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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Clerc
Pascal
P
INSERM U531, Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
Leung-Theung-Long
Stéphane
S
Wang
Timothy C
TC
Dockray
Graham J
GJ
Bouisson
Michèle
M
Delisle
Marie-Bernadette
MB
Vaysse
Nicole
N
Pradayrol
Lucien
L
Fourmy
Daniel
D
Dufresne
Marlène
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007515:Islets of Langerhans / Q000254:growth & development / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010179:Pancreas / Q000254:growth & development / Q000473:pathology / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000235:genetics*
D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin