Unraveling of mechanisms of mesenchymal stem cell-dependent tumor progression

• Project/Area Number: 25460955
• 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: Naishiro Yasuka 札幌医科大学, 医療人育成センター, 講師 (80347161)
• Co-Investigator(Kenkyū-buntansha): Yoshiaki Arimura 札幌医科大学, 医学部, 講師 (80305218)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 間葉系幹細胞 / 大腸癌細胞 / ニッチ / 骨髄間葉系幹細胞 / MSC依存性腫瘍増殖 / MSCニッチ

Outline of Final Research Achievements

This study aimed to clarify mechanisms of MSC-dependent tumor progression. Tumor growth progressed in two manners, either independent of or dependent on MSCs. COLO 320 xenograft angiogenesis was CXCL12 dependent but vascular endothelial growth factor (VEGF) less dependent, whereas HT-29 angiogenesis was not CXCL12 but VEGF dependent. MSCs differentiated into pericytes that enhanced angiogenesis as a perivascular niche, which was designated MSC-dependent angiogenesis. CXCL12 was epigenetically inactivated in most colorectal cancer cells except for COLO 320 cells, in which the promoter region was demethylated, but ten eleven translocation 1-3 (TET1-3)/activation-induced cytidine deaminase (AID) did not work as DNA demethylases. Either VEGF overexpression or CXCL12 knockdown was not sufficient for MSC-independent growth. In contrast, the MSC niche conferred an anti-proliferative property to HT-29 cells, through mesenchymal-epithelial transition.

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: M 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