Trial to treat gastric cancer via regulating the status of gastrointestinal differentiation

• Project/Area Number: 16K08612
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Yamamichi Nobutake 東京大学, 医学部附属病院, 准教授 (30463897)
• Research Collaborator: Tomida Shuta ; Inada Ken-ichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 胃癌 / 消化管分化 / 癌 / 発現・制御 / 内科 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We found that intestinal differentiation induced by CDX caused growth arrest of several gastric cancer cells. Using the CDX-related gene probe markers, we analyzed gene expression data of many gastric cancer cases and found that gene expression of CDX-positive gastric cancer was clearly closer to that of non-cancerous gastric mucosa than CDX-negative gastric cancer. Based on these results, we concluded that CDX-induced intestinal differentiation can show a tumor suppressive effect on gastric cancer (Cancer Sci 2018, 109: 3853). In addition, in the process of this experiment, we succeeded in developing a method to perform comprehensive gene expression analysis from a small biopsy specimen (about 10ug) of a gastrointestinal tract tumor (J Gastroenterol 2018, 54: 131).

Academic Significance and Societal Importance of the Research Achievements

切除が唯一の根治療法とされている胃癌が、分化誘導によって制御できることを発見し、薬物療法に繋がりうる新たな可能性を報告した。また、これまで様々な分類がなされてきた胃癌分類において、予後・悪性度の予測や治療方針の決定の有用性が期待される「消化管分化の視点に基く新しい分類（CDX発現に基づく胃癌分類）」について、詳細な遺伝子発現データの解析に基いた提唱を行った。さらに、消化管腫瘍の微少な生検検体から正確に網羅的な遺伝子発現解析を施行する手法の開発に成功し、将来のオーダーメイド医療（網羅的な遺伝子発現解析に基づく病態予測・治療プラン決定）の基盤となる医療技術を確立した。

Research Products

• [Journal Article] Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas (2019)
  • Author(s): Sakaguchi Yoshiki、Yamamichi Nobutake、Tomida Shuta、Takeuchi Chihiro、Kageyama-Yahara Natsuko、Takahashi Yu、Shiogama Kazuya、Inada Ken-ichi、Ichinose Masao、Fujishiro Mitsuhiro、Koike Kazuhiko
  • Journal Title: Journal of Gastroenterology Volume: 54 Issue: 2 Pages: 131-140
  • DOI: 10.1007/s00535-018-1489-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Detection of gastritis by a deep convolutional neural network from double-contrast upper gastrointestinal barium X-ray radiography (2019)
  • Author(s): Togo Ren、Yamamichi Nobutake、Mabe Katsuhiro、Takahashi Yu、Takeuchi Chihiro、Kato Mototsugu、Sakamoto Naoya、Ishihara Kenta、Ogawa Takahiro、Haseyama Miki
  • Journal Title: Journal of Gastroenterology Volume: 54 Issue: 4 Pages: 321-329
  • DOI: 10.1007/s00535-018-1514-7
  • NAID: 120006820165
  • Peer Reviewed
• [Journal Article] Gastroesophageal Reflux Disease-Related Disorders of Systemic Sclerosis Based on the Analysis of 66 Patients (2018)
  • Author(s): Matsuda Rie、Yamamichi Nobutake、Shimamoto Takeshi、Sumida Hayakazu、Takahashi Yu、et al.
  • Journal Title: Digestion Volume: 98 Issue: 4 Pages: 201-208
  • DOI: 10.1159/000489848
  • Peer Reviewed
• [Journal Article] Expression of Gastric Markers Is Associated with Malignant Potential of Nonampullary Duodenal Adenocarcinoma. (2018)
  • Author(s): Minatsuki C, Yamamichi N, Inada KI, Takahashi Y, Sakurai K, Shimamoto T, Tsuji Y, Shiogama K, Kodashima S, Sakaguchi Y, Niimi K, Ono S, Niwa T, Ohata K, Matsuhashi N, Ichinose M, Fujishiro M, Tsutsumi Y, Koike K.
  • Journal Title: Dig Dis Sci. Volume: 10 Issue: 10 Pages: 2617-2625
  • DOI: 10.1007/s10620-018-5179-0
  • Peer Reviewed
• [Journal Article] Transparency-enhancing technology allows three-dimensional assessment of gastrointestinal mucosa: A porcine model. (2018)
  • Author(s): Mizutani H, Ono S, Ushiku T, Kudo Y, Ikemura M, Kageyama N, Yamamichi N, Fujishiro M, Someya T, Fukayama M, Koike K, Onodera H.
  • Journal Title: Pathology International Volume: 68 Issue: 2 Pages: 102-108
  • DOI: 10.1111/pin.12627
  • Peer Reviewed
• [Journal Article] Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation (2018)
  • Author(s): Nakayama Chiemi、Yamamichi Nobutake、Tomida Shuta、Takahashi Yu、Kageyama-Yahara Natsuko、Sakurai Kouhei、Takeuchi Chihiro、Inada Ken-ichi、Shiogama Kazuya、Nagae Genta、Ono Satoshi、Tsuji Yosuke、Niimi Keiko、Fujishiro Mitsuhiro、Aburatani Hiroyuki、Tsutsumi Yutaka、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3853-3864
  • DOI: 10.1111/cas.13821
  • Peer Reviewed / Open Access
• [Journal Article] Sessile serrated adenoma detection rate is correlated with adenoma detection rate (2018)
  • Author(s): Ohki Daisuke、Tsuji Yosuke、Shinozaki Tomohiro、Sakaguchi Yoshiki、Minatsuki Chihiro、Kinoshita Hiroto、Niimi Keiko、Ono Satoshi、Hayakawa Yoku、Yoshida Shuntaro、Yamada Atsuo、Kodashima Shinya、Yamamichi Nobutake、Hirata Yoshihiro、Ushiku Tetsuo、Fujishiro Mitsuhiro、Fukayama Masashi、Koike Kazuhiko
  • Journal Title: World J Gastrointest Oncol Volume: 10 Issue: 3 Pages: 82-90
  • DOI: 10.4251/wjgo.v10.i3.82
  • Peer Reviewed / Open Access
• [Journal Article] Nectin1 expression is frequently decreased in gastric cancers. (2018)
  • Author(s): Takahashi Y, Yamamichi N, Inada KI, Shiogama K, Sakurai K, Takeuchi C, Mizutani Y, Tsutsumi Y, Koike K.
  • Journal Title: Pathol Int. Volume: 10 Issue: 10 Pages: 557-562
  • DOI: 10.1111/pin.12721
  • Peer Reviewed
• [Journal Article] Serum anti-Helicobacter pylori antibody titer and its association with gastric nodularity,atrophy,and age: A cross-sectional study. (2018)
  • Author(s): Toyoshima, O., Nishizawa, T., Sakitani, K., Yamakawa, T., Takahashi, Y., Yamauchi, N., Hata, K., Seto, Y., Koike, K., Watanabe, H., Suzuki, H.
  • Journal Title: World J. Gastroenterol. Volume: 24 Issue: 35 Pages: 4061-4068
  • DOI: 10.3748/wjg.v24.i35.4061
  • Peer Reviewed
• [Journal Article] Gastric polyps diagnosed by double-contrast upper gastrointestinal barium X-ray radiography mostly arise from the Helicobacter pylori-negative stomach with low risk of gastric cancer in Japan. (2017)
  • Author(s): Takeuchi C, Yamamichi N, Shimamoto T, Takahashi Y, Mitsushima T, Koike K.
  • Journal Title: Gastric Cancer Volume: 20 Issue: 2 Pages: 314-321
  • DOI: 10.1007/s10120-016-0607-3
  • NAID: 40021129497
  • Peer Reviewed
• [Journal Article] High impact of methylation accumulation on metachronous gastric cancer: 5-year follow-up of a multicentre prospective cohort study. (2017)
  • Author(s): Maeda M, Nakajima T, Oda I, Shimazu T, Yamamichi N, Maekita T, Asada K, Yokoi C, Ando T, Yoshida T et al
  • Journal Title: GUT Volume: in press Issue: 9 Pages: 1721-1723
  • DOI: 10.1136/gutjnl-2016-313387
  • Peer Reviewed / Open Access
• [Journal Article] Columnar Metaplasia in Three Types of Surgical Mouse Models of Esophageal Reflux. (2017)
  • Author(s): Terabe F, Aikou S, Aida J, Yamamichi N, Kaminishi M, Takubo K, Seto Y, Nomura S.
  • Journal Title: Cell Mol Gastroenterol Hepatol. Volume: 4 Issue: 1 Pages: 115-123
  • DOI: 10.1016/j.jcmgh.2017.03.009
  • Peer Reviewed
• [Journal Article] Evaluation of endoscopic submucosal dissection using a new endosurgical knife DN-D2718B: a first clinical feasibility study. (2017)
  • Author(s): Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y, Saito I, Shichijo S, Minatsuki C, Asada-Hirayama I, Yamaguchi D, Niimi K, Ono S, Kodashima S, Yamamichi N, Koike K.
  • Journal Title: Endosc Int Open. Volume: 5 Issue: 07 Pages: E670-E674
  • DOI: 10.1055/s-0043-111720
  • Peer Reviewed
• [Journal Article] Evaluation of image-enhanced endoscopic technology using advanced diagnostic endoscopy for the detection of early gastric cancer: a pilot study. (2017)
  • Author(s): Yamaguchi D, Kodashima S, Fujishiro M, Ono S, Niimi K, Mochizuki S, Tsuji Y, Asada-Hirayama I, Sakaguchi Y, Shichijo S, Minatsuki C, Yamamichi N, Koike K.
  • Journal Title: Endosc Int Open. Volume: 5 Issue: 09 Pages: E825-E833
  • DOI: 10.1055/s-0043-113632
  • Peer Reviewed
• [Journal Article] Comparative analysis of upper gastrointestinal endoscopy, double-contrast upper gastrointestinal barium X-ray radiography, and the titer of serum anti-Helicobacter pylori IgG focusing on the diagnosis of atrophic gastritis. (2016)
  • Author(s): Yamamichi N, Hirano C, Takahashi Y, Minatsuki C, Nakayama C, Matsuda R, Shimamoto T, Takeuchi C, Kodashima S, Ono S, Tsuji Y, Fujishiro M, Wada R, Mitsushima T, Koike K.
  • Journal Title: Gastric Cancer. Volume: 19 Issue: 2 Pages: 670-675
  • DOI: 10.1007/s10120-015-0515-y
  • NAID: 40020836534
  • Peer Reviewed
• [Journal Article] Atrophic gastritis and enlarged gastric folds diagnosed by double-contrast upper gastrointestinal barium X-ray radiography are useful to predict future gastric cancer development based on the 3-year prospective observation. (2016)
  • Author(s): Yamamichi N, Hirano C, Ichinose M, Takahashi Y, Minatsuki C, Matsuda R, Nakayama C, Shimamoto T, Kodashima S, Ono S et al:
  • Journal Title: Gastric Cancer Volume: 19 Issue: 3 Pages: 1016-1022
  • DOI: 10.1007/s10120-015-0558-0
  • NAID: 40020882076
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Incidence of and risk factors for metachronous gastric cancer after endoscopic resection and successful Helicobacter pylori eradication: results of a large-scale, multicenter cohort study in Japan. (2016)
  • Author(s): Mori G, Nakajima T, Asada K, Shimazu T, Yamamichi N, Maekita T, Yokoi C, Fujishiro M, Gotoda T, Ichinose M et al
  • Journal Title: Gastric Cancer Volume: 19 Issue: 3 Pages: 911-918
  • DOI: 10.1007/s10120-015-0544-6
  • NAID: 40020881816
  • Peer Reviewed
• [Journal Article] Successful closure of a large perforation during colorectal endoscopic submucosal dissection by application of polyglycolic acid sheets and fibrin glue. (2016)
  • Author(s): Sakaguchi Y, Tsuji Y, Yamamichi N, Fujishiro M, Koike K.
  • Journal Title: Gastrointest Endos. Volume: 84 Issue: 2 Pages: 374-375
  • DOI: 10.1016/j.gie.2016.03.787
  • Peer Reviewed
• [Journal Article] Triamcinolone Injection and Shielding with Polyglycolic Acid Sheets and Fibrin Glue for Postoperative Stricture Prevention after Esophageal Endoscopic Resection: A Pilot Study. (2016)
  • Author(s): Sakaguchi Y, Tsuji Y, Fujishiro M, Kataoka Y, Takeuchi C, Yakabi S, Saito I, Shichijo S, Minatsuki C, Asada-Hirayama I, Yamaguchi D, Niimi K, Ono S, Kodashima S, Yamamichi N, Koike K.
  • Journal Title: Am J Gastroenterol. Volume: 111 Issue: 4 Pages: 581-583
  • DOI: 10.1038/ajg.2016.60
  • Peer Reviewed
• [Presentation] 逆流性食道炎有病率の四半世紀の変遷とピロリ菌感染との関連 (2018)
  • Author(s): 山道信毅
  • Organizer: 第104回日本消化器病学会総会
• [Presentation] 消化管分化と胃癌 (2018)
  • Author(s): 山道信毅
  • Organizer: 第5回Smart-C (Specific Molecule Antiviral tReatment Tokyo Hepatitis C)
  • Invited
• [Presentation] 酸関連疾患の四半世紀の変遷、今後の胃酸分泌抑制剤の戦略 (2018)
  • Author(s): 山道信毅
  • Organizer: 第43回日本外科連合学会学術集会
  • Invited
• [Presentation] Helicobacter pylori と 上部消化管疾患――最新の疫学的動向、感染診断のトピックス (2018)
  • Author(s): 山道信毅
  • Organizer: JDDW2018
  • Invited
• [Presentation] 胃X線検査で診断される「慢性胃炎」―― エビデンスと現状・未来 (2018)
  • Author(s): 山道信毅
  • Organizer: 第25回関西消化管造影懇話会
  • Invited
• [Presentation] 胃Ｘ線検査で診断される胃ポリープの背景因子の解析，胃癌発症リスクとの関連 (2016)
  • Author(s): 山道信毅、高橋悠
  • Organizer: JDDW2016
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03
• [Book] X線と内視鏡の比較で学ぶH.pylori胃炎診断 (2018)
  • Author(s): ピロリ菌感染を考慮した胃がん検診研究会
  • Total Pages: 168
  • Publisher: 文光堂
  • ISBN: 9784830621048
• [Remarks] 東京大学消化器内科 消化管グループ 第406（旧108）研究室の基礎研究の紹介
  • URL: https://www.todai-shoukakan.com/cont5/33.html
• [Remarks] 東京大学消化器内科 消化管グループ ホームページ
  • URL: https://www.todai-shoukakan.com/index.html
• [Remarks] 東京大学消化器内科消化管グループ 基礎・疫学研究の紹介
  • URL: http://www.todai-shoukakan.com/cont5/main.html