Development of fundic gland type adenocarcinomas; mechanism of carcinogenesis and role of eradication of Helicobacter pylori

• Project/Area Number: 15K08960
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Fujita Health University
• Principal Investigator: Tsukamoto Tetsuya 藤田保健衛生大学, 医学部, 准教授 (00236861)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: Stomach / Fundic gland / Pyloric gland / Helicobacter pylori / Intestinal metaplasia / Eradication / Development / 胃底腺 / 幽門腺 / 発生分化 / 胃がん / stomach / eradication / intestinal metaplasia / fundic gland / pyloric gland

Outline of Final Research Achievements

Helicobacter pylori (Hp) represents an important factor in the development of intestinal metaplasia (IM) and gastric cancer. Eradication of Hp could control gastric foveolar hyperplasia but not proliferation of IM glands, suggesting the IM could represent a histological irreversible point with eradication. Elimination of the bacteria induced regression of the gastric adenocarcinomas by the replacement with less atypical or normal epithelia at the surface and the bottom as early as 2 months after eradication both in fundic and pyloric mucosa. Microarray analyses using 4 and 49-day-old mice stomach revealed that H19 and insulin like growth factor 2 were overexpressed in the younger age, when fundic glands have not been fully developed. Higher expression of these two genes in gastric cancers revealed worse prognosis using The Cancer Genome Atlas data. Gastric cancer may take advantage of their own growth regulatory mechanisms especially in fundic mucosa.

Research Products

• [Journal Article] Unveiling the protein coding-independent function of the TET family in gastric cancer (2018)
  • Author(s): Sakurai, K., Tsukamoto, T.
  • Journal Title: Non-coding RNA Investig Volume: 2 Pages: 17-17
  • DOI: 10.21037/ncri.2018.03.03
  • Peer Reviewed / Open Access
• [Journal Article] Prevention of Gastric Cancer: Eradication of Helicobacter Pylori and Beyond. (2017)
  • Author(s): Tsukamoto, T., Nakagawa, M., Kiriyama, Y., Toyoda, T., Cao, X.
  • Journal Title: Int J Mol Sci Volume: 18 Issue: 8 Pages: 1699-1699
  • DOI: 10.3390/ijms18081699
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Morphologic characterization of residual DNA methylation in the gastric mucosa after Helicobacter pylori eradication. (2017)
  • Author(s): Tahara, S., Tahara, T., Tuskamoto, T., Horiguchi, N., Kawamura, T., Okubo, M., Ishizuka, T., Nagasaka, M., Nakagawa, Y., Shibata, T., Kuroda, M., Ohmiya, N.
  • Journal Title: Cancer Med Volume: 6 Issue: 7 Pages: 1730-1737
  • DOI: 10.1002/cam4.1082
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic features of lymphoid follicles using blue laser imaging (BLI) endoscopy in the colorectum and its association with chronic bowel symptoms (2017)
  • Author(s): Tahara, T., Takahama, K., Tahara, S., Yoshida, D., Horiguchi, N., Kawamura, T., Okubo, M., Nagasaka, M., Nakagawa, Y., Urano, M., Shibata, T., Tuskamoto, T., Ieda, H. O., Kuroda, M., Ohmiya, N.
  • Journal Title: PLoS One Volume: 12 Issue: 8 Pages: e0182224-e0182224
  • DOI: 10.1371/journal.pone.0182224
  • Peer Reviewed / Open Access
• [Journal Article] Telomere Length in Leukocyte DNA in Gastric Cancer Patients and its Association with Clinicopathological Features and Prognosis. (2017)
  • Author(s): Tahara, T, Tahara, S, Horiguchi, N, Kawamura, T, Okubo, M, Ishizuka, T, Yamada, H, Yoshida, D, Ohmori, T, Maeda, K, Komura, N, Ikuno, H, Jodai, Y, Kamano, T, Nagasaka, M, Nakagawa, Y, Tuskamoto, T, Urano, M, Shibata, T, Kuroda, M, Ohmiya, N.
  • Journal Title: Anticancer Research Volume: 37 Issue: 4 Pages: 1997-2001
  • DOI: 10.21873/anticanres.11543
  • Peer Reviewed
• [Journal Article] 18beta-glycyrrhetinic acid suppresses gastric cancer by activation of miR-149-3p-Wnt-1 signaling (2016)
  • Author(s): Cao, D, Jia, Z, You, L, Wu, Y, Hou, Z, Suo, Y, Zhang, H, Wen, S, Tsukamoto, T, Oshima, M, Jiang, J, Cao, X
  • Journal Title: Oncotarget Volume: 7 Issue: 44 Pages: 71960-71973
  • DOI: 10.18632/oncotarget.12443
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gastric-and-Intestinal Mixed Intestinal Metaplasia is Irreversible Point with Eradication of Helicobacter Pylori. (2016)
  • Author(s): Kiriyama, Y., Tahara, T., Shibata, T., Okubo, M., Nakagawa, M., Okabe, A., Ohmiya, N., Kuroda, M., Sugioka, A., Ichinose, M., Tatematsu, M., Tsukamoto, T.
  • Journal Title: Open J Pathol Volume: 6 Issue: 02 Pages: 93-104
  • DOI: 10.4236/ojpathology.2016.62012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Epithelial cell-derived a disintegrin and metalloproteinase-17 confers resistance to colonic inflammation through EGFR activation (2016)
  • Author(s): Shimoda M, Horiuchi K, Sasaki A, Tsukamoto T, Okabayashi K, Hasegawa H, Kitagawa Y and Okada Y
  • Journal Title: EBioMedicine Volume: 5 Pages: 114-24
  • DOI: 10.1016/j.ebiom.2016.02.007
  • Peer Reviewed / Open Access
• [Journal Article] Anti-inflammatory effects of capsaicin and piperine on Helicobacter pylori-induced chronic gastritis in Mongolian gerbils (2016)
  • Author(s): Toyoda T, Shi L, Takasu S, Cho YM, Kiriyama Y, Nishikawa A, Ogawa K, Tatematsu M, Tsukamoto T
  • Journal Title: Helicobacter Volume: 21 Issue: 2 Pages: 131-142
  • DOI: 10.1111/hel.12243
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Protective Effects of 18beta-Glycyrrhetinic Acid on Helicobacter pylori-Infected Gastric Mucosa in Mongolian Gerbils. (2016)
  • Author(s): Cao, D., Jiang, J., You, L., Jia, Z., Tsukamoto, T., Cai, H., Wang, S., Hou, Z., Suo, Y. E., Cao, X.
  • Journal Title: BioMed Res Int Volume: 2016 Pages: 4943793-4943793
  • DOI: 10.1155/2016/4943793
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The green tea polyphenol epigallocatechin-3-gallate effectively inhibits Helicobacter pylori-induced gastritis in Mongolian gerbils. (2016)
  • Author(s): Jiang, J., Cao, D., Jia, Z., You, L., Tsukamoto, T., Hou, Z., Suo, Y., Wang, S., Cao, X.
  • Journal Title: Int J Clin Exp Med Volume: 9 Pages: 2479-2485
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Canolol Inhibits Gastric Tumors Initiation and Progression through COX-2/PGE2 Pathway in K19-C2mE Transgenic Mice. (2015)
  • Author(s): Cao D, Jiang J, Tsukamoto T, Liu R, Ma L, Jia Z, Kong F, Oshima M, Cao X.
  • Journal Title: PLoS One Volume: 10 Issue: 3 Pages: e0120938-e0120938
  • DOI: 10.1371/journal.pone.0120938
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preventive effect of rebamipide on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats. (2015)
  • Author(s): Tsukamoto H, Mizoshita T, Katano T, Hayashi N, Ozeki K, Ebi M, Shimura T, Mori Y, Tanida S, Kataoka H, Tsukamoto T, Tatematsu M, Joh T.
  • Journal Title: Toxicol Pathol. Volume: 67 Issue: 3 Pages: 271-277
  • DOI: 10.1016/j.etp.2015.01.003
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] DNA二重鎖切断マーカーγ-H2AXを用いた胃発がん物質の短期同定 (2018)
  • Author(s): 岡部麻子、桐山諭和、鈴木周五、櫻井浩平、高橋智、塚本徹哉
  • Organizer: 日本毒性病理学会総会
• [Presentation] Helicobacter pylori除菌後ヒト胃癌の経時的な形態および増殖能の変化 (2017)
  • Author(s): 中川満、桐山諭和、岡部麻子、田原沙佑美、田原智満、堀口徳之、大宮直木、黒田誠、杉岡篤、塚本徹哉
  • Organizer: 日本病理学会総会
• [Presentation] ヘリコバクター・ピロリ菌除菌による胃腺癌退縮の経時的推移 (2017)
  • Author(s): 中川満、塚本徹哉
  • Organizer: 日本癌学会総会
• [Presentation] Immunohistochemical study of γ-H2AX and p53 in human gastric carcer (2016)
  • Author(s): Kiriyama Y, Toyoda T, Ogawa K, TsukamotoT
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Gastric-and-intestinal mixed intestinal metaplasia as an irreversible point with eradication of Helicobacter pylori in the human stomach (2016)
  • Author(s): Kiriyama Y, Tsukamoto T
  • Organizer: 10th AACR-JCA Joint Conference
  • Place of Presentation: Lahaina, HI, USA
  • Year and Date: 2016-02-16
  • Int'l Joint Research
• [Presentation] Histological irreversible point with eradication of H. pylori: Comparison of gastric and intestinal-metaplastic glands (2015)
  • Author(s): Kiriyama Y, Tsukamoto T
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Book] Laboratory Models for Foodborne Infections (2017)
  • Author(s): Tsukamoto, T., Kiriyama, Y., Tatematsu, M. (Chapter 22, Helicobacter), Ed: Liu, D.
  • Total Pages: 832
  • Publisher: CRC Press
  • ISBN: 9781498721677
• [Book] 基礎から学ぶ胃癌の病理：胃粘膜の正常構造・分化に基づいた胃生検診断（Group分類）へのアプローチ (2015)
  • Author(s): 塚本徹哉
  • Total Pages: 136
  • Publisher: 日本メディカルセンター