title: Inverse genetic predisposition to colon versus lung carcinogenesis in mouse lines selected based on acute inflammatory responsiveness.
abstract: Mouse lines produced by bidirectional selection on the basis of maximum (AIRmax) or minimum (AIRmin) acute inflammatory reactions were examined for the development of chemically induced acute colitis and colon tumors and the development of lung tumors. AIRmax mice were more susceptible than AIRmin to acute colitis induced by ingestion of dextran sodium sulfate showing a 3-fold higher disease activity index and presenting an intense inflammatory infiltrate in the base of colon crypts as well as elevated expression of IL-1beta, TNFalpha, IFNgamma and IL-6 mRNA in colon tissue. AIRmax were also more susceptible than AIRmin to colon cancer induced by 2 or 7 weekly doses of 1,2-dimethylhydrazine (DMH), showing significantly higher numbers of colonic aberrant crypt foci (ACF) at 150 days after DMH treatment (P = 0.01) and significantly higher numbers of tumors affecting larger intestinal areas at 300-475 days. At the latter time point, however, multiple lung adenomas and large adenocarcinomas were found in AIRmin but not in AIRmax mice. Treatment of mice with nimesulide for 60 days beginning 24 h before the first of two DMH doses almost completely inhibited the appearance of ACF in both lines. Furthermore, ACF numbers and the degree of acute inflammation directly co-segregated in an F2 (AIRmax x AIRmin) intercross population. The results demonstrate that genetic determinants of the inflammatory response differentially influence susceptibility to colon and lung carcinogenesis in the AIRmax and AIRmin mouse model.
authors.affiliation: Laboratório de Imunogenética, Instituto Butantan, São Paulo, SP, Brazil.
authors.forename: Roberto Francisco
authors.initials: RF
authors.lastname: Di Pace
authors.forename: Solange
authors.initials: S
authors.lastname: Massa
authors.forename: Orlando Garcia
authors.initials: OG
authors.lastname: Ribeiro
authors.forename: Wafa Hanna Koury
authors.initials: WH
authors.lastname: Cabrera
authors.forename: Marcelo
authors.initials: M
authors.lastname: De Franco
authors.forename: Nancy
authors.initials: N
authors.lastname: Starobinas
authors.forename: Michel
authors.initials: M
authors.lastname: Seman
authors.forename: Olga Célia Martinez
authors.initials: OC
authors.lastname: Ibañez
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000633:toxicity; D000208:Acute Disease; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D007111:Immunity, Cellular / Q000235:genetics*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains
chemical_list: D000998:Antiviral Agents; D002273:Carcinogens; D016207:Cytokines; D016264:Dextran Sulfate; D019813:1,2-Dimethylhydrazine