title: Conditional loss of TGF-beta signalling leads to increased susceptibility to gastrointestinal carcinogenesis in mice.
abstract: BACKGROUND
  Downregulation of TGF-beta receptors is implicated in colon cancer development. Inactivation of either of the two transmembrane serine/threonine kinases, TGF-beta1 types I/II receptors, is now implicated in carcinogenesis, especially gastrointestinal carcinogenesis.
  
  
  METHODS
  We generated transgenic mice, called pS2-dnRII or ITF-dnRII, of which the dominant negative mutant of the TGF-beta type II receptor was expressed under the control of tissue-specific promoters, the pS2 promoter for stomach and ITF for intestine. They were either infected with H.pylori (ATCC 43504 strain, CagA+ and VacA+) or administered with azoxymethane to determine the significance of loss of TGF-beta signalling in gastrointestinal carcinogenesis.
  
  
  RESULTS
  Gastric adenocarcinoma developed in pS2-dnRII mice, whereas only chronic active gastritis was noted in wild-type littermates after 36 weeks of H.pylori infection. Mice lacking in TGF-beta signalling specifically in the stomach showed a significantly higher proliferation cell nuclear antigen-labelling index when infected with H.pylori than wild-type littermates (P < 0.01). Development of colonic aberrant crypt foci was provoked in mice by intraperitoneal injections of azoxymethane, and ITF-dnRII mice showed significantly higher incidences of ACF and colon cancers than wild-type littermates.
  
  
  CONCLUSIONS
  Maintaining normal TGF-beta signalling in the gastrointestinal tract seems to be important either for preventing abnormal mucosal proliferation, or for suppressing or retarding carcinogenesis.
authors.affiliation: Ajou Helicobacter Research Group, Ajou University School of Medicine, Wonchon-dong, Padal-ku, Suwon, Korea. hahmkb@hotmail.com
authors.forename: K-B
authors.initials: KB
authors.lastname: Hahm
authors.forename: K M
authors.initials: KM
authors.lastname: Lee
authors.forename: Y B
authors.initials: YB
authors.lastname: Kim
authors.forename: W S
authors.initials: WS
authors.lastname: Hong
authors.forename: W H
authors.initials: WH
authors.lastname: Lee
authors.forename: S U
authors.initials: SU
authors.lastname: Han
authors.forename: M W
authors.initials: MW
authors.lastname: Kim
authors.forename: B O
authors.initials: BO
authors.lastname: Ahn
authors.forename: T Y
authors.initials: TY
authors.lastname: Oh
authors.forename: M H
authors.initials: MH
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Green
authors.forename: S J
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002277:Carcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004198:Disease Susceptibility; D005756:Gastritis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori; D051379:Mice; D008822:Mice, Transgenic; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D001397:Azoxymethane