β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas

Tsukamoto, Tetsuya; Yamamoto, Masami; Ogasawara, Nagahisa; Nomoto, Tomoko; Fujita, Hirofumi; Matsushima, Taijiro; Nozaki, Koji; Cao, Xueyuan; Tatematsu, Masae

doi:10.1111/j.1349-7006.2003.tb01399.x

Cited by 23 publications

(47 citation statements)

References 25 publications

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“…These findings suggest that an initiating event in the stomach of an MNU-induced model is independent of Wnt activation. This notion is consistent with previous findings in rodents, which suggest that h-catenin accumulation may be a later event of gastric carcinogenesis in MNU-induced models (48)(49)(50). The fact that Apc Min/+ mice treated with MNU tend to develop more aggressive tumors in the stomach may be attributable to the combined activation of different oncogenic pathways in both models.…”

Section: Of the Stomach In Apcsupporting

confidence: 92%

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

Tomita¹,

Yamada²,

Oyama³

et al. 2007

Cancer Research

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Although several lines of evidence suggest the involvement of the Wnt pathway in the development of gastric cancers, the functional significance of the pathway in gastric carcinogenesis is still poorly defined. To examine the role of the Apc/Bcatenin signaling pathway in the development of gastric cancers, we investigated the gastric mucosa of the Apc Min/+ mouse, which is a murine model for familial adenomatous polyposis, carrying a germ-line mutation at codon 850 of Apc. We found that aged ApcMin/+ mice spontaneously develop multiple tumors in the stomach, which are accompanied by loss of heterozygosity of Apc. Such tumors consisted of adenomatous glands with strong nuclear accumulation of Bcatenin. Even a single adenomatous gland already showed nuclear accumulation of B-catenin, suggesting that Apc/Bcatenin pathway is an initiating event in gastric tumorigenesis in ApcMin/+ mice. Myc and cyclin D1 expressions, which are transcriptional targets of B-catenin/Tcf, increased in the adenomatous lesions. Furthermore, B-catenin/Tcf reporter transgenic mice with Apc Min allele showed higher levels of the transcriptional activity of B-catenin/Tcf in the gastric tumors. We also treated Apc Min/+ and wild-type mice with N-methyl-Nnitrosourea (MNU), an alkylating agent that induces adenomas and adenocarcinomas in the stomach. Consequently, MNU-treated Apc Min/+ mice significantly enhanced the tumor development in comparison with Apc Min/+ mice or MNUtreated wild-type mice. Several gastric tumors in MNU-treated Apc Min/+ mice showed invasion into the submucosal layer. These results indicate that the Apc/B-catenin pathway may play an important role in at least subset of gastric carcinomas. In addition, Apc Min/+ mice combined with MNU could be a useful short-term model to investigate multistage carcinogenesis in the stomach. [Cancer Res 2007;67(9):4079-87]

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Section: Of the Stomach In Apcsupporting

confidence: 92%

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

Tomita¹,

Yamada²,

Oyama³

et al. 2007

Cancer Research

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“…In a rat model of gastric cancer, mutations in h-catenin contribute to tumor progression rather than initiation (11). Human studies of Wnt pathway mutations in gastric cancer have failed to show a clear relationship to stage.…”

Section: Discussionmentioning

confidence: 99%

“…Gastric cancers previously collected as part of Southwestern Oncology Group Study 9008 and stored in the Southwestern Oncology Group Gastrointestinal Tumor Repository at the University of Cincinnati comprised the tissues used in this study. Seventeen of these tumors had previously been shown to contain mutations in exon 3 of the b-catenin gene (11). Formalin-fixed, paraffinembedded tissue blocks from these tumors were cut into 4-Am-thick sections and placed onto positively charged slides.…”

Section: Methodsmentioning

confidence: 99%

“…Persons with germ line mutations of the APC tumor suppressor gene have a 10-fold increased risk of developing gastric cancer compared with normal persons (8). Mutations in APC and b-catenin have been found in sporadic gastric adenocarcinomas, as well as in tumors from carcinogen-based animal models of gastric cancer (9)(10)(11). Recently, our group reported a 29% rate of Wnt pathway activation in gastric adenocarcinoma as defined by the presence of nuclear h-catenin and the occurrence of activating b-catenin mutations in these tumors (12).…”

Section: Introductionmentioning

confidence: 99%

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β-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer

Lowy

Clements

Bishop³

et al. 2006

Cancer Research

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Activation of Wnt signaling through B-catenin dysregulation occurs in numerous human tumors, including gastric cancer. The specific consequences of Wnt signaling in gastric cancer, however, are not well characterized. This study shows that the introduction of mutant B-catenin into gastric cancer cell lines by adenoviral infection enhances invasiveness and proliferation and up-regulates the expression of the gene encoding the matrix metalloproteinase (MMP) family member membrane type 3 MMP (MT3-MMP). Up-regulation of MT3-MMP is critical to the invasive phenotype as shown by small interfering RNA (siRNA) studies. Immunohistochemical staining also showed that MT3-MMP was highly expressed in gastric cancers with activating B-catenin mutations. These observations suggest that Wnt activation may contribute to gastric cancer progression by increasing the invasiveness of neoplastic cells in the stomach via up-regulation of MT3-MMP expression.

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“…In MNNG-induced rat adenocarcinomas, four of twenty-two tumors showed nuclear localization of β-catenin with the characteristic mutation of exon 3 [100]. This study suggested that β-catenin mutations could be associated with the progression of chemical-induced rat adenocarcinoma at the late stage.…”

Section: Wnt/β-cateninmentioning

confidence: 69%

Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

et al. 2014

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Since the discovery of Helicobacter pylori (H. pylori), many efforts have been made to establish animal models for the investigation of the pathological features and molecular mechanisms of gastric carcinogenesis. Among the animal models, Mongolian gerbils and mice are particularly useful for the analysis of H. pylori-associated inflammatory reactions and gastric cancer development. Inhibitors of oxidative stress, cyclooxygenase-2 (COX-2) and nuclear factor-κB, exert preventive effects on chronic gastritis and the development of adenocarcinomas in H. pylori-infected gerbils. Genetically-modified mouse models, including transgenic and knockout mice, have also revealed the importance of p53, COX-2/prostaglandin, Wnt/β-catenin, proinflammatory cytokines, gastrin and type III mucin in the molecular mechanisms of gastric carcinogenesis. Microarray technology is available for comprehensive gene analysis in the gastric mucosa of mouse models, and epigenetics, such as DNA methylation, could be an alternative approach to correlate the observations in animal models with the etiology in humans.

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β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas

Cited by 23 publications

References 25 publications

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

Development of Gastric Tumors in ApcMin/+ Mice by the Activation of the β-Catenin/Tcf Signaling Pathway

β-Catenin/Wnt Signaling Regulates Expression of the Membrane Type 3 Matrix Metalloproteinase in Gastric Cancer

Molecular Mechanism of Gastric Carcinogenesis in Helicobacter pylori-Infected Rodent Models

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