Research for development of novel therapeutic approaches targeting molecules regulating invasion and drug resistance of malignant gliomas

• Project/Area Number: 19209048
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: Keio University
• Principal Investigator: SAYA Hideyuki Keio University, 医学部, 教授 (80264282)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥50,440,000 (Direct Cost: ¥38,800,000、Indirect Cost: ¥11,640,000); Fiscal Year 2008: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2007: ¥26,390,000 (Direct Cost: ¥20,300,000、Indirect Cost: ¥6,090,000)
• Keywords: 細胞・組織 / 脳腫瘍 / シグナル伝達 / 癌 / 低分子化合物

Research Abstract

悪性グリオーマの強い浸潤能と治療抵抗性を規定する分子シグナルを明らかにし、それらに基づく新たな治療戦略の基礎を構築することを目的として研究を行った。具体的には : (1) 悪性グリオーマの浸潤能は細胞外マトリクスの産生能と極めて強い相関を示すので、マトリクスの産生を評価するアッセイ系を確立し、そのアッセイを用いて浸潤能を抑制できる低分子化合物の候補を取得した。(2) 抗がん剤効果が細胞分裂期での停止時間と相関することを見出し、その概念を用いて抗がん剤の効果を判定するシステムを構築した。(3) ヒトグリオブラストーマおよびPNETに類似した組織型を持つマウス脳腫瘍モデルを構築した。

Research Products

• [Journal Article] Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress (2009)
  • Author(s): Inumaru J, Nagano O, Takahashi E, Ishimoto T, Nakamura S, Suzuki Y, NiwaSI, Umezawa K, Tanihara H and Saya H
  • Journal Title: Genes Cells(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis (2009)
  • Author(s): Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H and Suda T
  • Journal Title: J Exp Med 206 Pages: 1089-1102
  • Peer Reviewed
• [Journal Article] K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells (2009)
  • Author(s): Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, Akasaka K, Ichikawa S, Ishida H, Kusaka H, Akinaga S, Murakata C, Honda S, Nitta M, Saya H and Yamashita Y
  • Journal Title: Cancer Res 69 Pages: 3901-3909
  • Peer Reviewed
• [Journal Article] Reversible whole-organism cell cycle arrest in a living vertebrate (2009)
  • Author(s): Sampetrean O, Iida S, Makino S, Matsuzaki Y, Ohno K and Saya H
  • Journal Title: Cell Cycle 8 Pages: 620-627
  • Peer Reviewed
• [Journal Article] Reversible whole-organism cell cycle arrest in a living vertebrate. (2009)
  • Author(s): Sampetrean o., et al.
  • Journal Title: Cell Cycle 8 Pages: 620-627
  • Peer Reviewed
• [Journal Article] K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor a gent, induces cell death in cancer cells. (2009)
  • Author(s): Nakai R., et al.
  • Journal Title: Cancer Research (in press)
  • Peer Reviewed
• [Journal Article] p53 regulates TLR3 expression and function in human epithelial cell lines (2008)
  • Author(s): Taura M, Eguma A, Suico MA, Shuto T, Koga T, Komatsu K, Komune T, Sato T, Saya H, Li JD and Kai H
  • Journal Title: Mol Cell Biol 28 Pages: 6557-6567
  • Peer Reviewed
• [Journal Article] Activated macrophages promote Wnt signaling through tumor necrosis factor- in gastric tumor cells (2008)
  • Author(s): Oguma K, Oshima H, Aoki M, Uchio R, Naka K, Nakamura S, Hirao A, Saya H, Taketo MM and Oshima M
  • Journal Title: EMBO J 27 Pages: 1671-1681
  • Peer Reviewed
• [Journal Article] Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristics of the epithelial to mesenchymal transition (2008)
  • Author(s): Arima Y, Inoue Y, Shibata T, Hayashi H, Nagano O, Saya H and Taya Y
  • Journal Title: Cancer Res 68 Pages: 5104-5112
  • Peer Reviewed
• [Journal Article] AIP regulates stability of Aurora-A at early mitotic phase coordinately with GSK-3 (2008)
  • Author(s): Fumoto K, Lee PC, Saya H and Kikuchi A
  • Journal Title: Oncogene 27 Pages: 4478-4487
  • Peer Reviewed
• [Journal Article] Aurora-A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice (2008)
  • Author(s): Zhang D, Shimizu T, Araki N, Hirota T, Yoshie M, Ogawa K, Nakagata N, Takeya M and Saya H
  • Journal Title: Oncogene 27 Pages: 4305-4314
  • Peer Reviewed
• [Journal Article] NF1 tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein,collapsin response mediator protein-2 (2008)
  • Author(s): Patrakitkomjorn S, Kobayashi D, Morikawa T, Wilson MM, Tsubota N, Irie A, Ozawa T, Aoki M, Arimura N, Kaibuchi K, Saya H and Araki N
  • Journal Title: J Biol Chem 283 Pages: 9399-9413
  • Peer Reviewed
• [Journal Article] HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint (2008)
  • Author(s): Kim S, Park SY, Yong H, Famulski JK, Chae S, Lee JH, Kang CM, Saya H, Chan GK, and Cho H
  • Journal Title: Oncogene 27 Pages: 3457-3464
  • Peer Reviewed
• [Journal Article] Aurora-A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice. (2008)
  • Author(s): Zhang D., et al.
  • Journal Title: Oncogene 27 Pages: 4305-4314
  • Peer Reviewed
• [Journal Article] AIP regulates stability of Aurora-A at early mitotic phase coordinately with GSK-3〓. (2008)
  • Author(s): Fumoto K
  • Journal Title: Oncogene (印刷中)
  • Peer Reviewed
• [Journal Article] Aurora-A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice (2008)
  • Author(s): Zhang D
  • Journal Title: Oncogene (印刷中)
  • Peer Reviewed
• [Journal Article] Visualizing the dynamics of p21^<Waf1/Cip1> cyclin-dependent kinase inhibitor expression in living animals (2007)
  • Author(s): Ohtani N, Imamura Y, Yamakoshi K, Hirota F, Nakayama R, Kubo Y, Ishimaru N, Takahashi A, Hirao A, Shimizu T, Mann DJ, Saya H, Hayashi Y, Arase S, Matsumoto M, Kazuki N and Hara E
  • Journal Title: Proc Natl Acad Sci USA 104 Pages: 15034-15039
  • Peer Reviewed
• [Journal Article] Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation (2007)
  • Author(s): Kuninaka S, Iida S, Hara T, Nomura M, Naoe H, Morisaki T, Nitta M, Arima Y, Mimori T, Yonehara S and Saya H
  • Journal Title: Oncogene 26 Pages: 2395-2406
  • Peer Reviewed
• [Journal Article] Wynshaw-Boris A and Hirotsune S. NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation,separation, and TACC3 recruitment (2007)
  • Author(s): Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H, Toyoshima YY, Kinoshita K
  • Journal Title: Mol Cell Biol 27 Pages: 352-367
  • Peer Reviewed
• [Journal Article] NDEL1 phosphorylation by Aurora-A kinase is essential for centroso mal maturation,separation,and TACC3 recruitment. (2007)
  • Author(s): Mori D., et. al.
  • Journal Title: Mol Cell Biol 27 Pages: 352-367
  • Peer Reviewed
• [Presentation] 癌幹細胞モデルの作製と応用。ランチョンセミナー (2009)
  • Author(s): 佐谷秀行
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場。名古屋
  • Year and Date: 2009-10-30
• [Presentation] Analysis of Myc-induced cancer stem cell models (2009)
  • Author(s): Saya H
  • Organizer: USA-Japan Cooperative Cancer Workshop 'Stem Cells in Normal and Malignant Hematopoiesis'
  • Place of Presentation: Hilton Waikoloa Village in Hawaii Big Island.Hawaii
  • Year and Date: 2009-03-28
• [Presentation] 誘導性腫瘍形成モデルを用いたがん幹細胞の解析 (2009)
  • Author(s): 佐谷秀行
  • Organizer: 第11回泌尿器疾患ゲノム解析研究会
  • Place of Presentation: 大阪リーガロイヤルホテル。大阪(招待講演)
  • Year and Date: 2009-03-14
• [Presentation] マウスモデルを用いた癌幹細胞の性状解析と応用。シンポジウム3がん幹細胞 (2009)
  • Author(s): 佐谷秀行
  • Organizer: 第8回日本再生医療学会総会
  • Place of Presentation: 東京国際フォーラム。東京
  • Year and Date: 2009-03-05
• [Presentation] Role of Hyaluronan-CD44 Interaction in Epithelial-Mesenchymal Transition and Cancer Invasion (2009)
  • Author(s): Saya H
  • Organizer: Invited Speaker. Global Center of Excellence (COE) Program 1^<st> International Symposium
  • Place of Presentation: Nagoya University School of Medicine.Nagoya
  • Year and Date: 2009-01-23
• [Presentation] Role of Hyaluronan-CD44 Interaction in Epithelial-Mesenchymal Transition and Cancer Invasion. (2009)
  • Author(s): Saya H.
  • Organizer: Global Center of Excellence (GCOE)Program 1^<st> International Symposium
  • Place of Presentation: 名古屋
  • Year and Date: 2009-01-23
• [Presentation] 胎盤からみた細胞周期制御因子APC/cdh1の機能 (2008)
  • Author(s): 佐谷秀行
  • Organizer: 第31回日本分子生物学会年会第81回日本生化学会大会合同大会。シンポジウム。
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-11
• [Presentation] 癌幹細胞に基づく癌発生及び維持機構の解析 (2008)
  • Author(s): 佐谷秀行
  • Organizer: 第47回日本臨床細胞学会秋期大会
  • Place of Presentation: 東京(要望講演)
  • Year and Date: 2008-11-14
• [Presentation] Establishment of osteosarcoma cancer stem cells from mouse bone marrow stromal cells (2008)
  • Author(s): Saya H
  • Organizer: Invited Speaker. Cancer Genes and Cancer Stem Cells. The 5^<th> Nikko International Symposium 2008
  • Place of Presentation: Jichi Medical University (JMU) Information and In-service Training Center, Japan
  • Year and Date: 2008-10-25
• [Presentation] 癌の浸潤転移能を決定づける細胞-マトリクス相互作用 (2008)
  • Author(s): 佐谷秀行
  • Organizer: 第41回日本整形外科学会・骨・軟部腫瘍学術学会
  • Place of Presentation: 浜松(教育講演)
  • Year and Date: 2008-07-18
• [Presentation] 癌の浸潤転移能を決定づける細胞-マトリクス相互作用 (2008)
  • Author(s): 佐谷秀行
  • Organizer: 第41回日本整形外科学会・骨・軟部腫瘍学術学会
  • Place of Presentation: 浜松
  • Year and Date: 2008-07-18
• [Presentation] 癌の浸潤・転移抑制創薬への新しいアプローチ (2008)
  • Author(s): 佐谷秀行
  • Organizer: 第12回がん分子標的治療研究会総会
  • Place of Presentation: 東京
  • Year and Date: 2008-06-26
• [Presentation] 癌幹細胞について解決すべき諸問題 (2007)
  • Author(s): 佐谷 秀行
  • Organizer: 第30回日本分子生物学会年会、第80回日本生化学会大会シンポジウム3S28「癌幹細胞一組織幹細胞と何が似て、何が違うか」
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-11
• [Presentation] 細胞-マトリクス間相互作用と癌細胞浸潤。ランチョンセミナー (2007)
  • Author(s): 佐谷秀行
  • Organizer: 第25回日本ヒト細胞学会学術集会
  • Place of Presentation: 都市センターホテル、東京
  • Year and Date: 2007-08-04
• [Presentation] 癌幹細胞について解決すべき諸問題。シンポジウム (2007)
  • Author(s): 佐谷秀行
  • Organizer: 第30回日本分子生物学会年会、第80回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] Molecular mechanism of anti-cancer therapies. Luncheon Seminar (2007)
  • Author(s): Saya H
  • Organizer: Organization for Oncology and Translational Research 4^<th> Annual Conference
  • Place of Presentation: Kyoto, Japan
• [Presentation] Auroraキナーゼの発がんにおける役割,合同シンポジウム5「シグナル伝達研究と分子標的療法」 (2007)
  • Author(s): 佐谷秀行
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] 抗がん剤による細胞死の分子機構。シンポジウム4「細胞死と血液疾患」 (2007)
  • Author(s): 佐谷秀行
  • Organizer: 第69回日本血液学会総会
  • Place of Presentation: 横浜
• [Presentation] 抗がん剤治療の分子メカニズム。Meet the Expert Seminar (2007)
  • Author(s): 佐谷秀行
  • Organizer: 第66回日本癌学会総会
  • Place of Presentation: パシフィコ横浜。横浜
• [Remarks]
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• [Patent(Industrial Property Rights)] in vitro Fibrotic Focus モデル及び、それを用いた治療薬評価システム (2007)
  • Inventor(s): 佐谷秀行、永野修、丹羽眞一郎、中村賢志、鈴木良美
  • Industrial Property Rights Holder: 学校法人 慶應義塾、リンク・ジェノミクス(株)
  • Industrial Property Number: 2007-209591
  • Filing Date: 2007-08-10
• [Patent(Industrial Property Rights)] In vitro Fibrotic Focusモデル及び、それを用いた治療薬評価システム (2007)
  • Inventor(s): 佐谷 秀行、永野 修、丹羽 真一郎、中村 賢志、鈴木 良美
  • Industrial Property Rights Holder: 学校法人慶慮義塾、リンク・ジェノミクス株式会社
  • Industrial Property Number: 2007-209591
  • Filing Date: 2007-08-10