Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma

Abstract

The current study tests the hypothesis that chronic atrophic gastritis from hypochlorhydria in the gastrindeficient mouse predisposes the stomach to gastric cancer. Gross morphology and histology of 12-month-old wildtype (WT), gastrin-deficient (GÀ/À) and somatostatindeficient (SOMÀ/À) mice were examined. Parietal and G cells, Ki67, TUNEL, villin and MUC2 expression were analysed by immunohistochemistry. RUNX3 and STAT3 expression was analysed by Western blot. Anchorageindependent growth was determined by cell cluster formation in soft agar. Compared to the WT and SOMÀ/À mice, hypochlorhydric GÀ/À mice developed parietal cell atrophy, significant antral inflammation and intestinal metaplasia. Areas of metaplasia within the GÀ/ À mouse stomach showed decreased RUNX3 expression with elevated MUC2 and villin expression. Cells isolated from the tumor grew in soft agar. However, the cells isolated from WT, nontransformed GÀ/À and SOMÀ/À gastric tissue did not form colonies in soft agar. Consistent with elevated antral proliferation, tumor tissue isolated from the GÀ/À mice showed elevated phosphorylated STAT3 expression. We then examined the mechanism by which STAT3 was constitutively expressed in the tumor tissue of the GÀ/À mice. We found that IFNc expression was also significantly higher in the tumor tissue of GÀ/À mice compared to WT and SOMÀ/À animals. To determine whether STAT3 was regulated by IFNc, MKN45 cells were cocultured with IFNc or gastrin. IFNc significantly stimulated phosphorylation of STAT3 in the MKN45 cell line, but not gastrin. Therefore, we show here that in the hypochlorhydric mouse stomach, the chronic gastritis, atrophy, metaplasia, dysplasia paradigm can be recapitulated in mice. Moreover, neoplastic transformation of the antral gastric mucosa does not require gastrin.

Inflammation, atrophy, and gastric cancer

“…In many patients with gastric cancer, H. pylori infection is often difficult to detect even with multiple modalities (91). This is consistent with the observation that gastrin-deficient mice, which are achlorhydric, housed in a conventional facility develop bacterial overgrowth and chronic atrophic gastritis and progress to antral gastric cancer (92,93). This pathological process is very similar to that which develops in H. felis-infected wild-type mice, again after long-standing achlorhydria and after Helicobacter spp.…”

Effect of Helicobacter pylori eradication on gastric carcinogenesis

“…35 Increased mucosal levels of IFN-g are associated with STAT3 activation, which likely mediates gastric cancer that develops in mice harboring a mutated IL-6 receptor. 36,37 Finally, Th1-polarized gastric responses are linked to reduced mucosal somatostatin and elevated plasma gastrin levels in H. pylori-infected patients, 10 and increased gastrin levels are significantly associated with increased gastric epithelial cell proliferation. 38 Establishment of H. pylori as a risk factor for cancer of the stomach has permitted an approach to identify persons at increased risk; however, infection with this organism is extremely common and most colonized persons never develop cancer.…”

Runx3 expression in gastrointestinal tract epithelium: resolving the controversy

“…A mutation of Arg122 to Cys in the conserved Runt domain abolished the tumor-suppressive effect of RUNX3 (Li et al, 2002). Several other groups have also demonstrated the expression of RUNX3 mRNA and/or protein in gastric epithelial cells (Osaki et al, 2004;Oshimo et al, 2004;Torquati et al, 2004;Wei et al, 2005;Zavros et al, 2005;Katuri et al, 2006;Peng et al, 2006;Usui et al, 2006). However, others have failed to demonstrate the expression of Runx3 in normal gastric epithelial cells immunohistochemically using G-poly and this has led them to question its contribution to carcinogenesis in GIT epithelium (Levanon et al, 2001(Levanon et al, , 2003Brenner et al, 2004, Carvalho et al, 2005.…”