Association of Spasmolytic Polypeptide–Expressing Metaplasia with Carcinogen Administration and Oxyntic Atrophy in Rats

Yamaguchi, Hideyo; Goldenring, James R.; Kaminishi, Michio; Lee, Jeffrey R.

doi:10.1097/01.lab.0000022225.45996.21

Cited by 32 publications

(21 citation statements)

References 21 publications

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“…Large gland cells expressing both TFF2 and IF in different subcellular compartments are typical for spasmolytic polypeptide-expressing metaplasia. 43 Here, in fundic polyps, TFF2 expression levels were comparable with those normally found in fundic neck cells and overlapping with the pattern of GS-lectin/Muc6 staining. The size of TFF2 expressing cells was the same 2 in a wild-type mouse).…”

Section: Fundic Polyp Glands Distinct From Spasmolytic Polypeptide Exmentioning

confidence: 53%

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Udd

Katajisto

Kyyrönen

et al. 2010

The American Journal of Pathology

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Gastrointestinal hamartomatous polyps in the PeutzJeghers cancer predisposition syndrome and its mouse model (Lkb1؉/؊ ) are presumed to contain all cell types native to the site of their occurrence. This study aimed to explore the pathogenesis of PeutzJeghers syndrome polyposis by characterizing cell types and differentiation of the epithelium of gastric polyps and predisposed mucosa. Both antral and fundic polyps were characterized by a deficit of pepsinogen C-expressing differentiated gland cells (antral gland, mucopeptic, and chief cells); in large fundic polyps, parietal cells were also absent. Gland cell loss was associated with an increase in precursor neck cells, an expansion of the proliferative zone, and an increase in smooth muscle ␣-actin expressing myofibroblasts in the polyp stroma. Lack of pepsinogen C-positive gland cells identified incipient polyps, and even the unaffected mucosa of young predisposed mice displayed an increase in pepsinogen C negative glands (25%; P ‫؍‬ 0045). In addition, in small intestinal polyps, gland cell differentiation was defective, with the absence of Paneth cells. There were no signs of metaplastic differentiation in any of the tissues studied, and both the gastric and small intestinal defects were seen in Lkb1 ؉/؊ mice, as well as polyps from patients with Peutz-Jeghers syndrome. These results identify impaired epithelial differentiation as the earliest pathological sign likely to contribute to tumorigenesis in individuals with inherited Lkb1 mutations. (Am J

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Section: Fundic Polyp Glands Distinct From Spasmolytic Polypeptide Exmentioning

confidence: 53%

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Udd

Katajisto

Kyyrönen

et al. 2010

The American Journal of Pathology

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“…In previous studies, we have reported that SPEM is observed in the gastric mucosa adjacent to human gastric cancer. 20,21 SPEM was also observed at the base of fundic glands showing oxyntic atrophy in rodent models such as Helicobacter felis-infected mice, 14 rats with remnant gastric cancer 16 and mice treated with DMP-777. 17 DMP-777 is a cell-permeant neutrophil elastase inhibitor that depletes parietal cells by acting as a secretory membrane protonophore.…”

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confidence: 96%

“…11 Since the parietal cell plays a critical role in the differentiation of gastric mucosal lineages, 12,13 the loss of parietal cells is associated with a number of lineage changes, including foveolar hyperplasia, loss of chief cells and mucous cell metaplasia. [14][15][16][17] The normal gastric mucosa includes two types of mucous cells: surface mucous cells secrete trefoil factor family 1 (TFF1) and mucin M1 (MUC5AC), whereas mucous neck cells secrete spasmolytic polypeptide/trefoil factor 2 (SP/ TFF2) and MUC6. A number of investigations in rodents have shown that loss of gastric parietal cells leads to the evolution of SP-expressing metaplasia (SPEM), a gastric fundic metaplastic lineage with TFF2-expressing mucous cells with Brunner's gland or deep antral gland morphology.…”

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confidence: 99%

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Yoshizawa

Takenaka

Yamaguchi

et al. 2007

Laboratory Investigation

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106

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Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM-and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.

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“…Since some SPEM cells have been found to coexpress TFF2 and intrinsic factor (IF), 11 a specific secretory product of mouse chief cells, we examined whether IF was also expressed in the expanded fundic mucous cell compartment of the GÀ/À mice. Using double-fluorescent labeling with GSII and rabbit-a-IF, we found little overlap of GSII-positive cells with IF-positive cells in either WT (Figure 4c) or GÀ/À mice (Figure 4d).…”

Section: Fundic Gland Mucous Cells In Gà/à Mice Do Not Express Chief mentioning

confidence: 99%

“…6 Emergence of a prominent mucous cell lineage (the so-called 'mucous cell metaplasia') was found to be one of the earliest histological changes in the fundic mucosa of these mice. 5 Mucosal changes bearing similar features have also been reported in a variety of pathological processes in human and mouse, which include H. pylori infection; [7][8][9] loss of parietal cells upon chemical administration; 10 treatment with a carcinogen, 11 mutation of the Kcnq1 gene encoding a potassium channel, 12 and constitutively active STAT3. 13 This type of mucosal change may therefore represent a common, and possibly reversible 10 response of the stomach, to mucosal injury and tissue inflammation triggered by various stimuli.…”

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confidence: 99%

Interferon gamma induction of gastric mucous neck cell hypertrophy

Kang

Rathinavelu

Samuelson

et al. 2005

Laboratory Investigation

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Chronic inflammation of the gastric epithelium is believed to induce mucosal changes that can eventually develop into gastric cancer. In gastrin-deficient (GÀ/À) mice exhibiting chronic inflammation in the hypochlorhydric stomach, we documented a prominent fundic mucous cell lineage sharing morphological similarity with preneoplastic changes reported in Helicobacter-infected mice. To study the identity and origin of this cell lineage, we screened for different gastric mucosal cell markers. The clusters of large, foamy cells stained for trefoil factor 2 (TFF2/SP), MUC6 and the lectin Griffonia Simplicifolia II (GSII), but not for the intestine-specific transcription factor Cdx2, suggested that they arise from gastric mucous neck cells. Ki67-labeled GSII-positive neck cells in Helicobacter felis-infected, but not GÀ/À stomachs, suggested that mucous neck cell proliferation accounted for expansion of this compartment in the H. felis model of gastritis, but not the GÀ/À model. Using RNase protection assays and quantitative PCR, we found that interferon gamma (IFNc) was the most abundant proinflammatory cytokine in the GÀ/À stomach. We also found that this Th1 cytokine can increase the abundance of mucous neck cells, since its infusion into mice recapitulated the appearance of these cells as observed in both GÀ/À and H. felis-infected mice. Using the human gastric cell line NCI-N87, we showed that IFNc induces the secretion of mucus and expression of MUC6, TFF2 and pepsinogen II, but not of pepsinogen I and intrinsic factor. In conclusion, our results demonstrate that inflammation, specifically the proinflammatory cytokine IFNc, induced expansion of the fundic mucous neck cell compartment, which likely represents both increased mucus production and cell number.

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Association of Spasmolytic Polypeptide–Expressing Metaplasia with Carcinogen Administration and Oxyntic Atrophy in Rats

Cited by 32 publications

References 21 publications

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Impaired Gastric Gland Differentiation in Peutz-Jeghers Syndrome

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Interferon gamma induction of gastric mucous neck cell hypertrophy

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