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Carcinogenesis Advance Access published online on August 27, 2007
Carcinogenesis, doi:10.1093/carcin/bgm150
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Protective role of 17ß-estradiol against the development of Helicobacter pylori-induced gastric cancer in INS-GAS mice

Masahiro Ohtani1,+, Alexis Garcia1, Arlin B. Rogers1, Zhongming Ge1, Nancy S. Taylor1, Shilu Xu1, Koichiro Watanabe1, Robert P. Marini1, Mark T. Whary1, Timothy C. Wang2 and James G. Fox1,*

1 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139
2 Columbia University Medical Center, New York, NY 10032

* Corresponding author: James G. Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Ave., Bldg. 16-825C, Cambridge, MA 02139; Tel: 617-253-1735; Fax: 617-252-1877; Email: jgfox{at}mit.edu

The incidence of gastric cancer is higher in men than women. Epidemiological studies suggest that female hormones reduce gastric cancer risk. We examined the effect of ovarian-dependent female hormones on Helicobacter pylori-induced gastric cancer in hypergastrinemic INS-GAS mice. Male and female sexually intact or ovariectomized (OVX) mice were inoculated with H. pylori SS1 or vehicle-only at 10 weeks of age, and tissues were evaluated at 16 or 28 weeks postinfection (WPI). A subset of OVX females were supplemented with 17ß-estradiol (E2), beginning at 16 WPI. Stomachs were evaluated by histopathology, Ki-67 proliferation index, H. pylori quantitative culture, and quantitative PCR for mRNA expression of iNOS and inflammatory cytokines. Infected OVX females developed significantly more severe gastritis (p< 0.05) than infected intact females at both time points. E2 treatment in infected OVX females attenuated the severity of gastritis. Gastrointestinal intraepithelial neoplasia (GIN) developed in 42% of infected males and 10% of infected OVX females by 28 WPI, whereas infected intact females and E2-treated OVX females did not develop GIN. Infected OVX females showed significantly increased iNOS expression and epithelial cell proliferation when compared to intact, infected females. Likewise, IFN-{gamma}, TNF-{alpha}, and IL-1ß expression in infected OVX females were significantly increased at 28 WPI when compared to intact counterparts. E2 treatment in infected OVX females significantly decreased IL-1ß expression, increased IL-10 expression, and reduced epithelial cell proliferation. These results demonstrate a protective effect of E2 in H. pylori-induced gastric cancer in a mouse model.

Key Words: Gastric cancer • Helicobacter pylori • estradiol • iNOS • epithelial proliferation

+ Current address: Masahiro Ohtani, Fukui University, Faculty of Medical Science, 2nd Department of Internal Medicine, 23-3 Matsuokashimoaizuki, eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan

Received April 2, 2007; revised June 4, 2007; accepted June 14, 2007.


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