Cell proliferation and apoptosis in the exocrine pancreas of azaserine-treated rats and N-nitrosobis(2-oxopropyl)amine-treated hamsters

Abstract

Altered cell proliferation is an important characteristic of neoplastic development, hence the quantitation of cell growth in normal and (pre)neoplastic pancreatic tissue will provide useful information on the process (and modulation) of pancreatic tumour promotion in experimental animals. Cell proliferation was estimated by means of BrdU-incorporation in normal pancreatic tissue and in putative preneoplastic pancreatic tissue of azaserine-treated rats and of N-nitrosobis(2-oxopropyl)amine (BOP)-treated hamsters at 2, 6, 12, 26 and 52 weeks post-treatment. Furthermore, the effects of diets high in vegetable oil or fish oil on the BrdU labeling index, the Ki-67 labeling index as well as the apoptotic labeling index were determined in azaserine-induced atypical acinar cell foci (AACF) in the pancreas of rats. In saline- and azaserine-treated rats, the BrdU labeling index (LI) in normal pancreatic acinar cells showed a similar time-related decrease. In azaserine-treated rats, the BrdU-LI in AACF was significantly higher than in normal acinar tissue. The BrdU, Ki-67 and apoptotic labeling indices in pancreatic AACF of rats fed diets high in vegetable oil versus fish oil were 24.8+/-1.7 vs 15.5+/-1.2 (BrdU; P<0.05), 9.9+/-0.8 vs 6.5+/-0.5 (Ki-67; P<0.001) and 1.31+/-0.12 vs 0.97+/-0.11 (apoptosis; P<0.05), respectively. In hamsters, up to 26 weeks after BOP-treatment the BrdU-LI in acinar cells was significantly higher than in saline-treated animals. In BOP-treated hamsters, ductal cells showed a significantly increased LI 2 weeks post-treatment, whereas the LI in centroacinar cells had significantly increased 2 and 26 weeks post-treatment. In hamster pancreas the LI was significantly higher in tubular ductal complexes than in cystic ductal complexes and was highest in borderline lesions. It is concluded that (i) determination of BrdU-LI provides a reliable parameter to discriminate between putative preneoplastic lesions with a high or low growth potential, hence with a high or low potential to develop into ultimate carcinomas, (ii) BOP causes increased DNA synthesis in normal acinar cells, leading to increased risk of additional DNA damage, implicating the acinar cell to be putatively involved in the development of ductular adenocarcinomas in the hamster pancreas and (iii) quantitation of cell proliferation and apoptosis may be useful to determine the enhancing or inhibitory effects of life-style factors on pancreatic carcinogenesis.