Elucidation of chemopreventive mechanisms of mesenchymal stem cells for inflammatory carcinogenesis

• Project/Area Number: 25460954
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: Motoya Masayo 札幌医科大学, 医学部, 助教 (60468080)
• Co-Investigator(Kenkyū-buntansha): Yoshiaki Arimura 札幌医科大学, 医学部, 講師 (80305218) ; Yasuyoshi Naishiro 札幌医科大学, 医療人育成センター, 講師 (80347161)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 間葉系幹細胞 / 発癌 / 化学予防 / 骨髄間葉系幹細胞 / chemoprevention / azoxymethane (AOM) 関連発癌

Outline of Final Research Achievements

MSCs canceled AOM-induced tumor initiation. MSCs inhibited the acute apoptotic response of a genotoxic carcinogen (AARGC) in colonic epithelial cells because of the removal of O6-methylguanine adducts through O6-methylguanine-DNA methyltransferase (Mgmt) activation. However, MSCs did not induce epigenetic Mgmt reactivation. Furthermore, MSCs broadly affected the cell-cycle machinery, leading to G1 arrest. Coculture of IEC-6 intestinal cells with MSCs not only induced G1 arrest, but also apoptosis. The anti-carcinogenetic properties of MSCs required transforming growth factor (TGF)-beta signaling. MSCs inhibited AOM-induced tumor initiation by preventing the initiating cells from sustaining DNA insults and inducing G1 arrest in the initiated cells that escaped from the AARGC. Tumor initiation perturbed by MSCs might potentially dysregulate classical WNT and TGF-beta-Smad signaling pathways.

Research Products

• [Journal Article] Malignant potential of gastrointestinal cancers assessed by structural equation modeling (2016)
  • Author(s): Shimizu H, Arimura Y, Onodera K, Takahashi H, Okahara S, Kodaira J, Oohashi H, Isshiki H, Kawakami K, Yamashita K, Shinomura Y, Hosokawa M
  • Journal Title: PLoS ONE Volume: 11 Issue: 2 Pages: e0149327-e0149327
  • DOI: 10.1371/journal.pone.0149327
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 間葉系幹細胞を用いた消化管再生医療 (2016)
  • Author(s): 川上賢太郎, 永石歓和, 有村佳昭
  • Journal Title: Medical Science Digest Volume: 2 Pages: 65-68
• [Journal Article] Low-frequency IL23R coding variant associated with Crohn's disease susceptibility in Japanese subjects identified by personal genomics analysis (2015)
  • Author(s): Onodera K, Arimura Y, Isshiki H, Kawakami K, Nagaishi K, Yamashita K, Yamamoto E, Niinuma T, Naishiro Y, Suzuki H, Imai K, Shinomura Y
  • Journal Title: PLoS ONE Volume: 10 Issue: 9 Pages: e0137801-e0137801
  • DOI: 10.1371/journal.pone.0137801
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stem cell therapy for inflammatory bowel disease (2015)
  • Author(s): Nagaishi K, Arimura Y, Fujimiya M
  • Journal Title: J Gastroenterol Volume: 50 Issue: 3 Pages: 280-6
  • DOI: 10.1007/s00535-015-1040-9
  • Peer Reviewed
• [Journal Article] 間葉系幹細胞による消化管再生医療 (2014)
  • Author(s): 有村佳昭, 小野寺 馨，一色裕之，川上賢太郎
  • Journal Title: G.I. Research Volume: 22 Pages: 435-42
• [Journal Article] Mesenchymal stem cells cancel azoxymethane-induced tumor initiation (2014)
  • Author(s): Nasuno M, Arimura Y, Nagaishi K, Isshiki H, Onodera K, Nakagaki S, Watanabe S, Idogawa M, Yamashita K, Naishiro Y, Adachi Y, Suzuki H, Fujimiya M, Imai K, Shinomura Y
  • Journal Title: Stem Cells Volume: 32 Issue: 4 Pages: 913-925
  • DOI: 10.1002/stem.1594
  • Peer Reviewed / Open Access
• [Journal Article] Conditioned mesenchymal stem cells produce pleiotropic gut trophic factors (2014)
  • Author(s): Watanabe S, Arimura Y, Nagaishi K, Isshiki H, Onodera K, Nasuno M, Yamashita K, Idogawa M, Naishiro Y, Murata M, Adachi Y, Fujimiya M, Imai K, Shinomura Y
  • Journal Title: J Gastroenterol Volume: 49 Issue: 2 Pages: 270-282
  • DOI: 10.1007/s00535-013-0901-3
  • Peer Reviewed
• [Journal Article] Characteristics of Japanese inflammatory bowel disease susceptibility loci (2014)
  • Author(s): Arimura Y, Isshiki H, Onodera K, Nagaishi K, Yamashita K, Sonoda T, Matsumoto T, Takahashi A, Takazoe M, Yamazaki K, Kubo M, Fujimiya M, Imai K, Shinomura Y
  • Journal Title: J Gastroenterol Volume: 49 Issue: 8 Pages: 1217-30
  • DOI: 10.1007/s00535-013-0866-2
  • Peer Reviewed
• [Journal Article] Mesenchymal stem cell therapy ameliorates diabetic hepatocyte damage in mice by inhibiting infiltration of bone marrow-derived cells. (2013)
  • Author(s): Nagaishi K, Ataka K, Echizen E, Arimura Y, Fujimiya M
  • Journal Title: Hepatology Volume: Epub ahead of print Issue: 5 Pages: 1816-29
  • DOI: 10.1002/hep.26975
  • Peer Reviewed
• [Journal Article] A Genome-Wide Association Study Identifies 2 Susceptibility Loci for Crohn's Disease in a Japanese Population (2013)
  • Author(s): Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA, Kumasaka N, Morizono T, Hosono N, Kawaguchi T, Takazoe M, Yamada T, Suzuki Y, Tanaka H, Motoya S, Hosokawa M, Arimura Y, Shinomura Y, Matsui T, Matsumoto T, Iida M, Tsunoda T, Nakamura Y, Kamatani N, Kubo M
  • Journal Title: Gastroenterology Volume: 144 Issue: 4 Pages: 781-8
  • DOI: 10.1053/j.gastro.2012.12.021
  • Peer Reviewed
• [Presentation] 日本人のIBD感受性遺伝子 (2015)
  • Author(s): 有村佳昭
  • Organizer: 第154回日本消化器内視鏡学会東北支部例会（ランチョンセミナー）
  • Place of Presentation: 仙台国際センター（宮城県・仙台市）
  • Year and Date: 2015-02-06
  • Invited
• [Presentation] 骨髄間葉系幹細胞依存性の大腸癌細胞増殖の機序
  • Author(s): 一色裕之，有村佳昭，永石歓和，苗代康可，篠村恭久，今井浩三
  • Organizer: JDDW2013
  • Place of Presentation: 東京
• [Presentation] 骨髄間葉系幹細胞依存性大腸癌細胞増殖の機序
  • Author(s): 一色裕之，有村佳昭，小野寺馨，永石歓和，苗代康可，篠村恭久，今井浩三
  • Organizer: 第50回日本消化器免疫学会総会
  • Place of Presentation: 東京
  • Invited