The role of endogenous hypercholecystokininemia and hypergastrinemia in growth and carcinogenesis of the exocrine pancreas

Sammanfattning: The gut hormones cholecystokinin (CCK) and gastrin are phylogeneticallyand structurally related. Under normal conditions, CCK regulates growth of the exocrine pancreas and gastrin growth of the oxyntic mucosa of the stomach. The effects of chronically increased endogenous secretion ofCCK or gastrin on pancreatic growth and carcinogenesis are not fully investigated. This thesis deals with such studies in rats and hamsters, using pancreaticobiliary diversion (PBD) to accomplish endogenous hypercholecystokininemia and gastric fundectomy to accomplish endogenous hypergastrinemia. PBD caused an immediate and persistent increase in the plasma CCKconcentration without affecting the plasma gastrin concentration. In hamsters, PBD induced an initial hyperplasia (increased [3H]-thymidine labeling index) of acinar cells followed by a persistent hypertrophy (increased weight, protein content, and DNA content) of the pancreas. No such changes were found in PBD operated hamsters receiving a CCK-A receptor antagonist. Longterm (14 months) PBD in rats lead to an increased fraction of aneuploid cells (DNA flow cytometry) in pancreatic tissue, and development of putative pre-neoplastic lesions (PPL) (acidophilic atypical acinar cell foci) and adenoma of the pancreas. No PPL or neoplasia were observed after longterm ( 8 months) PBD in hamsters. When rats were given a pancreatic carcinogen (azaserine), addition of PBD caused an increase in the fraction of aneuploid cells and in the volume fraction and cellular proliferation ( [3H]-thymidine labeling index) of the PPL. When hamsters were given a panceatic carcinogen (N-nitrosobis(2-oxopropyl)amine) (BOP), addition of PBD caused an increase in the incidence of PPL (ductal complexes) and ductal carcinoma in situ was observed. Furthermore, PBD caused an increase in the proliferative activity of the PPL. No increased proliferation in the PPL was seen in PBD operated animals receiving a CCK-A receptor antagonist. Gastric fundectomy caused an immediate and persistent increase in theplasma gastrin concentration without affecting the plasma CCK concentration. In hamsters, fundectomy induced an initial hyperplasia of acinar, ductal, and centroacinar cells followed by a persistent hypertrophy of the pancreas. No such changes were found in fundectomized animals receiving a CCK-B/gastrin receptor antagonist. Longterm (14 months) fundectomy in rats lead to an increase in the fraction of aneuploid cells in pancreatic tissue and development of PPL, but not neoplasia. No PPL or neoplasia were observed after long-standing ( 8 months) fundectomy in hamsters. When rats were given a pancreatic carcinogen (azaserine), addition of fundectomy lead to an increase in the fraction of aneuploid cells and an increase in the volumefraction, but not the proliferative activity, of the PPL. When hamsters weregiven a panceatic carcinogen (BOP), addition of fundectomy did not cause any significant change in the incidence or proliferative activity of PPL, and no neoplasia was observed. In conclusion, PBD induced persistent hypercholecystokininemia andfundectomy persistent hypergastrinemia, both of which induced exocrine tissue hyperplasia leading to persistent hypertrophy of the pancreas in rats and hamsters. The effects of PBD and fundectomy seemed to be mediated by CCK and gastrin, since they were blocked by simultaneous administration of a specific CCK-A and CCK-B/gastrin receptor antagonist, respectively. In longterm studies, both procedures caused development of PPL of the pancreas in rats but not in hamsters. In both rats and hamsters treated with a pancreatic carcinogen, addition of PBD enhanced the development of PPL. In rats, but not in hamsters, addition of fundectomy to carcinogen treatment also enhanced the development of PPL. Overall, the trophic as well as the promotive effects were significantly more pronounced after PBD than after fundectomy. In both rats and hamsters, pancreatic neoplasia was observed after PBD, but not after fundectomy.