title: Carcinogen-induced pancreatic lesions in the mouse: effect of Smad4 and Apc genotypes.
abstract: Mutations in the tumour suppressor genes SMAD4 (DPC4, deleted in pancreatic cancer locus 4) and adenomatous polyposis coli (APC) have been implicated in the development of pancreatic cancer in humans. Treatment of wild-type, Smad4(+/-), Apc(Min/+) or Apc(Min/+)Smad4(+/-) mice with N-Nitroso-N-Methyl Urea (NMU) results in abnormal foci in pancreatic acinar cells characterized by increased levels of beta-catenin. Previously such foci have been shown to be the precursors of pancreatic neoplasia. Interestingly, only NMU-treated Apc(Min/+)Smad4(+/-) mice exhibit a significant increase in abnormal pancreas, which was found to be due to increased number of abnormal foci rather than increased focus size. A range of foci sizes were analysed, but only smaller abnormal foci were characterized by morphological nuclear atypia. These studies suggest functional co-operation between TGF-beta and Wnt signalling pathways in the suppression of pancreatic tumorigenesis in the mouse.
authors.affiliation: Sir Alastair Currie Cancer Research UK Laboratories, Molecular Medicine Centre, Western General Hospital, Edinburgh EH4 2XU, UK.
authors.forename: Jan
authors.initials: J
authors.lastname: Cullingworth
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hooper
authors.forename: David J
authors.initials: DJ
authors.lastname: Harrison
authors.forename: John O
authors.initials: JO
authors.lastname: Mason
authors.forename: Christian
authors.initials: C
authors.lastname: Sirard
authors.forename: Charles E
authors.initials: CE
authors.lastname: Patek
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051901:Smad4 Protein; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; C490809:smad4a protein, zebrafish; D008770:Methylnitrosourea