Abstract 4159: Progastrin inhibits Helicobacter-associated gastric corpus carcinogenesis in mice
Authors: Takaishi Shigeo , Jin Guangchun , Shibata Wataru , Tomita Hiroyuki , Betz Kelly S. , Whary Mark T. , Muthupalani Sureshkumar , Yim Mildred EL , Shulkes Arthur , Fox James G. , Wang Timothy C. 
Published: February 2011

Background & Aims: We have previously reported that overexpression of amidated gastrin in transgenic (INS-GAS) mice with Helicobacter felis (H. felis) infection accelerated gastric corpus carcinogenesis, while overexpression of non-amidated glycine-extended gastrin in transgenic (MTI-G-gly) mice inhibited parietal cell loss and atrophy in stomach. We have also reported that overexpression of the full length progastrin in transgenic (hGAS) mice stimulated colon carcinogenesis in azoxymethane-treated mice. In this study, we investigated the role of progastrin for Helicobacter-associated gastric carcinogenesis in mice. Methods: hGAS, INS-GAS and non-transgenic wild type (B6 wt) mice on a C57BL/6 background were infected with H. felis for 12 or 18 months (m). We also analyzed male hGAS, INS-GAS and wild type (FVB wt) mice on a FVB/N background with H. felis infection for 7 m. Infection status was assessed by realtime PCR, microscopic evaluation and serum titer of H. felis-specific IgG antibodies. Proliferating cells and parietal cells were investigated by immunohistochemistry (IHC) with Ki-67 and HK-ATP-beta antibodies, respectively. Expression of stem cell-related genes such as CD44 & DCAMKL-1 was also analyzed by IHC. Results: At 12 m post infection (p.i.), INS-GAS mice had mild corpus dysplasia and B6 wt mice had severe gastritis or metaplasia, while hGAS mice had only mild to moderate gastritis, respectively. At 18 m p.i., both INS-GAS and B6 wt mice had severe atrophic gastritis and corpus dysplasia, while hGAS mice showed only moderate gastritis with mild gastric atrophy but no corpus dysplasia. In contrast, hGAS mice had moderate to severe antral or pyloric dysplasia, while INS-GAS and B6 wt mice did not. H. felis colonization remained stable over time among 3 groups of mice. The serum titer of H. felis-specific IgG antibody as well as Th1-Th2 polarization calculated by IgG1/IgG2c subclass ratio showed no significant differences among 3 groups. At 18 m p.i., the number of Ki-67(+) cells per gastric corpus gland was the highest in INS-GAS and the lowest in hGAS mice. Parietal cell loss was remarkable in INS-GAS and B6 wt, but minimal in hGAS mice. CD44(+) and DCAMKL-1(+) cell numbers were significantly increased in INS-GAS and B6 wt, while essentially unchanged in hGAS mice. On a FVB/N background, INS-GAS mice with H. felis infection for 7 m showed gastric corpus adenocarcinoma, and infected FVB wt mice showed severe gastric atrophy with intestinal metaplasia, while infected hGAS mice showed only moderate gastritis without metaplasia or dysplasia. Conclusions: These results point to a protective effect of progastrin on Helicobacter-associated gastric corpus carcinogenesis perhaps by inhibiting the loss of parietal cells. In contrast antral pathology is increased in hGAS mice. We conclude that the different forms of gastrin have contrasting effects on Helicobacter-associated gastric corpus carcinogenesis in mice.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4159.