Development of novel antiangiogenic therapy based on tumor microenviroenment

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390506
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Hokkaido University
• Principal Investigator: HIDA Kyoko Hokkaido University, 大学院・歯学研究科, 特任准教授 (40399952)
• Co-Investigator(Kenkyū-buntansha): SHINDOH Masanobu 北海道大学, 大学院・歯学研究科, 教授 (20162802) ; TOTSUKA Yasunori 北海道大学, 大学院・歯学研究科, 教授 (00109456) ; HIGASHINO Fumihiro 北海道大学, 大学院・歯学研究科, 准教授 (50301891) ; HIDA Yasuhiro 北海道大学, 北海道大学病院, 講師 (30399919) ; KITAMURA Tetsuya 北海道大学, 大学院・歯学研究科, 助教 (00451451)
• Project Period (FY): 2008 – 2010
• Keywords: 血管新生阻害 / 腫瘍 / 微小環境 / 血管内皮

Research Abstract

To develope novel anti-angiogenic therapy reflecting on tumor microenvironment more, we compared gene expression between tumor endothelial cell (TEC) and normal endothelial cell (NEC) and identified TEC specific genes by DNA microarray analysis.
We picked up these genes and analyzed the function of these molecules in TECs by knock down using siRNA.
Knock down of some genes inhibited TEC survival and some inhibited cell migration on TEC. Furthermore, inhibition of several TEC markers showed tumor growth suppression in vivo. These results suggested that it enabled us to develope novel anti-angiogenic therapy targeting TEC specifically.

Research Products

• [Journal Article] Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells (2011)
  • Author(s): Muraki C., Ohga N., Hida Y., Nishihara H., Kato Y., Tsuchiya K., Matsuda K., Totsuka Y., Shindoh M., Hida K.
  • Journal Title: Int J Cancer (in press)
  • Peer Reviewed
• [Journal Article] HuR keeps an angiogenic switch on by stabilizing mRNA of VEGF and COX-2 in tumor endothelium (2011)
  • Author(s): Kurosu T., Ohga N., Hida Y., Maishi N., Akiyama K., Kakuguchi W., Kuroshima T., Kondo M., Akino T., Totsuka Y., Shindoh M., Higashino F., Hida K.
  • Journal Title: Br J Cancer 104(5) Pages: 819-829
  • Peer Reviewed
• [Journal Article] Crosstalk between blood vessels and tumor microenvironment (2010)
  • Author(s): Hida K., Ohga N., Kurosu T., Totsuka Y., Shindoh M.
  • Journal Title: Oral Sci Int 7(1) Pages: 1-10
  • Peer Reviewed
• [Journal Article] Isolated tumor endothelial cells maintain specific character during long-term culture (2010)
  • Author(s): Matsuda K., Ohga N., Hida Y., Muraki C., Kurosu T., Tsuchiya K., Akino T., Shih SC, Totsuka Y., Klagsbrun M., Shindoh M., Hida K.
  • Journal Title: Biochem Biophys Res Commun 394 Pages: 947-954
  • Peer Reviewed
• [Journal Article] Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization (2010)
  • Author(s): Tsuchiya K., Hida K., Hida Y., Muraki C., Ohga N., Kondo T., Miseki T., Nakagawa K, Shindoh M., Harabayashi T., Shinohara N, Nonomura K., Kobayashi M.
  • Journal Title: Int J Oncol 36(6) Pages: 1379-1386
  • Peer Reviewed
• [Journal Article] Inhibitory Effects of Epigallocatechin-3 Gallate, a Polyphenol in Green Tea, on Tumor-Associated Endothelial Cells and Endothelial Progenitor Cells (2009)
  • Author(s): Ohga N., Hida K., Hida Y., Muraki C., Tsuchiya K., Matsuda K., Ohiro Y., Totsuka Y., Shindoh M.
  • Journal Title: Cancer Sci 100(10) Pages: 1963-1970
  • Peer Reviewed
• [Journal Article] Cytogenetic Abnormalities of Tumor-Associated Endothelial Cells in Human Malignant Tumor (2009)
  • Author(s): Akino T., Hida K., Hida Y., Tsuchiya K., Freedman D., Muraki C., Ohga N., Matsuda K., Harabayashi T., Shinohara N., Nonomura K., Klagsbrun M., Shindoh M.
  • Journal Title: Am J Pathol 175(6) Pages: 2657-2667
  • Peer Reviewed
• [Presentation] 第9回口腔医科学フロンティア学術集会 (2011)
  • Author(s): 樋田京子
  • Organizer: がん微小環境内における腫瘍-血管の相互作用
  • Place of Presentation: 九州大学(福岡)
  • Year and Date: 2011-03-05
• [Presentation] The 8^<th> Annual Meeting for the Japanese Association for Cancer and Hypoxia Research (2011)
  • Author(s): 樋田京子
  • Organizer: 低酸素環境における腫瘍血管ダイナミクス
  • Place of Presentation: 北海道大学(札幌)
  • Year and Date: 2011-01-29
• [Presentation] Crosstalk between Tumor Endothelial Cells and Microenvironment (2010)
  • Author(s): 樋田京子
  • Organizer: 北海道大学・ソウル大学合同シンポジウムInnovative Nanomedicine based on functional nucleic acidsナノバイオが拓く次世代核酸医薬
  • Place of Presentation: 北海道大学(札幌)
  • Year and Date: 2010-11-26
• [Presentation] 第56回日本病理学会秋期特別総会 (2010)
  • Author(s): 樋田京子
  • Organizer: Crosstalk between tumor endothelial cells and microenvironment
  • Place of Presentation: 西日本総合展示場、北九州国際会議場(北九州)
  • Year and Date: 2010-11-26
• [Presentation] Crosstalk between blood vessels and tumor microenvironment (2010)
  • Author(s): 樋田京子
  • Organizer: 北海道大学大学院歯学研究科・全北大学校歯医学専門大学院姉妹校提携20周年記念学術講演会
  • Place of Presentation: 北海道大学(札幌)
  • Year and Date: 2010-10-14
• [Presentation] 腫瘍血管内皮細胞を標的とした新たな治療法の開発 (2010)
  • Author(s): 樋田京子
  • Organizer: 平成22年度北海道癌談話会秋季シンポジウム「腫瘍血管新生の基礎と臨床」
  • Place of Presentation: アスティ45(札幌)
  • Year and Date: 2010-10-09
• [Presentation] 第64回日本口腔科学会学術集会 (2010)
  • Author(s): 樋田京子
  • Organizer: 腫瘍血管内皮細胞の異常と新たな治療法の開発
  • Place of Presentation: 札幌プリンスホテル(札幌)
  • Year and Date: 2010-06-24
• [Presentation] Endothelial cells acquire abnormalities by factors from tumor cells (2010)
  • Author(s): Akiyama K., Ohga N., Hida Y., Akino T., Hirata N., Kurosu T., Ishikawa S., Kondo M., Maishi N., Kawamoto T., Inoue N., Shindoh M., Hida K.
  • Organizer: AACR 101st ANNUAL MEETING 2010
  • Place of Presentation: Washington DC(USA)
  • Year and Date: 2010-04-20
• [Presentation] Cytogenetic Abnormalities of Tumor Endothelial Cells in Human Malignant Tumors (2010)
  • Author(s): Hida K., Akino T., Hida Y., Tsuchiya K., Freedman D., Muraki C., Ohga N., Matsuda K., Akiyama K., Kurosu T., Kondo M., Maishi N., Harabayashi T., Shinohara N., Nonomura K., Klagsbrun M., Shindoh M.
  • Organizer: AACR 101st ANNUAL MEETING 2010
  • Place of Presentation: Washington DC(USA)
  • Year and Date: 2010-04-19
• [Presentation] A Green Tea Polyphenol Epigallocatechin-3 Gallate Specifically Targets Tumor-Associated Endothelial Cells (2010)
  • Author(s): Hida Y., Ohga N., Muraki C., Akiyama K., Kondoh M., Maishi N., Kurosu T., Ishikawa S., Hirata N., Shindoh M., Hida K.
  • Organizer: AACR 101st ANNUAL MEETING 2010
  • Place of Presentation: Washington DC(USA)
  • Year and Date: 2010-04-19
• [Presentation] 第43回加齢医学研究所シンポジウム「血管から見る医科学研究の新展開」 (2010)
  • Author(s): 樋田京子
  • Organizer: 腫瘍血管内皮細胞の特性と治療抵抗性
  • Place of Presentation: 東北大学加齢医学研究所(仙台)
  • Year and Date: 2010-03-24
• [Presentation] The 4^<th> Lecture Meeting SUTENT by Urology Specialist (2010)
  • Author(s): 樋田京子
  • Organizer: がん治療の最前線 血管新生阻害の最新アプローチ
  • Place of Presentation: フォーシーズンズ椿山荘(東京)
  • Year and Date: 2010-02-26
• [Presentation] Inhibitory Effects of Epigallocatechin-3 Gallate, a Polyphenol in Green Tea, on Tumor-Associated Endothelial Cells and Endothelial Progenitor Cells (2010)
  • Author(s): Ohga N., Hida K.
  • Organizer: AACR-JCA Joint conference : CANCER GENOMICS, EPIGENOMICS, AND THE DEVELOPMENT OF NOVEL THERAPEUTICS
  • Place of Presentation: Waikoloa, Hawaii (USA)
  • Year and Date: 2010-02-08
• [Presentation] 公開シンポジウム「生体ナノ環境の時空間制御を目指して」、戦略的研究推進経費プロジェクト主催「血管を標的とする革新的医薬分子送達法の基盤技術の確立」 (2010)
  • Author(s): 樋田京子
  • Organizer: 生体ナノ環境を構成する間質細胞の時空間的ダイナミクスの解明
  • Place of Presentation: 北海道大学大学院薬学研究院臨床薬学講義室(札幌)
  • Year and Date: 2010-01-05
• [Presentation] 腫瘍血管内皮細胞の異常と薬剤抵抗性 (2009)
  • Author(s): 樋田京子
  • Organizer: 第32回日本分子生物学会年会ワークショップ
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2009-12-12
• [Presentation] 腫瘍血管内皮細胞の異常性 (2009)
  • Author(s): 樋田京子
  • Organizer: 第17回日本血管生物医学会
  • Place of Presentation: 東京大学(東京)
  • Year and Date: 2009-10-08
• [Book] 血管医学 特集「がんと血管-イメージングから治療まで-」 10(4)(丸山征郎、安藤丈治、佐藤靖史、倉林正彦、江頭健輔、山岸昌一編)(腫瘍血管内皮細胞の特性と治療抵抗性) (2009)
  • Author(s): 樋田京子
  • Total Pages: 23-28
  • Publisher: メディカルレビュー社
• [Book] 実験医学増刊号「癌の微小環境と適応応答の最前線」 27(2)(落合淳志・高倉伸幸編)(がん組織中の血管内皮細胞の異常性-遺伝子発現から染色体異常まで) (2009)
  • Author(s): 樋田京子、秋野文臣、樋田泰浩
  • Total Pages: 149-155
  • Publisher: 羊土社
• [Book] 細胞 40(12)(渋谷正史・佐藤靖史編 腫瘍血管内皮細胞の特性、血管新生up-to-date) (2008)
  • Author(s): 樋田京子、樋田泰浩
  • Total Pages: 16-19
  • Publisher: ニューサイエンス社
• [Book] (2008)
  • Author(s): 樋田京子
  • Total Pages: 211-214
  • Publisher: がん転移研究の実験手法 第1版(日本がん転移学会編 清木元治・愛甲孝 編金芳堂 磁気ビーズを用いたがん組織からの細胞分離法)
• [Remarks] ホームページ等
  • URL: http://www.den.hokudai.ac.jp/vascular-biology/
• [Patent(Industrial Property Rights)] 腫瘍血管新生阻害剤 (2010)
  • Inventor(s): 樋田京子、樋田泰浩
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 特許出願, 特願2010-254205
  • Filing Date: 2010-11-12
• [Patent(Industrial Property Rights)] 腫瘍血管新生阻害剤 (2010)
  • Inventor(s): 樋田京子、樋田泰浩
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 特許出願, PCT/JP2010/063669
  • Filing Date: 2010-08-11
  • Overseas
• [Patent(Industrial Property Rights)] 腫瘍血管新生阻害剤 (2010)
  • Inventor(s): 樋田京子、樋田泰浩
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 特許出願, PCT/JP2010/063124
  • Filing Date: 2010-08-03
  • Overseas
• [Patent(Industrial Property Rights)] 腫瘍血管新生阻害剤 (2010)
  • Inventor(s): 樋田京子、樋田泰浩
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 特許出願, PCT/JP2010/063669
  • Filing Date: 2010-03-18