Development of in vitro assay system for carcinogenesis using iPS-derived intestinal epithelial stem cells

• Project/Area Number: 26640089
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Mutoh Michihiro 国立研究開発法人国立がん研究センター, 社会と健康研究センター, 室長 (30392335)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 大腸がん / iPS / 放射線照射 / 上皮間葉変換 / iPS細胞 / がん予防 / 発がん事象 / 3次元細胞培養

Outline of Final Research Achievements

<Aim> The processes of carcinogenesis are so complex that they are difficult to reproduce in a cell system. However, establishment of a simple model may accelerate our knowledge of carcinogenetic processes. In the present study, we tried to reproduce carcinogenetic processes by the induction of stochastic changes in vitro. <Methods & Results> We first obtained stem cells from the lower digestive tract derived from iPS cells. The maintenance medium allowed us to culture the cells for more than a half-year without any neoplastic feature changes. We next tried to induce somatic mutation by treating 53-passage-cells with 5 Gy radiation. Five months later, the cells were obviously changed in shape to spindle formation. The molecular markers of differentiation and intestinal epithelium were down-regulated, and we obtained epithelial-mesenchymal transformed cells. <Future plan> We are now evaluating the neoplastic characters using a xenograft model.

Research Products

• [Journal Article] Intestinal Peyer’s patches prevent tumorigenesis in <i>Apc</i>^Min/+ mice (2015)
  • Author(s): Fujimoto K, Fujii G, Sakurai H, Yoshitome H, Mutoh M, Wada M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 56 Issue: 1 Pages: 43-48
  • DOI: 10.3164/jcbn.14-115
  • NAID: 130004704978
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Involvement of NADPH oxidases in suppression of cyclooxygenase-2 promoter-dependent transcriptional activities by sesamol (2015)
  • Author(s): Shimizu S, Ishigamori R, Fujii G, Takahashi M, Onuma W, Terasaki M, Yano T, Mutoh M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 56 Issue: 2 Pages: 118-122
  • DOI: 10.3164/jcbn.14-89
  • NAID: 130004879380
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Sesamol suppresses cyclooxygenase-2 transcriptional activity in colon cancer cells and modifies intestinal polyp development in <i>Apc</i>^Min/+ mice (2014)
  • Author(s): Shimizu S, Fujii G, Takahashi M, Nakanaishi R, Komiya M, Shimura M, Noma N, Onuma W, Yano T, Mutoh M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 54 Issue: 2 Pages: 95-101
  • DOI: 10.3164/jcbn.13-91
  • NAID: 130004879356
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed
• [Journal Article] Bi-directional regulation between adiponectin and plasminogen activator-inhibitor-1 in 3T3-L1 cells. (2014)
  • Author(s): Komiya M, Fujii G, Takahashi M, Shimura M, Noma N, Shimizu S, Onuma W, Mutoh M.
  • Journal Title: IN VIVO Volume: 28 Pages: 13-19
  • Peer Reviewed
• [Journal Article] Association of pancreatic fatty infiltration with pancreatic ductal adenocarcinoma. (2014)
  • Author(s): Hori M, Takahashi M, Hiraoka N, Yamaji T, Mutoh M, Ishigamori R, Furuta K, Okusaka T, Shimada K, Kosuge T, Kanai Y, Nakagama H
  • Journal Title: Clinical and Translational Gastroenterology Volume: 5 Issue: 3 Pages: e53-e53
  • DOI: 10.1038/ctg.2014.5
  • Peer Reviewed / Open Access
• [Journal Article] Potential of drug repositioning for colorectal cancer prevention: Inhibition of colorectal polyp recurrence by aspirin. (2014)
  • Author(s): Mutoh M, Fujii G
  • Journal Title: BioIndustry Volume: 31 Pages: 29-34
  • NAID: 40020263479
• [Journal Article] Potential ability of xanthophylls to prevent obesity-associated cancer. (2014)
  • Author(s): Terasaki M, Mutoh M, Fujii G, Takahashi M, Ishigamori R, Masuda S.
  • Journal Title: World J Pharmacol Volume: 3 Pages: 140-152
  • Peer Reviewed / Open Access
• [Journal Article] The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. (2013)
  • Author(s): Ishikawa H, Mutoh M, Suzuki S, Tokudome S, Saida Y, Abe T, Okamura S, Tajika M, Joh T, Tanaka S, Kudo SE, Matsuda T, Iimuro M, Yukawa T, Takayama T, Sato Y, Lee K, Kitamura S, Mizuno M, Sano Y, Gondo N, Sugimoto K, Kusunoki M, Goto C, Matsuura N, Sakai T, Wakabayashi K.
  • Journal Title: Gut. Volume: Jan 31 Issue: 11 Pages: 1755-1759
  • DOI: 10.1136/gutjnl-2013-305827
  • Peer Reviewed
• [Presentation] Suppression of intestinal carcinogenesis in Apc-mutant mice by the citrus limonid limonin. (2014)
  • Author(s): Shimizu S, Fujii G, Nakanishi R, Onuma W, Mutoh M, Yano T.
  • Organizer: The 38th Annual Scientific Meeting, Nutrition Society of Australia.
  • Place of Presentation: Tasmania, Australia
  • Year and Date: 2014-11-26 – 2014-11-28
• [Presentation] ドラッグリポジショニングによる大腸がん予防。 (2014)
  • Author(s): 武藤倫弘。
  • Organizer: 第42回日本潰瘍学会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-31 – 2014-11-01
  • Invited
• [Presentation] Inhibition of intestinal polyp formation in Min mice by acetazolamide. (2014)
  • Author(s): Mutoh M, Takahashi M, Ishigamori R, Shimizu S, Onuma W, Imai T, Fujii G.
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Agoutiによるマウス膵臓発がん促進メカニズム。 (2014)
  • Author(s): 高橋真美、石ヶ守里加子、藤井 元、武藤倫弘、今井俊夫。
  • Organizer: 第73回日本癌学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 炭酸脱水素酵素による腸発がん抑制。 (2014)
  • Author(s): 武藤倫弘、中西るり、尾沼若奈、清水聡美、藤井 元。
  • Organizer: 第29回発癌病理研究会
  • Place of Presentation: いわき市
  • Year and Date: 2014-09-01 – 2014-09-03
• [Presentation] Effect of cytokines on human primary hepatic stellate cell. (2014)
  • Author(s): Inoue A, Obayashi K, Ogasawara F, Nakamura A, Ueno T, Fujii G, Mutoh M, Kuhara S, Tashiro K. Effect of cytokines on human primary hepatic stellate cell.
  • Organizer: the FEBS-EMBO 2014 congress
  • Place of Presentation: Paris, France
  • Year and Date: 2014-08-30 – 2014-09-04
• [Presentation] 大腸がん幹細胞におけるビタミンＤ受容体の機能解析 (2014)
  • Author(s): 寺崎 将、三上 唯、濱崎祐輔、前田紗菜恵、加藤雄也、武藤倫弘、増田園子。
  • Organizer: 日本ビタミン学会第66回大会
  • Place of Presentation: 姫路
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] がん化学予防剤を用いた予防介入試験の集団への適用。 (2014)
  • Author(s): 武藤倫弘。
  • Organizer: がん予防学術大会2014東京
  • Place of Presentation: 東京
  • Year and Date: 2014-06-13 – 2014-06-14
  • Invited
• [Presentation] 腸前がん病変由来細胞の長期培養方法の確立。 (2014)
  • Author(s): 尾沼若奈、中西るり、藤井 元、清水聡美、石ヶ守里加子、武藤倫弘、高橋真美、今井俊夫、深井文雄。
  • Organizer: がん予防学術大会2014東京
  • Place of Presentation: 東京
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] ゴマ由来成分 sesamol によるアラキドン酸カスケード及びPGE2関連分子の抑制。 (2014)
  • Author(s): 清水聡美、 石ヶ守里加子、 藤井 元、 小宮雅美、 中西るり、 尾沼若奈、 矢野友啓、 武藤倫弘。
  • Organizer: がん予防学術大会2014東京
  • Place of Presentation: 東京
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] ポンカン果皮粉末によるazoxymethane誘発F344ラット大腸aberrant crypt foci生成の抑制。 (2014)
  • Author(s): 浅井大智、小林亜里子、中西るり、藤井 元、清水聡美、尾沼若奈、石ヶ守里加子、武藤倫弘、高橋 智、若林敬二。
  • Organizer: がん予防学術大会2014東京
  • Place of Presentation: 東京
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] 高脂肪食による乳腺発がん促進に関与する発現遺伝子の探索。 (2014)
  • Author(s): 今井俊夫、打屋尚章、高橋真美、藤井 元、武藤倫弘。
  • Organizer: がん予防学術大会2014東京
  • Place of Presentation: 東京
  • Year and Date: 2014-06-13 – 2014-06-14
• [Presentation] ラット若齢期乳腺に対する高脂肪食の影響と発がん促進 (2014)
  • Author(s): 今井俊夫、打屋尚章、藤井 元、武藤倫弘、高橋真美。
  • Organizer: 第61回日本実験動物学会
  • Place of Presentation: 札幌
  • Year and Date: 2014-05-15 – 2014-05-17
• [Book] Critical Dietary Factors in Cancer Chemoprevention (2015)
  • Author(s): Miyamoto S, Fujii G, Komiya M, Terasaki M and Mutoh M.
  • Total Pages: 20
  • Publisher: Springer Publishers (Basel, Switzerland)