Fat Diet-Induced Complement Activation Mediates Intestinal Inflammation and Neoplasia, Independent of Obesity.
abstract: Obesity and related metabolic disturbances are closely associated with pathologies that represent a significant burden to global health. Epidemiological and molecular evidence links obesity and metabolic status with inflammation and increased risk of cancer. Here, using a mouse model of intestinal neoplasia and strains that are susceptible or resistant to diet-induced obesity, it is demonstrated that high-fat diet-induced inflammation, rather than obesity or metabolic status, is associated with increased intestinal neoplasia. The complement fragment C5a acts as the trigger for inflammation and intestinal tumorigenesis. High-fat diet induces complement activation and generation of C5a, which in turn induces the production of proinflammatory cytokines and expression of proto-oncogenes. Pharmacological and genetic targeting of the C5a receptor reduced both inflammation and intestinal polyposis, suggesting the use of complement inhibitors for preventing diet-induced neoplasia.
  
  
  
  This study characterizes the relations between diet and metabolic conditions on risk for a common cancer and identifies complement activation as a novel target for cancer prevention. Mol Cancer Res; 14(10); 953-65. ©2016 AACR.
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Doerner
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Edimara S
authors.initials: ES
authors.lastname: Reis
authors.affiliation: Pacific Northwest Research Institute, Seattle, Washington.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Leung
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Justine S
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Heaney
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Berger
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Department of Genetics, Case Western Reserve University, Cleveland, Ohio. Pacific Northwest Research Institute, Seattle, Washington. jnadeau@pnri.org.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Nadeau
mesh_terms: D000818:Animals; D003167:Complement Activation; D015936:Complement C5a / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009765:Obesity / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D011519:Proto-Oncogenes
chemical_list: D016207:Cytokines; D015936:Complement C5a