© 1995 Oxford University Press
research-article |
Transforming growth factor-
and epidermal growth factor expression in the exocrine pancreas of azaserine-treated rats: modulation by cholecystokinin or a low fat, high fiber (caloric restricted) diet
1Departments of Pathology and Molecular Biology, University Hospital Utrecht PO Box 85500, 3508 GA, Utrecht
2Department of Pathology, Division of Toxicology, TNO Nutrition and Food Research Institute PO Box 360, 3700 AJ Zeist, The Netherlands
3To whom correspondence should be addressed
Expression of transforming growth factor-
(TGF-) and epidermal growth factor (EGF) was studied in normal pancreatic tissue and in (pre)neoplastic pancreatic lesions of azaserine-treated rats. They were given either a low fat, high fiber (low caloric) diet, to inhibit carcinogenesis, or a low fat diet combined with injections of the cholecystokinin analog caerulein to enhance carcinogenesis. The control groups, maintained on a low fat diet, were injected with azaserine or were not treated at all. Autopsy was performed at 6 and 15 months after the last azaserine injection. After both 6 and 15 months immunohistochemistry revealed a weak expression of EGF and TGF- peptides in the acinar cells and a stronger expression in the ductular and centroacinar cells. TGF- peptide expression was reduced in both putative preneoplastic and neoplastic acinar cell lesions, but no differences in EGF peptide expression were observed between the various stages of exocrine pancreatic carcinogenesis. After 16 months an increase in TGF- mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF- mRNA levels in macroscopically isolated tumors were significantly lower, but EGF mRNA levels were significantly higher, than in total pancreatic homogenates from azaserine treated rats. Furthermore, EGF and TGF- mRNA levels in isolated tumors did not differ significantly from mRNA levels in non-carcinogen-treated rats. Neither with immunohistochemistry nor with PCR were differences in EGF or TGF- expression observed due to either inhibition or stimulation of carcinogenesis. It is concluded that putative preneoplastic acinar cell lesions induced in rat pancreas by azaserine may develop into acinar adenocarcinomas independently of TGF- and EGF. The results suggest involvement of these growth factors at the early stage of the carcinogenic process, during the initiation of normal acinar cells into putative preneoplastic cells. However, modulation of azaserine-induced pancreatic carcinogenesis by cholecystokinin or a low fat, high fiber (caloric restricted) diet appeared not to be regulated by EGF or TGF-.