title: Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen-induced preneoplastic lesions formation.
abstract: In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis.
authors.affiliation: INSERM U531, IFR31, Hospital Rangueil, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Mathieu
authors.forename: Pascal
authors.initials: P
authors.lastname: Clerc
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Portolan
authors.forename: Christiane
authors.initials: C
authors.lastname: Bierkamp
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.forename: Lucien
authors.initials: L
authors.lastname: Pradayrol
authors.forename: Catherine
authors.initials: C
authors.lastname: Seva
authors.forename: Daniel
authors.initials: D
authors.lastname: Fourmy
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
mesh_terms: D000236:Adenoma / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001377:Azaserine / Q000737:chemistry / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002273:Carcinogens; D018267:Carcinoma, Acinar Cell / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics*; D049109:Cell Proliferation; D004396:Coloring Agents / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D006720:Homozygote; D007150:Immunohistochemistry; D007249:Inflammation; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics*; D010641:Phenotype; D011230:Precancerous Conditions / Q000378:metabolism; D043887:Receptor, Cholecystokinin B / Q000235:genetics* / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012306:Risk; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D019076:Transgenes
chemical_list: D000964:Antimetabolites, Antineoplastic; D002273:Carcinogens; D004396:Coloring Agents; D018398:Homeodomain Proteins; D043887:Receptor, Cholecystokinin B; D043562:Receptors, G-Protein-Coupled; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D001377:Azaserine; D001973:Bromodeoxyuridine