This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tomita, H. Articles by Mori, H. Search for Related Content PubMed PubMed Citation Articles by Tomita, H. Articles by Mori, H.

Development of Gastric Tumors in Apc^Min/+ Mice by the Activation of the ß-Catenin/Tcf Signaling Pathway

Departments of ¹ Tumor Pathology, ² Oncologic Surgery, and ³ Tissue and Organ Development, Gifu University Graduate School of Medicine, Gifu, Japan and ⁴ Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts

Requests for reprints: Yasuhiro Yamada, Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan. Phone: 81-58-230-6225; Fax: 81-58-230-6226; E-mail: y-yamada{at}gifu-u.ac.jp.

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/ß-catenin 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 Apc^Min/+ 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 ß-catenin. Even a single adenomatous gland already showed nuclear accumulation of ß-catenin, suggesting that Apc/ß-catenin pathway is an initiating event in gastric tumorigenesis in Apc^Min/+ mice. Myc and cyclin D1 expressions, which are transcriptional targets of ß-catenin/Tcf, increased in the adenomatous lesions. Furthermore, ß-catenin/Tcf reporter transgenic mice with Apc^Min allele showed higher levels of the transcriptional activity of ß-catenin/Tcf in the gastric tumors. We also treated Apc^Min/+ and wild-type mice with N-methyl-N-nitrosourea (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 MNU-treated wild-type mice. Several gastric tumors in MNU-treated Apc^Min/+ mice showed invasion into the submucosal layer. These results indicate that the Apc/ß-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]

This article has been cited by other articles:

				B. Humar, V. Blair, A. Charlton, H. More, I. Martin, and P. Guilford E-Cadherin Deficiency Initiates Gastric Signet-Ring Cell Carcinoma in Mice and Man Cancer Res., March 1, 2009; 69(5): 2050 - 2056. [Abstract] [Full Text] [PDF]

				Y. Guo, J. Xie, E. Rubin, Y.-X. Tang, F. Lin, X. Zi, and B. H. Hoang Frzb, a Secreted Wnt Antagonist, Decreases Growth and Invasiveness of Fibrosarcoma Cells Associated with Inhibition of Met Signaling Cancer Res., May 1, 2008; 68(9): 3350 - 3360. [Abstract] [Full Text] [PDF]

				T. Oyama, Y. Yamada, K. Hata, H. Tomita, A. Hirata, H. Sheng, A. Hara, H. Aoki, T. Kunisada, S. Yamashita, et al. Further upregulation of {beta}-catenin/Tcf transcription is involved in the development of macroscopic tumors in the colon of ApcMin/+ mice Carcinogenesis, March 1, 2008; 29(3): 666 - 672. [Abstract] [Full Text] [PDF]