Analysis of a mouse model of diffuse-type gastric cancer

• Project/Area Number: 24650609
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Carcinogenesis
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: YUASA Yasuhito 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (80111558)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 胃がん / マウスモデル / 治療薬 / E-カドヘリン / p53 / エピジェネティクス / 遺伝子改変動物 / 抗がん剤 / がん幹細胞

Research Abstract

We have reported an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered diffuse-type gastric cancer (DGC), which recapitulates human DGC morphologically and molecularly. Recently, we have also established mouse DGC (MDGC) cell lines from primary tumors and lymph node metastases of the DCKO mice. We observed that the expression levels of epigenetic modulators and frequently methylated genes were up- and down-regulated in mouse primary DGC, respectively. Treatment with some epigenetic inhibitors induced differentiation and attenuated sphere formation of the MDGC cell lines in vitro. Moreover, we could validate tumor-suppressing activity of these agents in vivo. These results suggest that epigenetic alterations may play significant roles in diffuse-type gastric carcinogenesis and support to develop a relevant therapeutic strategy in human DGC.

Research Products

• [Journal Article] BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors (2014)
  • Author(s): Tsuchida R, Osawa T, Wang F, Nishii R, Das B, Tsuchida S, Muramatsu M, Takahashi T, Inoue T, Wada Y, Minami T, Yuasa Y, Shibuya M
  • Journal Title: Oncogene Volume: 33 Issue: 29 Pages: 3803-3811
  • DOI: 10.1038/onc.2013.358
  • Peer Reviewed / Open Access
• [Journal Article] NF-κB Inducing Kinase, a Central Signaling Component of the Non-Canonical Pathway of NF-κB, Contributes to Ovarian Cancer Progression. (2014)
  • Author(s): Uno M, Saitoh Y, Mochida K, Tsuruyama E, Kiyono T, Imoto I, Inazawa J, Yuasa Y, Kubota T, Yamaoka S.
  • Journal Title: PLoS One Volume: 9(2) Issue: 2 Pages: e88347-e88347
  • DOI: 10.1371/journal.pone.0088347
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Circulating microRNAs as biomarkers for early detection of diffuse-type gastric cancer using a mouse model (2013)
  • Author(s): Rotkrua P, Shimada S, Mogushi, K, Akiyama Y, Tanaka H, Yuasa Y
  • Journal Title: Brit. J. Cancer Volume: 108 Issue: 4 Pages: 932-940
  • DOI: 10.1038/bjc.2013.30
  • Peer Reviewed
• [Journal Article] CD49f^<high> cells retain sphere-forming and tumor-initiating activities in human gastric tumors (2013)
  • Author(s): Fukamachi H, Seol HS, Shimada S, Funasaka C, Baba K, Kim JH, Park YS, Kawachi H, Yook JH, Eishi Y, Kojima K, Kim WH, Jang SJ, Yuasa Y
  • Journal Title: PLoS One Volume: 8 Issue: 8 Pages: e72438-e72438
  • DOI: 10.1371/journal.pone.0072438
  • Peer Reviewed
• [Journal Article] Multiple-to-multiple relationships between microRNAs and target genes in gastric cancel (2013)
  • Author(s): Hashimoto Y, et al.
  • Journal Title: PLoS One Volume: 8 Issue: 5 Pages: e62589-e62589
  • DOI: 10.1371/journal.pone.0062589
  • Peer Reviewed
• [Journal Article] Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor associated macrophages (2013)
  • Author(s): Shimamura T, Wang F, Suehiro J, Kanki Y, Wada Y, Yuasa Y, Aburatani H, Miyano S, Minami T, Kodama T, Shibuya M
  • Journal Title: Cancer Res Volume: 73 Issue: 10 Pages: 3019-3028
  • DOI: 10.1158/0008-5472.can-12-3231
  • Peer Reviewed
• [Journal Article] Activin A regulates growth of gastro-intestinal epithelial cells by mediating epithelial-mesenchymal interaction (2013)
  • Author(s): Fukamachi H, Kato S, Asashima M, Ichinose M, Yuasa Y
  • Journal Title: Development Growth and Differentiation Volume: 55 Issue: 9 Pages: 786-791
  • DOI: 10.1111/dgd.12102
  • Peer Reviewed
• [Journal Article] Insulin-like growth factor 2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk (2012)
  • Author(s): Yuasa Y, Nagasaki H, Oze I, Akiyama Y, Yoshida S, Shitara K, Ito S, Hosono S, Watanabe M, Ito H, Tanaka H, Kang DH, Pan K-F, You W-C, Matsuo K
  • Journal Title: Int. J. Cancer Volume: 131 Pages: 2596-2603
  • Peer Reviewed
• [Journal Article] Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer (2012)
  • Author(s): Shimada S, Mimata A, Sekine M, Mogushi K, Akiyama Y, Fukamachi H, Jonkers J, Tanaka H, Eishi Y, Yuasa Y
  • Journal Title: Gut Volume: 61 Pages: 344-353
  • Peer Reviewed
• [Journal Article] Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer (2012)
  • Author(s): Song M-Y, Pan K-F, Su H-J, Zhang L, Ma J-L, Li J-Y, Yuasa Y, KangDH, Kim YS, You W-C
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] IGF2 hypomethylation of blood leukocyte DNA is associated with gastric cancer risk (2012)
  • Author(s): Yuasa Y, et al.
  • Journal Title: Int.J.Cancer Volume: (in press) Issue: 11 Pages: 2596-2603
  • DOI: 10.1002/ijc.27554
  • Peer Reviewed
• [Journal Article] Identification of serum microRNAs as novel non-invasive biomarkers for early detection of gastric cancer (2012)
  • Author(s): Song M-Y, et al.
  • Journal Title: PLoS One Volume: 7 Issue: 3 Pages: e33608-e33608
  • DOI: 10.1371/journal.pone.0033608
  • Peer Reviewed
• [Journal Article] DNA Methylation in Peripheral Blood: A Potential Biomarker for Cancer Molecular Epidemiology (2012)
  • Author(s): Li L, Choi JY, Lee KM, Sung H, Park SK, Oze I, Pan KF, You WC, Chen YX, Fang JY, Matsuo K, Kim WH, Yuasa Y, Kang D.
  • Journal Title: Journal of Epidemiology Volume: 22 Issue: 5 Pages: 384-394
  • DOI: 10.2188/jea.JE20120003
  • NAID: 130001913612
  • ISSN: 0917-5040, 1349-9092
  • Peer Reviewed
• [Journal Article] スキルス胃癌マウスモデル研究の展望 (2012)
  • Author(s): 島田周、秋山好光、湯浅保仁
  • Journal Title: 日本臨床 Volume: 70 Pages: 1660-1665
• [Presentation] Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2013)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 扶余,韓国
• [Presentation] Alterations of histone lysine methyltransferases, SETDB1 and SETDB2, in gastric cancers (2013)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar - Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: 扶余,韓国
• [Presentation] Frequent loss of SET7/9 protein and its clinicopathological significance in gastric carcinoma (2013)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Function and expression of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model (2013)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Patient-dependent differences in the features of human gastric tumor-initiating cells in primary culture (2013)
  • Author(s): Fukamachi H, Shimada S, Yuasa Y
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Targeting epigenetic alterations in a mouse model of E-cadherin/p53-deficient diffuse-type gastric cancer (2013)
  • Author(s): Shimada S, Akiyama Y, Fukamachi H, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar
  • Place of Presentation: 韓国プヨ
• [Presentation] Alterations of histone lysine methyltransferases, SETDB1 and SETDB2, in gastric cancers (2013)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y
  • Organizer: NRF A3 Foresight Program 2013 Seminar
  • Place of Presentation: 韓国プヨ
• [Presentation] Summary of GC stem cell researches in the A3 project (2013)
  • Author(s): Fukamachi H, Seol HS, Shimada S, Kim WH, Jang SJ, Yuasa Y
  • Organizer: NSFC A3 Foresight Program 2013 Seminar
  • Place of Presentation: 中国桂林
• [Presentation] 胃がんにおけるヒストン修飾関連遺伝子SET7の異常とその機能解析. (2012)
  • Author(s): 秋山好光、甲田裕樹、橋本裕、湯浅保仁.
  • Organizer: 第６回日本エピジェネティクス研究会年会
  • Place of Presentation: 東京
• [Presentation] Functional analysis of Twist1 in diffuse-type gastric cancer cell lines of an E-cadherin/p53-deficient mouse model. (2012)
  • Author(s): Sakamoto A, Shimada S, Akiyama Y, Yuasa Y.
  • Organizer: NRF A3 Foresight Program 2012 Seminar Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: Busan, Korea
• [Presentation] Loss of SET7, a histone H3K4 methyltransferase, and its function in gastric cancer. (2012)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Yuasa Y.
  • Organizer: 第71回日本癌学会総会
  • Place of Presentation: 札幌
• [Presentation] Human gastric tumor-initiating cells form spheres in culture, and are more resistant to anti-cancer agents. (2012)
  • Author(s): Fukamachi H, Shimada S, Yuasa Y.
  • Organizer: 第71回日本がん学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Identification of circulating miRNA as biomarkers for early detection of diffuse-type gastric cancer using a mouse model. (2012)
  • Author(s): Shimada S, Rotkrua P, Akiyama Y, Yuasa Y.
  • Organizer: 第71回日本がん学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Loss of SET7, a histone H3K4 methyltransferase, in gastric cancer. (2012)
  • Author(s): Akiyama Y, Koda Y, Nishikawaji T, Shimada S, Zhu WG, Yuasa Y.
  • Organizer: The Third International Cancer Epigenetics Meeting
  • Place of Presentation: Beijing, China
  • Invited
• [Presentation] Over-expression of SETDB2, a histone methyltransferase, in gastric cancers. (2012)
  • Author(s): Nishikawaji T, Akiyama Y, Shimada S, Yuasa Y.
  • Organizer: NSFC A3 Foresight Program 2012 Seminar Epigenetic Signatures in Gastric Carcinogenesis
  • Place of Presentation: Hangzhou, China
• [Remarks]
  • URL: http://www.tmd.ac.jp/grad/monc/index.html