To clarify the mechanism of the development of gastric well differentiated carcinoma from intestinal metaplasia

• Project/Area Number: 16590622
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: JICHI MEDICAL SCHOOL
• Principal Investigator: SATOH Kiichi JICHI MEDICAL SCHOOL, School of Medicine, Senior Lecturer, 医学部, 講師 (50275707)
• Co-Investigator(Kenkyū-buntansha): SUGANO Kentaro JICHI MEDICAL SCHOOL, School of Medicine, Professor, 医学部, 教授 (60179116) ; MUTOH Hiroyuki JICHI MEDICAL SCHOOL, School of Medicine, Senior Lecturer, 医学部, 講師 (50322392) ; OSAWA Hiroyuki JICHI MEDICAL SCHOOL, School of Medicine, Assistant Lecturer, 医学部, 助手 (70260833)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
• Keywords: intestinal metaplasia / gastric carcinoma / transcription factor / Cdx2 / transgenic mouse

Research Abstract

In the progression of chronic gastritis, gastric inucosal cells deviate from the normal pathway of gastric differentiation to an intestinal phenotype. Gastric intestinal metaplasia occurs as a pathological condition in the gastric mucosa. The intestine-specific transcription factor Cdx2 is expressed in the human gastric intestinal metaplastic mucosa. We established Cdx2-transgenic mice expressing transcription factor Cdx2 in the gastric mucosa. The gastric fundic mucosa of the Cdx2-transgenic mice was completely changed into intestinal metaplastic mucosa.
Many epidemiological studies have found an association between the formation of intestinal metaplasia and the development of gastric carcinoma. However, there is no direct evidence which shows intestinal metaplasia is a precursor lesion of gastric carcinoma to date. We periodically examined the intestinal metaplastic mucosa of Cdx2-transgenic mice. Gastric polyps developed from intestinal metaplastic mucosa in all stomachs of Cdx2-transgenic mice examined. These gastric polyps consisted of intestinal-type adenocarcinoma that invaded the submucosa and muscularis propria, and occasionally spread into the subserosa. p53 and APC gene mutations were recognized in the adenocarcinomas. The participation of APC and p53 gene mutations in gastric carcinogenesis from the intestinal metaplasia was verified by the Cdx2-transgenic mice, carrying Apc^<Min> mutation or p53 deficiency, that developed gastric polyps much earlier than Cdx2 alone. We successfully demonstrated that long-term intestinal metaplasia induces invasive gastric carcinoma. These results indicate that intestinal metaplasia itself plays a significant role in the genesis and progression of gastric carcinoma.

Research Products

• [Journal Article] The intestine-specific homeobox gene Cdx2 induces expression of the basic helix-loop-helix transcription factor Math1 (2006)
  • Author(s): Hiroyuki Mutoh, Hirotsugu Sakamoto, Hiroko Hayakawa, Yukitomo Arao, Kiichi Satoh, Mitsuhiro Nokubi, Kentaro Sugano
  • Journal Title: Differentiation (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The intestine-specific homeobox gene Csx2 induces expression of the basic helix-loop-helix transcription facter Math 1. (2006)
  • Author(s): Hiroyuki Mutoh, Hirotsugu Sakamoto, Hiroko Hayakawa, Yukitomo Arao, Kiichi Satoh, Mitsuhiro Nokubi, Kentaro Sugano
  • Journal Title: Differentiation (in press)
• [Journal Article] Pericryptal fibroblast sheath in intestinal metaplasia and gastric carcinoma (2005)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Osawa H, Tomiyama T, Kita H, Yoshida T, Tamada K, Yamamoto H, Isoda N, Ido K, Sugano K.
  • Journal Title: Gut 54 Pages: 33-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine (2005)
  • Author(s): Mutoh H, Satoh K, Kita H, Sakamoto H, Hayakawa H, Yamamoto H, Isoda N, Tamada K, Ido K, Sugano K
  • Journal Title: Int J Dev Biol 49 Pages: 867-871
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pericryptal fibroblast sheath in intestinal metaplasia and gastric carcinoma. (2005)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Osawa H, Tomiyama T, Kita H, Yoshida T, Tamada K, Yamamoto H, Isoda N, Ido K, Sugano K.
  • Journal Title: Gut. 54 Pages: 33-39
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. (2005)
  • Author(s): Mutoh H, Satoh K, Kita H, Sakamoto H, Hayakawa H, Yamamoto H, Isoda N, Tamada K, Ido K, Sugano K
  • Journal Title: Int J Dev Biol. 49 Pages: 867-871
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pericryptal fibroblast sheath in intestinal metaplasia and gastric carcinoma. (2005)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Osawa H, Tomiyama T, Kita H, Yoshida T, Tamada K, Yamamoto H, Isoda N, Ido K, Sugano K.
  • Journal Title: Gut 54 Pages: 33-39
• [Journal Article] Cdx2 specifies the differentiation of morphological as well as functional absorptive enterocytes of the small intestine. (2005)
  • Author(s): Motoh H, Satoh K, Kita H, Sakamoto H, Hayakawa H, Yamamoto H, Isoda N, Tamada K, Ido K, Sugano K.
  • Journal Title: Int.J.Dev.Biol. 49 Pages: 867-871
• [Journal Article] Pericryptal fibroblast sheath in intestinal metaplasia and gastric carcinoma. (2005)
  • Author(s): H.Mutoh, S.Sakurai, K.Satoh, H.Osawa, T.Tomiyama, H.Kita, K.Sugano et al.
  • Journal Title: Gut 54 Pages: 33-39
• [Journal Article] Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice (2004)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, Tomiyama T, Sato Y, Yamamoto H, Isoda N, Yoshida T, Ido K, Sugano K.
  • Journal Title: Cancer Res. 64 Pages: 7740-7747
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cdx1 induced intestinal metaplasia in the transgenic mouse stomach : comparative study with Cdx2 transgenic mice (2004)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K.
  • Journal Title: Gut 53 Pages: 1416-1423
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. (2004)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Tamada K, Kita H, Osawa H, Tomiyama T, Sato Y, Yamamoto H, Isoda N, Yoshida T, Ido K, Sugano K.
  • Journal Title: Cancer Res. 64 Pages: 7740-7747
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cdx1 induced intestinal metaplasia in the transgenic mouse stomach : comparative study with Cdx2 transgenic mice. (2004)
  • Author(s): Mutoh H, Sakurai S, Satoh K, Osawa H, Hakamata Y, Takeuchi T, Sugano K.
  • Journal Title: Gut. 53 Pages: 1416-1423
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cdx1 induced intestinal metaplasia in the transgenic mouse stomach : Comparative study with Cdx2 transgenic mice. (2004)
  • Author(s): H.Mutoh, S.Sakurai, K.Satoh, H.Osawa, Y.Hakamata, T.Takeuchi, K.Sugano
  • Journal Title: Gut 53・10 Pages: 1416-1423
• [Journal Article] Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. (2004)
  • Author(s): H.Mutoh, S.Sakurai, K.Sato, K.Tamada, H.Kita, H.Osawa, K.Sugano et al.
  • Journal Title: Cancer Research 64 Pages: 7740-7747
• [Journal Article] Aberrant expression of CDX2 in the metaplastic epithelium and inflammatory mucosa of gallbladder. (2004)
  • Author(s): H.Osawa, H.Kita, K.Satoh, H.Ohnishi, Y.Kaneko, H.Mutoh, K.Sugano et al.
  • Journal Title: Am.J.Surg.Pathol. 28・9 Pages: 1253-1254
• [Journal Article] The intestine-specific homeobox gene Cdx2 induces expression of the basic helix-loop-helix transcription factor Math 1
  • Author(s): Hiroyuki Mutoh, Hirotsugu Sakamoto, Hiroko Hayakawa, Yukitomo Arao, Kiichi Satoh, Mitsuhiro Nokubi, Kentaro Sugano
  • Journal Title: Differentiation (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] H.pylori発癌のエビデンス (2004)
  • Author(s): 菅野健太郎 他
  • Total Pages: 244
  • Publisher: 医学書院