Carcinogenesis Advance Access published online on August 29, 2003
Carcinogenesis, doi:10.1093/carcin/bgg156
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
* Corresponding author. E-mail: helge.waldum{at}medisin.ntnu.no.
Received 14 April 2003
; revised 9 July 2003
; accepted 19 August 2003
Background & Aims: In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. Methods: First, nine hypergastrinemic female cotton rats (ten months of age) were diagnosed by laparotomy to have gastric tumor. They were killed six month later. Second, 18 female cotton rats (two months of age) were dosed monthly for six months with YF476 (500 µmol/kg) by subcutaneous injections, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and Northern blot analysis. Results: The gastric tumors harboured cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL derived tumor cells were discovered in peritoneal fluid. At sacrifice only one out of 18 animals given YF476 displayed carcinoma (invasive growth) compared to seven out of 21 in the vehicle-dosed control group (p=0.048). Conclusion: The spontaneous gastric tumors in cotton rats derive from ECL cells. The tumors are able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.
Spontaneous ECL cell carcinomas in cotton rats - natural course and the prevention by a gastrin receptor antagonist
2 Division of Experimental Animals, Hokkaido Institute of Public Health, Japan
3 Department of Pharmacology, University of Lund, Sweden
4 Department of Pathology, University Hospital of Trondheim, Norway
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