In vivo analysis of Helicobacter pylori induced stomach cancers

• Project/Area Number: 16590335
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Aichi Cancer Center
• Principal Investigator: TSUKAMOTO Tetsuya Aichi Cancer Center Research Institute, Division of Oncological Pathology, Section Head, 腫瘍病理学部, 室長 (00236861)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: Stomach cancer / Helicobacter pylori / Intestinal metaplasia / Gastric type / Intestinal type / Transcription factor / beta-catenin / Wnt / 胃腸混合型胃がん / Sox2 / Cdx / 小腸型・大腸型 / gptΔトランスジェニックマウス / 高食塩食 / N-methyl-N-nitrosourea

Research Abstract

Helicobacter pylon has been revealed to be an important factor for gastric carcinogenesis. We have analyzed association of gastric and intestinal phenotypic expression and alteration of oncogenes and tumor suppressor genes in stomach cancers developed in human cases as well as rodent models.
1. Stomach cancers were classified into (1) gastric (G) type, expressing MUC5AC (mucin core protein localized in foveolar epithelium) or MUC6 (in pyloric gland cells), (2) intestinal (I) type, harboring MUC2 in intestinal goblet cells or villin on brush border, (3) gastric-and-intestinal mixed (GI) type, harboring both G and I types, and (4) null (N) type, possessing none of them.
2. Sox2 was found to be transcribed in G and GI-mixed type adenocarcinomas in accordance with MUC5AC and MUC6 expression, while Cdx1 and Cdx2 were up-regulated in GI-mixed and I types along with the expression of MUC2 and villin. In the N type, both gastric and intestinal transcription factors were suppressed. Immunohistochemistry confirmed expression of Sox2 in MUC5AC+ lesions and Cdx2 localization together with MUC2.
3. Thirteen (18.6%) advanced and 5 (16.7%) intramucosal gastric cancers were judged to be hMLH1-negative. In the intramucosal cases, MUC5AC expression was observed in all 5 hMLH1-negative differentiated-type cancers, showing the association of gastric phenotype and microsatellite instability
4. Seventy-seven regions in 39 stomach adenocarcinomas were evaluated according to the beta-catenin localization and gastric and intestinal phenotypes. The cases of nuclear beta-catenin localization showed increase from G to I types. Molecular analysis of beta-catenin and APC genes revealed 10 tumors to be heterogeneous out of 16 informative cases (62.5%).
5. The clinicopathological significance of colonic and small-intestinal phenotypes has hitherto remained unclear in gastric cancers. Of 86 gastric cancers, sucrase and CA1 expression was observed in 12 (14.0%) and only in two cases (2.3%), respectively.

Research Products

• [Journal Article] High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. (2006)
  • Author(s): Maekita, T., et al.
  • Journal Title: Clin Cancer Res. 12 Pages: 989-995
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen-treated, helicobacter pylori-infected Mongolian gerbils. (2006)
  • Author(s): Mizoshita, T., et al.
  • Journal Title: Cancer Sci. 97 Pages: 38-44
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. (2006)
  • Author(s): Maekita, T., Nakazawa, K., Mihara, M., Nakajima, T., Yanaoka, K., Iguchi, M., Arii, K., Kaneda, A., Tsukamoto, T., Tatematsu, M., Tamura, G., Saito, D., Sugimura, T., Ichinose, M., Ushijima, T.
  • Journal Title: Clin Cancer Res 12 Pages: 989-995
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen-treated, Helicobacter pylori-infected Mongolian gerbils. (2006)
  • Author(s): Mizoshita, T., Tsukamto, T., Takenaka, Y., Cao, X., Kato, S., Kaminishi, M., Tatemastu, M.
  • Journal Title: Cancer Sci 97 Pages: 38-44
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk (2006)
  • Author(s): Maekita, et al.
  • Journal Title: Clin.Cancer Res. 12 Pages: 989-995
• [Journal Article] Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen-treated, Helicobacter pylori-infected Mongolian gerbils (2006)
  • Author(s): Mizoshita, et al.
  • Journal Title: Cancer Sci. 97 Pages: 38-44
• [Journal Article] Paneth type gastric cancer cells exhibit expression of human defensin-5. (2005)
  • Author(s): Inada, K.I., et al.
  • Journal Title: Histopathology 47 Pages: 330-331
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory effect of etodolac, a selective cyclooxygrnase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils. (2005)
  • Author(s): Magari, H., et al.
  • Journal Title: Biochem. Biophys. Res. Commun. 334 Pages: 606-12
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Microsatellite instability is linked to loss of hMLH1 expression in advanced gastric cancers : lack of a relationship with the histological type and phenotype. (2005)
  • Author(s): Mizoshita, T., et al.
  • Journal Title: Gastric Cancer 8 Pages: 167-172
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Colonic and small-intestinal phenotypes in gastric cancers : Relationships with clinicopathological findings. (2005)
  • Author(s): Mizoshita, T., et al.
  • Journal Title: Pathol. Int., 55 Pages: 611-618
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mixed gastric- and intestinal-type metaplasia Is formed by cells with dual intestinal and gastric differentiation. (2005)
  • Author(s): Niwa, T., et al.
  • Journal Title: J. Histochem. Cytochem., 53 Pages: 75-85
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Coexistence of gastric- and intestinal-type endocrine cells in gastric and intestinal mixed intestinal metaplasia of the human stomach. (2005)
  • Author(s): Otsuka, T,. et al.
  • Journal Title: Pathol. Int. 55 Pages: 170-179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach. (2005)
  • Author(s): Tanaka, H., et al.
  • Journal Title: Virchows Arch. 447 Pages: 806-815
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of Helicobacter pylori in Gastric Carcinogenesis : The Origin of Gastric Cancers and Heterotopic Proliferative Glands in Mongolian Gerbils. (2005)
  • Author(s): Tatematsu, M., et al.
  • Journal Title: Helicobacter 10 Pages: 97-106
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. (2005)
  • Author(s): Tsukamoto, T., et al.
  • Journal Title: Histopathology 46 Pages: 649-658
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Paneth type gastric cancer cells exhibit expression of human defensin-5. (2005)
  • Author(s): Inada, K.I., Mizoshita, T., Tsukamoto, T., Porter, E.M., Tatematsu, M.
  • Journal Title: Histopathology 47 Pages: 330-331
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory effect of etodolac, a selective cyclooxygenase-2 inhibitor, on stomach carcinogenesis in Helicobacter pylori-infected Mongolian gerbils. (2005)
  • Author(s): Magari, H., Shimizu, Y., Inada, K.I., Enomoto, S., Tomeki, T., Yanaoka, K., Tamai, H., Arii, K., Nakata, H., Oka, M., Utsunomiya, H., Tsutsumi, Y., Tsukamoto, T., Tatematsu, M., Ichinose, M.
  • Journal Title: Biochem.Biophys.Res.Commun. 334 Pages: 606-612
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Microsatellite instability is linked to loss of hMLH1 expression in advanced gastric cancers : lack of a relationship with the histological type and phenotype. (2005)
  • Author(s): Mizoshita, T., Tsukamoto, T., Cao, X., Otsuka, T., Ito, S., Takahashi, E., Nakamura, S., Nakamura, T., Yamamura, Y., Tatematsu, M.
  • Journal Title: Gastric Cancer 8 Pages: 164-172
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Colonic and small-intestinal phenotypes in gastric cancers : Relationships with clinicopathological findings. (2005)
  • Author(s): Mizoshita, T., Tsukamoto, T., Tanaka, H., Takenaka, Y., Kato, S., Cao, X., Joh, T., Tatematsu, M.
  • Journal Title: Pathol.Int. 55 Pages: 611-618
  • NAID: 10017125700
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mixed gastric- and intestinal-type metaplasia Is formed by cells with dual intestinal and gastric differentiation. (2005)
  • Author(s): Niwa, T., Ikehara, Y., Nakanishi, H., Tanaka, H., Inada, K., Tsukamoto, T., Ichinose, M., Tateatsu, M.
  • Journal Title: J.Histochem.Cytochem. 53 Pages: 75-85
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Coexistence of gastric- and intestinal-type endocrine cells in gastric and intestinal mixed intestinal metaplasia of the human stomach. (2005)
  • Author(s): Otsuka, T., Tsukamoto, T., Mizoshita, T., Inada, K., Takenaka, Y., Kato, S., Yamamura, Y., Miki, K., Tatematsu, M.
  • Journal Title: Pathol.Int. 55 Pages: 170-179
  • NAID: 10016474960
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach. (2005)
  • Author(s): Tanaka, H., Tsukamoto, T., Mizoshita, T., Inada, K., Ogasawara, N., Cao, X., Kato, S., Joh, T., Tatematsu, M.
  • Journal Title: Virochows Arch 447 Pages: 806-815
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of Helicobacter pylon in Gastric Carcinogenesis : The Origin of Gastric Cancers and Heterotopic Proliferative Glands in Mongolian Gerbils. (2005)
  • Author(s): Tatematsu, M., Tsukamoto, T., Mizoshita, T.
  • Journal Title: Helicobacter 10 Pages: 97-106
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. (2005)
  • Author(s): Tsukamoto, T., Mizoshita, T., Mihara, M., Tanaka, H., Takenaka, Y., Yamamura, Y., Nakamura, S., Ushijima, T., Tatematsu, M.
  • Journal Title: Histopathology 46 Pages: 649-658
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Microsatellite instability is linked to loss of hMLH1 expression in advanced gastric cancers : lack of a relationship with the histological type and phenotype (2005)
  • Author(s): Mizoshita, et al.
  • Journal Title: Gastric Cancer 8 Pages: 164-172
• [Journal Article] Colonic and small-intestinal phenotypes in gastric cancers : Relationships with clinicopathological findings (2005)
  • Author(s): Mizoshita, et al.
  • Journal Title: Pathol.Int. 55 Pages: 611-618
• [Journal Article] Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes (2005)
  • Author(s): Tsukamoto, et al.
  • Journal Title: Histopathology 46 Pages: 649-658
• [Journal Article] Lack of elevated liver carcinogenicity of aminophenylnorharman in p53-deficient mice. (2005)
  • Author(s): Iidaka, T., et al.
  • Journal Title: Cancer Lett 217 Pages: 149-159
• [Journal Article] Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. (2005)
  • Author(s): Tsukamoto, T., et al.
  • Journal Title: Histopathology (in press)
• [Journal Article] Frequent c-Kit gene mutations not only in gastrointestinal stromal tumors but also in interstitial cells of Cajal in surrounding normal mucosa. (2005)
  • Author(s): Ogasawara, N., et al.
  • Journal Title: Cancer Lett. (in press)
• [Journal Article] Beta-catenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N-nitrosourea-treated and Helicobacter pylori-infected Mongolian gerbils. (2004)
  • Author(s): Cao, X.et al.
  • Journal Title: Cancer Sci. 95 Pages: 487-490
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Eradication of Helicobacter pylori induces apoptosis and inhibits proliferation of heterotopic proliferative glands in infected Mongolian gerbils. (2004)
  • Author(s): Cao, X., et al.
  • Journal Title: Cancer Sci. 95 Pages: 872-877
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Lysyloxidase in a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. (2004)
  • Author(s): Kaneda, A., et al.
  • Journal Title: Cancer Res. 64 Pages: 6410-6415
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells. (2004)
  • Author(s): Mizoshita, T., et al.
  • Journal Title: J. Cancer Res. Clin. Oncol. 130 Pages: 29-36
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immunohistochemically detectable Cdx2 is present in intestinal phenotypic elements in early gastric cancers of both differentiated and undifferentiated types, with no correlation to non-neoplastic surrounding mucosa. (2004)
  • Author(s): Mizoshita, T., et al.
  • Journal Title: Pathol. Int. 54 Pages: 392-400
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Down regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2 : Inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. (2004)
  • Author(s): Tsukamoto, T., et al.
  • Journal Title: J. Cancer Res. Clin. Oncol. 130 Pages: 135-145
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Beta-catenin gene alteration in glandular stomach adenocarcinomas in N-methyl- N-nitrosourea-treated and Helicobacter pylori-infected Mongolian gerbils. (2004)
  • Author(s): Cao, X., Tsukamoto, T., Nozaki, K., Mizoshita, T., Ogasawara, N., Tanaka, H., Takenaka, Y., Kaminishi, M., Tatematsu, M.
  • Journal Title: Cancer Sci. 95 Pages: 487-490
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Eradication of Helicobacter pylori induces apoptosis and inhibits proliferation of heterotopic proliferative glands in infected Mongolian gerbils. (2004)
  • Author(s): Cao, X., Tsukamoto, T., Nozaki, K., Shimizu, N., Mizoshita, T., Kumagai, T., Kaminishi, M., Tatematsu, M.
  • Journal Title: Cancer Sci. 95 Pages: 872-877
  • NAID: 10014197708
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. (2004)
  • Author(s): Kaneda, A., Wakaznono, K., Tsukamoto, T., Watanabe, N., Yagi, Y., Tatematsu, M., Kaminishi, M., Sugimura, T., Ushijima, T.
  • Journal Title: Cancer Res. 64 Pages: 6410-6415
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of the intestine-specific transcription factors, Cdx1 and Cdx2, correlates shift to an intestinal phenotype in gastric cancer cells. (2004)
  • Author(s): Mizoshita, T., Inada, K., Tsukamoto, T., Nozaki, K., Joh, T., Itoh, M., Yamamura, Y., Ushijima, T., Nakamura, S., Tatematsu, M.
  • Journal Title: J.Cancer Res.Clin.Oncol. 130 Pages: 29-36
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immunohistochemically detectable Cdx2 is present in intestinal phenotypic elements in early gastric cancers of both differentiated and undifferentiated types, with no correlation to non-neoplastic surrounding mucosa. (2004)
  • Author(s): Mizoshita, T., Tsukamoto, T., Inada, K., Ogasawara, N., Hirata, A., Kato, S., Joh, T., Itoh, M., Yamamura, Y., Tatematsu, M.
  • Journal Title: Pathol.Int. 54 Pages: 392-400
  • NAID: 10020555993
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2:Inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. (2004)
  • Author(s): Tsukamoto, T., Inada, K., Tanaka, H., Mizoshita, T., Mihara, M., Ushijima, T., Yamamura, Y., Nakamura, S., Tatematsu, M.
  • Journal Title: J.Cancer Res.Clin.Oncol. 130 Pages: 135-145
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Down regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2 : Inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. (2004)
  • Author(s): Tsukamoto, T., et al.
  • Journal Title: J.Cancer Res.Clin.Oncol 130 Pages: 135-145
• [Journal Article] Detection of initiating and promoting activity of aminophenylnorharman with a five-week in vivo initiation assay. (2004)
  • Author(s): Iidaka, T., et al.
  • Journal Title: J.Toxicol.Pathol. 17 Pages: 1-5
• [Journal Article] Beta-catenin gene alteration in glandular stomach adenocarcinomas in N-methyl-N-nitrosourea-treated and Helicobacter pylori-infected Mongolian gerbils. (2004)
  • Author(s): Cao, X., et al.
  • Journal Title: Cancer Sci. 95 Pages: 487-490
• [Journal Article] High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells.
  • Author(s): Kato, S., et al.
  • Journal Title: Int J Cancer in press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human stomach cancer.
  • Author(s): Ogasawara, N., et al.
  • Journal Title: Histopathology in press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Gastric-and-intestinal mixed intestinal metaplasia : aberrant expression of transcription factors and stem cell intestinalzation.
  • Author(s): Tsukamoto, T., et al.
  • Journal Title: Gastric Cancer in press
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylon-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells.
  • Author(s): Kato, S., Tsukamoto, T., Mizoshita, T., Tanaka, H., Kumagai, T., Ota, H., Katsuyama, T., Asaka, M., Tatematsu, M.
  • Journal Title: Int J Cancer (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutations and nuclear accumulation of beta-catenin correlate with intestinal phenotypic expression in human stomach cancer.
  • Author(s): Ogasawara, N., Tsukamoto, T., Mizoshita, T., Inada, K., Cao, X., Takenaka, Y., Joh, T., Tatematsu, M.
  • Journal Title: Histopathology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Gastric-and-intestinal mixed intestinal metaplasia : aberrant expression of transcription factors and stem cell intestinalization.
  • Author(s): Tsukamoto, T., Mizoshita, T., Tatematsu, M.
  • Journal Title: Gastric Cancer (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutations and nuclear accumulation of b-catenin correlate with intestinal phenotypic expression in human stomach cancer
  • Author(s): Ogasawara, et al.
  • Journal Title: Histopathology in press
• [Book] Linkage of tissue dependent susceptibility and p53 gene mutations due to chemical carcinogens in p53 knockout mice (2005)
  • Author(s): Tsukamoto et al.
  • Total Pages: 23
  • Publisher: Research Signpost