title: Expression of cholecystokinin-2/gastrin receptor in the murine pancreas modulates cell adhesion and cell differentiation in vivo.
abstract: The presence of gastrin and cholecystokinin-2 (CCK2) receptors in human preneoplastic and neoplastic gastrointestinal lesions suggests a role in cancer development. In addition to the growth-promoting action of gastrin, recently a role of the cholecystokinin-2/gastrin receptor (CCK2-R) modulating cellular morphology in cultured epithelial cells has been shown. Here, we have investigated in transgenic (ElasCCK2) mice whether ectopic expression of human CCK2-R in the exocrine pancreas affected epithelial differentiation. Cellular localization of cell adhesion molecules, differentiation markers, and transcription factors was determined using immunofluorescence techniques. Before tumor formation, expression and subcellular localization of proteins of the adherens junction complex, differentiation markers, and transcription factors were altered in ElasCCK2 exocrine pancreas, indicating an evolution from an acinar to a ductal phenotype. Loss of cell polarity, defective secretion, and loss of intercellular adhesion in acini of ElasCCK2 mice was confirmed by ultrastructural analysis. Finally, expression of the transgene in mice treated with the carcinogen azaserine resulted in enhanced size of preneoplastic lesions as well as an increased degree of acinar-ductal transdifferentiation. Thus, these data represent the first evidence for the CCK2-R modulating intercellular adhesion and cell fate in vivo and show that these alterations may contribute to enhanced sensitivity of ElasCCK2 pancreas to chemical carcinogens.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, INSERM U531, Hospital Rangueil, 31059 Toulouse Cedex 9, France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Bierkamp
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bonhoure
authors.forename: Anne
authors.initials: A
authors.lastname: Mathieu
authors.forename: Pascal
authors.initials: P
authors.lastname: Clerc
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
authors.forename: Lucien
authors.initials: L
authors.lastname: Pradayrol
authors.forename: Catherine
authors.initials: C
authors.lastname: Seva
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
mesh_terms: D000818:Animals; D001377:Azaserine / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D002448:Cell Adhesion; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D007515:Islets of Langerhans / Q000254:growth & development / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000254:growth & development / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*; D019076:Transgenes
chemical_list: D002273:Carcinogens; D043887:Receptor, Cholecystokinin B; D001377:Azaserine