Transgenic mice expressing cholecystokinin 2 receptors in the pancreas

Abstract

Several studies argue for the presence of CCK2 receptors in the human pancreas but their physiological role in normal exocrine pancreas and their contribution to pancreatic pathologies is unknown. In order to allow an easy investigation of their pancreatic function, we created the ElasCCK2 transgenic mice expressing the human receptor in pancreatic exocrine cells. In this model, the CCK2 receptor is specifically expressed in the exocrine pancreas and has typical molecular and binding features. It is functional and mediates enzyme release but stimulating concentrations of agonists are not physiological. Results of phenotypic and long-term studies show that activation of CCK2 receptors stimulates growth of the pancreas in correlation with an increase of acinar tissue. This finding is also consistent with the demonstration of an efficient coupling of the transgenic receptor to protein synthesis. Alterations in pancreatic histology and development of preneoplastic lesions are apparent from postnatal day 50. Moreover, expression of this G-protein-coupled receptor leads to the development of tumours in older animals with an incidence of 15%. Although tumours have distinct phenotypes they all exhibit ductular structures. Immunohistochemical analysis of these structures shows their acinar origin. These data, linking for the first time the development of pancreatic carcinogenesis in vivo to the expression of the CCK2 receptor, support a key role of the CCK2 receptor in the initiation of pancreatic cancer. Moreover, ElasCCK2 mice provide a model for carcinogenesis by transformation and dedifferentiation of acinar cells.