<i>Ink4a/Arf</i>-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis

Seishima, Ryo; Wada, Toshimi; Tsuchihashi, Kazufumi; Okazaki, Shogo; Yoshikawa, Masahide; Oshima, Hiroko; Oshima, Masanobu; Sato, Toshiro; Hasegawa, Hirotoshi; Kitagawa, Yuko; Goldenring, James R.; Saya, Hideyuki; Nagano, Osamu

doi:10.1158/1940-6207.capr-15-0025-t

Cited by 14 publications

(15 citation statements)

References 36 publications

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“…In addition, CD44 appears to be involved in the pathogenesis of SPEM and to label putative gastric cancer stem cells, suggesting that it might play an important role in the process of inflammation/injury-induced carcinogenesis. 38 , 39 , 40 , 41 , 42 , 43 It also has been shown that alternative mRNA splicing produces Cd44 variant isoforms, such as Cd44v9 , which are more specifically expressed in H pylori gastritis, SPEM, and in gastric carcinomas. 40 , 41 Thus, we examined if H felis –infected Lgr5-Cre;Bmpr1a flox-flox mice show perturbations in the expression of both CD44 and of CD44v9.…”

Section: Resultsmentioning

confidence: 99%

“…Although the level of deletion of Bmpr1a in Lgr5 cells was not complete, H felis –infected Lgr5-Cre;Bmpr1a flox-flox mice showed robust phenotypic changes, suggesting that even partial inhibition of BMP signaling in Lgr5 cells can induce significant aberrations in the normal homeostatic mechanisms of the gastric mucosa. A possible explanation for this finding lies in the observation that Lgr5 cells can express growth-promoting and proinflammatory peptides, 10 , 38 , 39 , 40 , 41 , 42 , 43 factors known to play an important role in the regulation of cell proliferation and in the response of the gastric mucosa to inflammatory stimuli. It therefore is conceivable that diminished BMP signaling in Lgr5 cells could induce the expression of these molecules leading to broader and more widespread responses that might affect the biological functions not only of Lgr5 cells, but also of other adjacent cell types.…”

Section: Discussionmentioning

confidence: 99%

“…CD44 has been implicated in the pathogenesis of inflammation, SPEM, and in the process of gastric carcinogenesis because Cd44 -expressing cells isolated from gastric tumors behave as gastric cancer stem cells. 38 , 39 , 40 , 41 , 42 , 43 Studies also have shown that induction of mitogen-activated protein kinase/ERK signaling leads to increased expression of CD44, 38 and to the activation of STAT3, a pro-oncogenic molecule that has been linked to gastric carcinogenesis. 48 , 49 Elegant biochemical experiments have shown that CD44 physically interacts with phosphorylated STAT3 and that the CD44/phosphorylated STAT3 complex is necessary for induction of cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Takabayashi

Yang

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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Background & AimsGastric Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) cells exert important functions during injury and homeostasis. Bone morphogenetic protein (BMP) signaling regulates gastric inflammation and epithelial homeostasis. We investigated if BMP signaling controls the fate of Lgr5+ve cells during inflammation.MethodsThe H+/K+-adenosine triphosphatase β-subunit promoter was used to express the BMP inhibitor noggin (Nog) in the stomach (H+/K+-Nog mice). Inhibition of BMP signaling in Lgr5 cells was achieved by crossing Lgr5-EGFP-ires-CreERT2 (Lgr5-Cre) mice to mice with floxed alleles of BMP receptor 1A (Lgr5-Cre;Bmpr1aflox/flox mice). Lgr5/GFP+ve cells were isolated using flow cytometry. Lineage tracing studies were conducted by crossing Lgr5-Cre mice to mice that express Nog and tdTomato (Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom). Infection with Helicobacter felis was used to induce inflammation. Morphology of the mucosa was analyzed by H&E staining. Distribution of H+/K+-adenosine triphosphatase-, IF-, Ki67-, CD44-, CD44v9-, and bromodeoxyuridine-positive cells was analyzed by immunostaining. Expression of neck and pit cell mucins was determined by staining with the lectins Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, respectively. Id1, Bmpr1a, Lgr5, c-Myc, and Cd44 messenger RNAs were measured by quantitative reverse-transcription polymerase chain reaction.ResultsLgr5-Cre;Bmpr1aflox/flox mice showed diminished expression of Bmpr1a in Lgr5/GFP+ve cells. Infection of Lgr5-Cre;Bmpr1aflox/flox mice with H felis led to enhanced inflammation, increased cell proliferation, parietal cell loss, and to the development of metaplasia and dysplasia. Infected Lgr5-Cre;H+/K+-Nog;Rosa26-tdTom mice, but not control mice, showed the presence of tomato+ve glands lining the lesser curvature that stained positively with Griffonia (Bandeiraea) simplicifolia lectin II and Ulex europaeus agglutinin 1, and with anti-IF, -CD44, -CD44v9, and -bromodeoxyuridine antibodies.ConclusionsInflammation and inhibition of BMP signaling activate Lgr5+ve cells, which give rise to metaplastic, dysplastic, proliferating lineages that express markers of mucus neck and zymogenic cell differentiation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Takabayashi

Yang

et al. 2018

Cellular and Molecular Gastroenterology and Hepatology

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“…That, together with our findings, indicates that, although gastrin is not essential for the development of SPEM, it might influence the metaplastic cascade, possibly through upregulating CLU expression in hypoacidic oxyntic glands. Upregulation of CLU could make metaplastic cells more resistant to harmful stimuli, such as oxidative stress due to chronic inflammation [ 18 ], and oxidative stress may play a central role in gastric tumorigenesis [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

Vange¹,

Bruland²,

Doseth³

et al. 2017

PLoS ONE

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The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.

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“…Mice given 3 consecutive daily doses of 5 mg of fully emulsified bolus doses of tamoxifen 68 had a 90% reduction in parietal cell mass in the stomach by 3 days after the first injection 26, 69. High-dose tamoxifen-treated mice also developed SPEM within 3 days of treatment with scattered proliferative SPEM cells identified.…”

Section: Murine Models Of Gastric Preneoplasiamentioning

confidence: 99%

Murine Models of Gastric Corpus Preneoplasia

Petersen

Mills

Goldenring

2017

Cellular and Molecular Gastroenterology and Hepatology

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Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)–expressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach.

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Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis

Cited by 14 publications

References 36 publications

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

Regulation of Gastric Lgr5+ve Cell Homeostasis by Bone Morphogenetic Protein (BMP) Signaling and Inflammatory Stimuli

The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

Murine Models of Gastric Corpus Preneoplasia

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