Gastrin-Mediated Alterations in Gastric Epithelial Apoptosis and Proliferation in a &lt;i&gt;Mastomys&lt;/i&gt; Rodent Model of Gastric Neoplasia

Kidd, Mark; Tang, Laura H.; Modlin, Irvin M.; Zhang, Tong; Chin, Kelly; Holt, Peter R.; Moss, Steven F.

doi:10.1159/000007806

Cited by 28 publications

(20 citation statements)

References 18 publications

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“…Gastrin is a critical trophic factor for the oxyntic mucosa both in humans and animals (27). An association between apoptosis and hypergastrinemia has been reported previously in a rodent (Mastomys) model using an H 2 receptor antagonist (28). Moreover, given the finding of accelerated parietal cell loss in INS-GAS mice, we considered the possibility that this was attributable to increased apoptosis, and we showed that the expression of G-gly led to significant protection against G-17-stimulated apoptosis.…”

Section: Glycine-extended Gastrin and Atrophy In Mouse Stomachmentioning

confidence: 75%

Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach

et al. 2004

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Recently we have reported synergistic effects between glycine-extended gastrin (G-gly) and amidated gastrin-17 on acid secretion in short-term infusion studies. In the present study, we examined the long-term effect of G-gly on the atrophy-promoting effects of amidated gastrin in the mouse stomach with or without Helicobacter infection. Transgenic mice overexpressing amidated gastrin (INS-GAS mice), G-gly (MTI/G-gly mice), and both peptides (INS-GAS/G-gly mice) were used for assessment of acid secretion and ulcer susceptibility and histologic examination and scoring of preneoplastic lesions in response to the 3 and 6 months Helicobacter felis (H. felis) infection. We found that MTI/G-gly mice had normal gastric histology and acid secretion. Double transgenic (INS-GAS/G-gly) mice showed 2-fold increases in acid secretion compared with INS-GAS mice. Acute peptic ulcers after pyloric ligation were noted in 50% of the INS-GAS/G-gly mice but in none of the INS-GAS mice at 6 months of age. Whereas male INS-GAS mice had a >50% decrease in the numbers of parietal cell and enterochromaffin-like cell at 6 months of age, the male double transgenic mice had no such decrease. Overexpression of G-gly reduced the scores of preneoplasia in the stomach; however, it did not prevent the development of amidated gastrin-dependent gastric cancer in both H. felis-infected mice and uninfected mice. We conclude that G-gly synergizes with amidated gastrin to stimulate acid secretion and inhibits parietal cell loss in INS-GAS/G-gly mice. The overexpression of G-gly seems to increase the susceptibility to peptic ulcer disease and delay the development of Helicobacter-mediated gastric preneoplasia in this model.

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Section: Glycine-extended Gastrin and Atrophy In Mouse Stomachmentioning

confidence: 75%

Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach

et al. 2004

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“…However, the therapeutic use of loxtidine was advised against on the basis of the rodent studies (7,8). Due to its antisecretagogue effect, loxtidine has also been used for rapid induction of ECL cell carcinoids in Mastomys for studying growth regulation of the gastric mucosa (11)(12)(13)(14). In Mastomys, there is no difference between the sexes in gastrin concentration or subsequent carcinoid development after loxtidine administration.…”

Section: Introductionmentioning

confidence: 99%

ECL-Cell Derived Gastric Cancer in Male Cotton Rats Dosed with the H2-Blocker Loxtidine

et al. 2004

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Spontaneously hypergastrinemic cotton rats (Sigmodon hispidus) develop tumors that have the phenotype of an adenocarcinoma but most likely originate from the enterochromaffin-like (ECL) cells. Among inbred animals ϳ50% of the females, but <1% of males develop spontaneous gastric carcinomas. Gastrin is the principle carcinogen in this model, as >4 months of hypergastrinemia results in carcinoma, but a gastrin receptor antagonist prevents carcinomas. Carcinomas can also be induced by partial corpectomy. In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months. The loxtidine-dosed animals developed hypergastrinemia, whereas control animals remained normogastrinemic. At termination, 4 of 5 cotton rats had cancer located to the oxyntic mucosa, whereas 1 animal had dysplasia. The gastric mucosa of all of the control animals was normal. In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique. In areas of high proliferation and cancer there were also histidine decarboxylase, chromogranin A, and Sevier-Munger-positive cells, altogether indicating an ECL cell origin of the tumors. This represents an interesting animal model where ECL cell-derived gastric cancer can be induced by pharmacological acid inhibition in 6 months.

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“…The CCK-B/gastrin receptor is expressed in parietal and enterochromaffin-like (ECL) cells (4,38), and gastrin stimulates the secretory function as well as the production of these cell lineages (23,33,40). Elevated levels of serum gastrin induce expansion of parietal cell numbers in patients with gastrinoma (30).…”

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confidence: 99%

Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice

Nomura¹,

Yamaguchi²,

Ogawa³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

134

209

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In addition to their role in gastric acid secretion, parietal cells secrete a number of growth factors that may influence the differentiation of other gastric lineages. Indeed, oxyntic atrophy is considered the most significant correlate with increased risk for gastric adenocarcinoma. We studied the alterations in gastric mucosal lineages elicited by acute oxyntic atrophy induced by treatment of C57BL/6 and gastrin-deficient mice with the parietal cell protonophore [S-(R*,S*)]-N-[1-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2-[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidinecarboxamide (DMP-777). In both wild-type and gastrin knockout mice, DMP-777 elicited the rapid loss of parietal cells within 2 days of treatment. In wild-type mice, oxyntic atrophy was accompanied by a rapid increase in 5-bromo-2'-deoxyuridine-labeled proliferative cells and attendant increase in surface cell numbers. However, gastrin knockout mice did not demonstrate significant foveolar hyperplasia and showed a blunted proliferative response. After 7 days of treatment in wild-type mice, a second proliferative population emerged at the base of fundic glands along with the development of a mucous cell metaplasia expressing TFF2/spasmolytic polypeptide (SPEM). However, in gastrin knockout mice, SPEM expressing both TFF2 mRNA and protein developed after only 1 day of DMP-777 treatment. In wild-type mice, all changes induced by DMP-777 were reversed 14 days after cessation of treatment. In gastrin-deficient mice, significant SPEM was still present 14 days after the cessation of treatment. The results indicate that foveolar hyperplasia requires the influence of gastrin, whereas SPEM develops in response to oxyntic atrophy independent of gastrin, likely through transdifferentiation of chief cells.

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Gastrin-Mediated Alterations in Gastric Epithelial Apoptosis and Proliferation in a <i>Mastomys</i> Rodent Model of Gastric Neoplasia

Cited by 28 publications

References 18 publications

Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach

Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach

ECL-Cell Derived Gastric Cancer in Male Cotton Rats Dosed with the H2-Blocker Loxtidine

Alterations in gastric mucosal lineages induced by acute oxyntic atrophy in wild-type and gastrin-deficient mice

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