Volume 124, Issue 7, Pages 1879-1890 (June 2003) Host and microbial constituents influence helicobacter pylori-induced cancer in a murine model of hypergastrinemia  James G Fox, Timothy C Wang, Arlin B Rogers, Theofilos Poutahidis, Zhongming Ge, Nancy Taylor, Charles A Dangler, Dawn A Israel, Uma Krishna, Kristen Gaus, Richard M Peek  Gastroenterology  Volume 124, Issue 7, Pages 1879-1890 (June 2003) DOI: 10.1016/S0016-5085(03)00406-2

Figure 1 Identification of H. pylori in situ. The presence of H. pylori was determined by Warthin-Starry silver staining (A), yellow-blue contrast staining (B), immunohistochemistry (C), and fluorescent in situ hybridization (D). (A–C: original magnification 1000×, bar = 10 μmol/L; D: original magnification 600×, bar = 15 μmol/L.) Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 2 Comparison of gastric inflammation in the corpus (A) and antrum (B) in male INS-GAS mice infected with H. felis, H. pylori strain B128, or broth alone. For 2 of the 4 H. felis-infected mice killed 12 weeks postchallenge, the lesser curvature was not represented; therefore, these samples were excluded from analysis. Mucosal inflammation was determined by histologic testing, as described in the text, and results are expressed as mean scores ± SD. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 3 Development of inflammation and injury within the gastric corpus of male INS-GAS mice 6 weeks postinoculation. Representative hematoxylin and eosin stains are shown (original magnification, 40×; bar = 250 μmol/L). (A) Uninfected INS-GAS mice. Minimal inflammatory and hyperplastic changes are present within the gastric mucosa. (B) INS-GAS mice infected with the H. pylori B128 isogenic cagE− mutant. Foci of minimal inflammation have developed (arrows), but there is no evidence of dysplasia or cystic dilation. (C) INS-GAS mice infected with wild-type H. pylori strain B128. Mild-moderate inflammation is present adjacent to the epithelial cell surface and within the submucosa (black arrows), which is accompanied by dysplasia with focal cystic dilation (white arrow). (D) INS-GAS mice infected with H. felis. Moderately severe inflammation is present (arrow), and multifocal areas of cystic dilation with dysplasia are interspersed between foci of infiltrating inflammatory cells. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 4 Chronology of gastric mucosal lesion progression in male INS-GAS mice infected with H. pylori wild-type strain B128 (solid columns) or its isogenic cagE− null derivative (shaded columns). Inflammation (A), hyperplasia (B), glandular atrophy (C), and dysplasia (D) are expressed as mean histologic scores ± SD. ∗P ≤ 0.05 for wild-type B128 compared with the H. pylori B128 cagE− mutant strain. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 5 Intensity of gastric injury in male INS-GAS mice infected for 24 weeks with Helicobacter. Scores for intestinal metaplasia (A), dysplasia (B), and tumor area (C) are presented as scatter-plots with mean values. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 6 Development of premalignant and malignant lesions within the gastric corpus of INS-GAS mice 24 weeks postinoculation, stratified by gender. Representative hematoxylin and eosin stains are shown (original magnification, 40×; bar = 250 μmol/L). (A and B) Mild dysplasia and a reduction in parietal cell numbers are present in uninfected male mice (A). In contrast, only minimal changes are present in uninfected females (B). (C–F) Mice infected with H. pylori strain B128 cagE− (C and D) or wild-type B128 (E and F). Infection of male mice with either H. pylori strain led to marked foveolar hyperplasia that was accompanied by extensive parietal cell loss and carcinoma in situ (C and E). In contrast, no tumors were present in any H. pylori-infected females (D and F). (G and H) All male mice challenged with H. felis developed adenocarcinomas, and the majority of lesions were complicated by submucosal and vascular invasion (G, arrow). Infection of female INS-GAS mice with H. felis resulted in cystic dilation with dysplasia, but this was not accompanied by tumor formation (H). Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 7 Comparison of gastric inflammation and injury scores in INS-GAS mice during long-term colonization, by gender status. Male (solid columns) and female (shaded columns) INS-GAS mice were killed 24 weeks after inoculation, and results for inflammation (A), glandular atrophy (B), intestinal metaplasia (C), and dysplasia (D) are expressed as mean histologic scores ± SD. ∗P ≤ 0.05 for male mice compared with correspondingly treated females. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)

Figure 8 Comparison of mucosal IL-1β concentrations in male INS-GAS mice (A) and chronically infected males and females (B). IL-1β concentrations are expressed as mean ± SEM. ∗P < 0.05 compared with uninfected controls. Gastroenterology 2003 124, 1879-1890DOI: (10.1016/S0016-5085(03)00406-2)