ceruletide and Cocarcinogenesis

Expression of transforming growth factor-alpha (TGF-alpha) 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-alpha peptides in the acinar cells, and a stronger expression in the ductular and centroacinar cells. TGF-alpha 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-alpha mRNA due to treatment with azaserine was detected by semi-quantitative PCR in total pancreatic homogenates, whereas EGF mRNA expression had decreased. TGF-alpha 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-alpha 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-alpha 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-alpha 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-alpha.

Topics: Animals; Azaserine; Base Sequence; Body Weight; Carcinogens; Ceruletide; Cocarcinogenesis; Diet, Fat-Restricted; Dietary Fiber; Drug Synergism; Energy Intake; Epidermal Growth Factor; Immunohistochemistry; Male; Molecular Sequence Data; Organ Size; Pancreas; Pancreatic Neoplasms; Polymerase Chain Reaction; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor alpha

The effect of caerulein on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Prolonged alternate-day administration of caerulein at 10 micrograms/kg body weight after treatment with the carcinogen for 20 weeks significantly increased the incidence and number of adenocarcinomas of the glandular stomach. Histological examination showed that treatment with caerulein had no influence on the histology of induced adenocarcinomas. Furthermore, administration of caerulein resulted in a significant increase in the bromodeoxyuridine-labeling indices of the antral mucosa but did not influence the bromodeoxyuridine-labeling indices of the fundic mucosa and the carcinomas. These findings indicate that caerulein enhances gastric carcinogenesis and that the effect may be related to the promoting effect of caerulein on cell proliferation in the antral mucosa.

Topics: Animals; Bromodeoxyuridine; Cell Division; Ceruletide; Cocarcinogenesis; Male; Methylnitronitrosoguanidine; Rats; Rats, Inbred Strains; Stomach Neoplasms