Expression of CCK2 receptors in the murine pancreas: proliferation, transdifferentiation of acinar cells, and neoplasia

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 122; no. 2; p. 428
• Main Authors: Clerc, Pascal, Leung-Theung-Long, Stéphane, Wang, Timothy C, Dockray, Graham J, Bouisson, Michèle, Delisle, Marie-Bernadette, Vaysse, Nicole, Pradayrol, Lucien, Fourmy, Daniel, Dufresne, Marlène
• Format: Journal Article
• Language: English
• Published: United States 01.02.2002
• Subjects: Animals; Cell Differentiation - physiology; Cell Division - physiology; Cell Transformation, Neoplastic; Disease Models, Animal; Gene Expression - physiology; Homeostasis - physiology; Humans; Islets of Langerhans - growth & development; Islets of Langerhans - pathology; Islets of Langerhans - physiology; Mice; Mice, Inbred Strains; Mice, Transgenic; Pancreas - growth & development; Pancreas - pathology; Pancreas - physiology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - physiopathology; Receptor, Cholecystokinin B; Receptors, Cholecystokinin - genetics
• ISSN: 0016-5085
• DOI: 10.1053/gast.2002.30984

To explore the pancreatic function of CCK2/gastrin receptor, we created ElasCCK2 transgenic mice expressing the human receptor in pancreatic exocrine cells. In previous studies, the transgenic CCK2/gastrin receptor was demonstrated to mediate enzyme release and protein synthesis. We now report results of phenotypic and long-term studies. Pancreas was characterized using morphometry and immunohistochemistry. ElasCCK2 mice were crossed with INS-GAS mice expressing gastrin in pancreatic beta cells to achieve continuous stimulation of the CCK2/gastrin receptor. The pancreatic weight of ElasCCK2 mice was increased by 40% and correlated with an increase in the area of exocrine tissue. Alterations in pancreatic histology were apparent from postnatal day 50. Crossing the ElasCCK2 mice with INS-GAS mice resulted in development of morphologic changes in younger animals. Malignant transformation occurred in 3 of 20 homozygous ElasCCK2 mice. Although tumors had different phenotypes, they all developed through an acinar-ductal carcinoma sequence. Our data show that transgenic expression of a G protein-coupled receptor can lead to cancer. This study also supports a key role of the CCK2/gastrin receptor in the development of pre- and neoplastic lesions of the pancreas. ElasCCK2 mice provide a model for carcinogenesis by transformation and dedifferentiation of acinar cells.