Protective role of 17 beta -estradiol against the development of Helicobacter pylori-induced gastric cancer in INS-GAS mice.
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 17beta-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-1beta (IL-1beta) 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-1beta 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.
Ohtani
Masahiro
M
Division of Comparative Medicine, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16-825C, Cambridge, MA 02139, USA.
García
Alexis
A
Rogers
Arlin B
AB
Ge
Zhongming
Z
Taylor
Nancy S
NS
Xu
Shilu
S
Watanabe
Koichiro
K
Marini
Robert P
RP
Whary
Mark T
MT
Wang
Timothy C
TC
Fox
James G
JG
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005756:Gastritis / Q000150:complications* / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000150:complications* / Q000473:pathology; D016480:Helicobacter pylori; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010052:Ovariectomy; D012737:Sex Factors; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*
D016207:Cytokines; D004967:Estrogens; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D004958:Estradiol; D052247:Nitric Oxide Synthase Type II