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

• Published in: Carcinogenesis (New York) Vol. 28; no. 12; pp. 2597 - 2604
• Main Authors: Ohtani, Masahiro, García, Alexis, Rogers, Arlin B., Ge, Zhongming, Taylor, Nancy S., Xu, Shilu, Watanabe, Koichiro, Marini, Robert P., Whary, Mark T., Wang, Timothy C., Fox, James G.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-12-2007
• Subjects: Animals; Bacterial diseases; Bacterial diseases of the digestive system and abdomen; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Transformation, Neoplastic - drug effects; Cytokines - metabolism; Epithelial Cells - metabolism; Epithelial Cells - pathology; Estradiol - pharmacology; Estradiol - therapeutic use; Estrogens - pharmacology; Estrogens - therapeutic use; Female; Gastric Mucosa - drug effects; Gastric Mucosa - metabolism; Gastric Mucosa - pathology; Gastritis - complications; Gastritis - microbiology; Gastritis - pathology; Helicobacter; Helicobacter Infections - complications; Helicobacter Infections - pathology; Helicobacter pylori; Human bacterial diseases; Infectious diseases; Ki-67 Antigen - metabolism; Male; Medical sciences; Mice; Nitric Oxide Synthase Type II - metabolism; Ovariectomy; Sex Factors; Stomach Neoplasms - drug therapy; Stomach Neoplasms - etiology; Stomach Neoplasms - pathology; Tumors; Spirillales; Estrogen; Rodentia; Spirillaceae; 17β-Estradiol; Malignant tumor; Stomach cancer; Ovarian hormone; Infection; Prevention; Vertebrata; Mammalia; Helicobacter pylori; Mouse; Animal; Bacteriosis; Development; Bacteria; Digestive diseases; Sex steroid hormone; Cancer; Gastric disease
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgm150

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 post-infection (WPI). A subset of OVX females were supplemented with 17β-estradiol (E2), beginning at 16 WPI. Stomachs were evaluated by histopathology, Ki-67 proliferation index, H.pylori quantitative culture and quantitative polymerase chain reaction for messenger RNA expression of inducible nitric oxide synthase (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 with intact, infected females. Likewise, interferon-gamma, tumor necrosis factor-alpha and interleukin-1β (IL-1β) expression in infected OVX females were significantly increased at 28 WPI when compared with intact counterparts. E2 treatment in infected OVX females significantly decreased IL-1β 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.