Male intact INS-GAS mouse (Mus musculus) on an FVB background, adult approximately 35 weeks old.These three mice were experimentally infected with Helicobacter pylori (SS1) strain at 6 weeks old.
All mice exhibited similar changes to the stomach; only the fundus exhibited diffusely thickened gastric folds.Â One mouse had gastric hemorrhage.
1.Â Stomach.Â Gastric intraepithelial neoplasia (GIN)
Serology was negative for a standard panel of murine
Gastric hyperplasia and dysplasia
Only one of the three mice is on each given slide, with 3 sections from one mouse.Â All mice exhibited similar histologic changes: gastric mucosal and submucosa inflammation, epithelial hyperplasia, metaplasia, and dysplasia.Â Dysplastic changes supportive of a diagnosis of GIN include severe loss of gland organization and columnar orientation, intraglandular folding, papillary and ductular projections, elongated branched and tortuous glands, and pseudostratification up to several cells deep.Â Moderate to marked cellular pleomorphism, cellular atypia, visible mitoses, and occasional bizarre mitotic figures are present.Â Within dysplastic foci are single apoptotic cells characterized by diffusely granular to hyaline eosinophilic cytoplasm, karryorhexis, and nuclear pyknosis.Â Phagocytosed apoptotic cells or their remnants were common in cytoplasmic vacuoles in neighboring epithelial cells.Â Transition zones from normal to hyperplastic to dysplastic epithelium were usually discernible and occurred in a wave of decreasing severity aborally from the cardia such that lesions were invariably most severe adjacent to the cardia.Â There is severe chief cell atrophy and loss of up to 50-70% of parietal cells.Â Parietal cells, sometimes in large numbers, exhibit small vacuolar to foamy metaplasia.Â Frequently there are cystic dilation of glands, often with crypt abscesses, surface epithelial tattering as well as small surface erosions.Â There are multifocal areas of mineralization within dilated glands.
The insulin gastrin (INS-GAS) mouse is a transgenic mouse bearing the transgene that overexpresses amidated gastrin, the main biologically active form of gastrin.Â The transgene targets expression of human gastrin to the pancreatic islets.Â In adult mammals, gastrin is expressed mainly in the astral G cells of the stomach where it controls the acid secretion and stimulates mucosal proliferation.Â The INS-GAS mice spontaneously develop gastric cancer, but this requires the virtual lifetime of the animal (1-2 years).Â However, when male INS-GAS mice are infected with H.Â pylori, they uniformly developed atrophy, intestinal metaplasia, and dysplasia by 6 weeks and carcinoma by 24 weeks.Â
Gastric carcinoma is the most common of malignant tumors of the stomach in people.Â It is the second most common tumor in the world.Â It exhibits a male-to-female ration of about 2:1.Â The major factors thought to affect the genesis of gastric cancer include environmental factors, host factors and genetic factors.Â One environmental factor, infection by H.Â pylori, present in most cases of intestinal-type carcinoma.Â Chronic infection with H.Â pylori generally increases the risk for developing gastric carcinoma by five-to six-fold.Â The bacterial infection causes chronic gastritis, followed by atrophy, intestinal metaplasia, dysplasia and carcinoma.Â One host determinant that may influence the development of gastric cancer is gastrin.Â Hypergastrinemia occurs early in the course of human H.Â pylori infection, precedes the development of atrophic gastritis, and often resolves after eradication.Â In addition, in vitro gastrin stimulates gastric epithelial cell proliferation.
In addition to host factors, bacterial determinants also contribute to gastric carcinogenesis.Â One virulence-associated H.Â pylori constituent is the CagA (cytotoxin associated gene A) pathogenicity island, which is present in approximately 60% of United States strains, and carriage of a Cag+/- strain augments the risk for atrophic gastritis and distal gastric adenocarcinoma compared with that incurred by Cag -/- strains.Â Several cag genes encode products that possess homology to components of type IV secretion systems, and, following H.Â pylori adherence to epithelial cells in vitro, the product of the terminal gene in the island (CagA) is translocated into the host cell, in which it undergoes Src-dependent phosphorylation and activates a phosphatase (SHP-2), leading to cellular morphologic changes.Â Loss of CagE temporally retards but does not abrogate pathologic progression.
All experiments were approved by the Committee on Animal care at Massachusetts Institute of Technology.
1.Â Stomach, glandular: Epithelial hyperplasia and dysplasia,
diffuse, marked, with lymphoplasmacytic and neutrophilic gastritis
(gastrointestinal intraepithelial neoplasia)
2.Â Duodenum and pancreas: No significant lesions
Gastrointestinal intraepithelial neoplasia (GIN) is a
term used to represent putative preinvasive neoplastic lesions not grossly visible.
GIN is synonymous with atypical hyperplasia, atypia, microadenoma, carcinoma
in situ, and dysplasia.1
Conference participants reviewed the primary cell types and functions of cells located within the stomach, such as parietal cells, chief cells, G cells, D cells, enterochromaffin-like cells, and mucous neck cells.
In the INS-GAS mouse, human heptadecapeptide gastrin is produced by the islet _ cells and secreted into circulation.Â This gastrin release in turn causes an initial stimulation of gastric acid secretion (2-3 months of age), increasing the number of parietal and enterochromaffin-like cells.Â However, mice older than 5 months have a decline in acid secretion until 20 months of age when there is virtually no secretion at all, which coincides with decreasing numbers of parietal and enterochromaffin-like cells.8
Helicobacter spp.Â are Gram-negative spirochetes, approximately 3_m in length with 4-6 flagellae.Â Several species may contain ureases, catalases, oxidases, proteases, and phospholipases.Â Helicobacter spp.Â have been implicated in gastric lymphoma and carcinoma in ferrets and humans.Â Helicobacter hepaticus can cause an acute focal, non-suppurative necrotizing hepatitis in mice.
In this case, despite experimental inoculation, no Helicobacter sp.Â were noted with Warthin-Starry or Steiners stains performed at AFIP.
Helicobacter sp.Â in various animal species:
|Mouse5||H.Â bilis, H.Â hepaticus, H.Â muridarum, H.Â rodentium,|
H. typhlonius, H.Â ganmani, H.Â rappini, H.Â mastomyrinus,
H. muricola (Korean wild mice)
|Rat5||H.Â bilis, H.Â muridarum, H.Â rodentium, H.Â trogontum,|
|Hamster5,6||H.Â aurati, H.Â cineadi, H.Â mesocricetorum, H.Â cholecystus|
|Gerbil5||H.Â hepaticus, H.Â bilis|
|Dog2||H.Â felis, H.Â heilmannii|
|Cat2||H.Â felis, H.Â pylori, H.Â heilmannii|
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