がん組織における血管内皮細胞増殖のシグナリング機構

2009 年度 研究成果報告書

• 研究課題/領域番号: 17014020
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 東京医科歯科大学 (2007-2009); 東京大学 (2005-2006)
• 研究代表者: 渋谷 正史 東京医科歯科大学, 医学部, 非常勤講師 (10107427)
• 研究期間 (年度): 2005 – 2009
• キーワード: VEGFR / マクロファージ / 腫瘍血管 / 血管阻害療法 / 低酸素・低栄養ストレス

研究概要

血管内皮増殖因子VEGFの受容体2(VEGFR2)からのシグナル伝達系の特徴を個体レベルで明らかにした。VEGFR1も脳腫瘍をはじめ固形癌の増殖に重要な役割を果たすこと、その際、VEGFR-1発現骨髄細胞が深く関与することを見出した。血管阻害療法に対する癌細胞の抵抗性の機序として、細胞内代謝系の変化を明らかにした。内因性血管阻害因子TSP1 の新たな作用機序を見出した。

研究成果

• [雑誌論文] VEGFR-1 signaling regulates the homing of bone marrow derived cells in a mouse stroke model. (2010)
  • 著者名/発表者名: Beck H, Raab S, Copanaki E, Heil M, Scholz A, Shibuya M, Deller T, Machein M, Plate KH.
  • 雑誌名: J. Neuropathol. Exp. Neurol. 69 ページ: 168-175
• [雑誌論文] An FGF4-FRS2α-Cdx2 axis in trophoblast stem cells induces BMP4 to regulate proper growth of early mouse embryos. (2010)
  • 著者名/発表者名: Murohashi M, Nakamura T, Tanaka S, Ichise T, Yoshida N, Yamamoto T, Shibuya M, Schlessinger J, Gotoh N.
  • 雑誌名: Stem Cells. 28 ページ: 113-121
• [雑誌論文] Hypoxia and Low Nutrition Double Stress Induces Aggressiveness in a Murine Model of Melanoma. (2009)
  • 著者名/発表者名: Osawa, T., Muramatsu, M., Watanabe, M., Shibuya, M.
  • 雑誌名: Cancer Sci. 100 ページ: 844-851
• [雑誌論文] M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. (2009)
  • 著者名/発表者名: Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T.
  • 雑誌名: J Exp Med. 206 ページ: 1089-102
• [雑誌論文] VEGFR-1 regulates adult olfactory bulb neurogenesis and migration of neural progenitors in the rostral migratory stream in vivo. (2009)
  • 著者名/発表者名: Wittko IM, Schanzer A, Kuzmichev A, Schneider FT, Shibuya M, Raab S, Plate KH
  • 雑誌名: J. Neurosci. 29 ページ: 8704-8714
• [雑誌論文] VEGF Receptor-2 Y1175 signaling controls VEGF-induced vWF release from endothelial cells via PLCgamma1- and PKA-dependent pathways. (2009)
  • 著者名/発表者名: Xiong Y, Huo Y, Chen C, Zeng H, Lu X, Wei C, Ruan C, Zhang X, Hu Z, Shibuya M, Luo J
  • 雑誌名: J Biol Chem 284 ページ: 23217-2324
• [雑誌論文] VEGFR1 Tyrosine Kinase Signaling Promotes Lymphangiogenesis as Well as Angiogenesis Indirectly via Macrophage Recruitment. (2008)
  • 著者名/発表者名: Murakami, M. Zheng Y, Hirashima M, Suda T, Morita Y, Ooehara J, Ema H, Fong GH, Shibuya M
  • 雑誌名: Arterioscler Thromb Vasc Biol 28 ページ: 658-664
• [雑誌論文] The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. (2008)
  • 著者名/発表者名: Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y
  • 雑誌名: Nature Cell Biol. 10 ページ: 1349-1355
• [雑誌論文] Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. (2008)
  • 著者名/発表者名: Fukuhara S, Sako K, Minami T, Noda K, Kim HZ, Kodama T, Shibuya M, Takakura N, Koh GY, Mochizuki N.
  • 雑誌名: Nature Cell Biol 10 ページ: 513-526
• [雑誌論文] Flt-1 signaling in macrophages promotes glioma growth in vivo. (2008)
  • 著者名/発表者名: Kerber M, Reiss Y, Wickersheim A, Jugold M, Kiessling F, Heil M, Tchaikovski V, Waltenberger J, Shibuya M, Plate KH, Machein MR
  • 雑誌名: Cancer Res 68 ページ: 7342-7351
• [雑誌論文] Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. (2008)
  • 著者名/発表者名: Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M, Waltari M, Hellstrom M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Yla-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K
  • 雑誌名: Nature 54 ページ: 656-660
• [雑誌論文] Chimeric VEGF-ENZ7/PlGF Specifically Binding to VEGFR-2 Accelerates Skin Wound Healing via Enhancement of Neovascularization. (2007)
  • 著者名/発表者名: Zheng Y, Watanabe M, Kuraishi T, Hattori S, Kai C, Shibuya M
  • 雑誌名: Arterioscler, Thromb, Vasc. Biol. 27 ページ: 503-511
• [雑誌論文] Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. (2007)
  • 著者名/発表者名: Wirzenius, M., Tammela, T., Uutelaff, M., He, Y., Odorisio, T., Sambruno, G., Nagy, JA, Dvorak, HF, Yla-Herttuala, S., Shibuya, M., Alitalo, K
  • 雑誌名: J. Exp. Med. 204 ページ: 1431-1340
• [雑誌論文] A novel anti-angiogenic pathway of thrombospondin-1 mediated by suppression of the cell cycle. (2007)
  • 著者名/発表者名: Yamauchi, M., Imajoh-Ohmi, S., Shibuya, M
  • 雑誌名: Cancer Science 98 ページ: 1491-1497
• [雑誌論文] Inhibitory Smad transcription factors protect arterial endothelial endothelial cells from apoptosis induced by BMP4. (2006)
  • 著者名/発表者名: Kiyono, M., Shibuya, M
  • 雑誌名: Oncogene 25 ページ: 7131-7137
• [雑誌論文] Chimeric VEGF-ENZ7/PlGF Promotes Angiogenesis via VEGFR-2 without Significant Enhancement of Vascular Permeability and Inflammation. (2006)
  • 著者名/発表者名: Zheng, Y., Murakami, M., Takahashi, H., Yamauchi, M., Kiba, A., Yamaguchi, S., Yabana, N., Alitalo, K., Shibuya, M
  • 雑誌名: Arterioscler, Thromb, Vasc. Biol. 26 ページ: 2019-2026
• [雑誌論文] Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages. (2006)
  • 著者名/発表者名: Murakami, M., Iwai, S., Hiratsuka, S., Yamauchi, M., Nakamura, K., Iwakura, Y., Shibuya, M
  • 雑誌名: Blood 108 ページ: 1849-1856
• [雑誌論文] Corneal avascularity is due to soluble VEGF receptor-1. (2006)
  • 著者名/発表者名: Ambati BK, Nozaki M, Singh N, Takeda A, JaniPD, Suthar T, Albuquerque RJ, Richter E, Sakurai E,Newcomb MT, Kleinman ME, Caldwell RB, Lin Q,Ogura Y, Orecchia A, Samuelson DA, Agnew DW,St Leger J, Green WR, Mahasreshti PJ, Curiel DT,Kwan D, Marsh H, Ikeda S, Leiper LJ, CollinsonJM, Bogdanovich S, Khurana TS, Shibuya M,Baldwin ME, Ferrara N, Gerber HP, De Falco S,Witta J, Baffi JZ, Raisler BJ, Ambati J.
  • 雑誌名: Nature 443 ページ: 993-997
• [雑誌論文] Membrane-fixation of VEGFR1 ligand-binding domain is important for vasculogenesis/angiogenesis in mice. (2005)
  • 著者名/発表者名: Hiratsuka, S., Nakao, K., Nakamura, K., Katsuki, M., Maru, Y., Shibuya, M
  • 雑誌名: Mol. Cell. Biol. 25 ページ: 346-354
• [雑誌論文] VEGF-A is involved in guidance of VEGF-receptor-positive cells to the anterior portion of early embryos. (2005)
  • 著者名/発表者名: Hiratsuka, S., Kataoka, Y., Nakao, K., Nakamura, K., Morikawa, S., Tanaka, S., Katsuki, M., Maru, Y., Shibuya, M
  • 雑誌名: Mol. Cell. Biol. 25 ページ: 355-363
• [雑誌論文] Essential role of Flk-1 (vascular endothelial growth factor receptor-2) tyrosine residue-1173 in vasculogenesis in mice. (2005)
  • 著者名/発表者名: Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N., Shibuya M
  • 雑誌名: Proc. Natl. Acad. Sci. USA 102 ページ: 1076-1081
• [雑誌論文] Vascular endothelial growth factor receptor-1 signaling is essential for osteoclast development and bone-marrow formation in CSF-1-deficient mice. (2005)
  • 著者名/発表者名: Niida, S., Kondo, T., Hiratsuka, S., Hayashi, S. -I., Amizuka, N., Noda, T., Ikeda, K., Shibuya, M
  • 雑誌名: Proc. Natl. Acad. Sci. USA 102 ページ: 14016-14021
• [学会発表] VEGF-dependent and -independent regulation of angiogenesis (2009)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: KSMBMB
  • 発表場所: Seoul, Korea(invited speaker)
  • 年月日: 20091029-20091030
• [学会発表] VEGF-dependent and -independent regulation of angiogenesis (2009)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: in 7th Int. Symposium on the Biology of Endothelial Cells
  • 発表場所: Vienna, Austria(invited speaker)
  • 年月日: 20090902-20090905
• [学会発表] A Unique Signal Transduction of VEGF Family Members, VEGF-A and VEGF-E. (2009)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: in the Int. Symposium on the Molecular and cellular mechanisms of angiogenesis
  • 発表場所: Chester Univ., UK(invited speaker, plenary lecture)
  • 年月日: 20090715-20090717
• [学会発表] Involvement of VEGF-VEGFR System in the Progression of Cancer including Brain Tumors (2009)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: 3rd Quandrennial Meeting of the World Federation of Neuro-Oncology
  • 発表場所: Yokohama, Japan(invited speaker)
  • 年月日: 20090511-20090514
• [学会発表] VEGF-dependent and independent regulation of angiogenesis. (2008)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: International Symposium, Vascular Differentiation and Remodeling
  • 発表場所: Frankfurt, Germany(invited speaker)
  • 年月日: 20080716-20080719
• [学会発表] VEGFR-1 is involved in tumor-growth and metastasis including melanoma. (2008)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The IPCC (International Pigment Cell Conference)-Melanoma Meeting-
  • 発表場所: Sapporo(invited speaker)
  • 年月日: 20080507-20080511
• [学会発表] VEGF-dependent and -independent regulation of angiogenesis. (2008)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The US-Japan Cancer Research Workshop
  • 発表場所: Kyoto(invited speaker)
  • 年月日: 20080319-20080321
• [学会発表] VEGF-dependent and independent regulation of angiogenesis (2007)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The First Pacific Meeting for Angiogenesis and Lymphangiogenesis
  • 発表場所: Jeju Island, Korea(invited speaker)
  • 年月日: 20071112-20071114
• [学会発表] A unique signal transduction of VEGF receptors is involved in tumor angiogenesis and metastasis (2007)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: Third International Conference on Tumor-stroma interaction
  • 発表場所: Ascona, Switzerland(invited speaker)
  • 年月日: 20071027-20071031
• [学会発表] VEGF-dependent and -independent regulation of angiogenesis (2007)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The Joint Scientific Meeting of Vascular Biology Organization in Asia Pacific Region
  • 発表場所: Tainan, Taiwan(invited speaker)
  • 年月日: 20071020-20071021
• [学会発表] VEGFR1 is involved in a variety of diseases, tumor growth/metastasis and rheumatoid arthritis. (2007)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: ESH EuroConference on Angiogenesis
  • 発表場所: Albufeira, Portugal(invited speaker)
  • 年月日: 20070511-20070514
• [学会発表] A unique signal transduction of VEGF receptors involved in tumor angiogenesis and metastasis. (2007)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The 22nd Nagoya International Cancer Treatment Symposium
  • 発表場所: Nagoya(invited speaker)
  • 年月日: 2007-10-25
• [学会発表] Involvement of VEGF and its receptor system in tumor growth and metastasis. (2006)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: The Joint Meeting of 3rd ISC-ICCT and 11th ISCC
  • 発表場所: Tokyo(invited speaker)
  • 年月日: 20061206-20061208
• [学会発表] Involvement of VEGFR-1 in lymphangiogenesis in vivo (2006)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: Gordon Research Conference on lymphangiogenesis
  • 発表場所: Les Diablerets, Switzerland(invited speaker)
  • 年月日: 20060902-20060908
• [学会発表] VEGF signaling toward angiogenesis and vascular permeability. (2006)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: KCIST 2006-Vascular Biology and Human Disease
  • 発表場所: Anmyondo, Korea(invited speaker)
  • 年月日: 20060720-20060722
• [学会発表] VEGF-dependent and independent regulation of angiogenesis. (2006)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: 20th IUBMB-Kyoto, Symposium on angiogenesis and lymphangiogenesis.
  • 発表場所: Kyoto, Japan(invited speaker, chairman)
  • 年月日: 20060618-20060623
• [学会発表] VEGF-receptor signaling, and its application for pro-angiogenic therapy (2006)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: ESH (European School of Hematology) Vascular Biology Meeting
  • 発表場所: Cannes, France(invited speaker)
  • 年月日: 20060513-20060516
• [学会発表] Novel VEGF family members define the differential signals for angiogenesis and vascular permeability (2005)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: ESH Angiogenesis Meeting
  • 発表場所: Ascona, Switzerland(invited speaker)
  • 年月日: 20051001-20051005
• [学会発表] VEGF-receptor signaling towards angiogenesis and vascular permeability (2005)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: Gordon Research Conference, Angiogenesis and Microcirculation
  • 発表場所: Rhod-island, USA(invited speaker)
  • 年月日: 20050814-20050818
• [学会発表] Molecular basis of angiogenesis (2005)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: Korea-Japan Vascular Biology Meeting
  • 発表場所: Korea(invited speaker)
  • 年月日: 20050811-20050812
• [学会発表] VEGF-dependent and independent regulation of angiogenesis (2005)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: ESH (European School of Hematology) Vascular Biology Meeting.
  • 発表場所: Spain(invited speaker)
  • 年月日: 20050527-20050529
• [学会発表] Molecular Mechanism of Angiogenesis (2005)
  • 著者名/発表者名: Shibuya, M
  • 学会等名: Third European Symposium on Vascular Biology and Medicine
  • 発表場所: Hamburg, Germany(invited speaker, Keynote lecture)
  • 年月日: 2005-09-30
• [産業財産権] 骨形成因子をもちいた癌増殖抑制法 (2009)
  • 発明者名: 渋谷正史、土田里香、大澤毅
  • 権利者名: 東京医科歯科大学
  • 産業財産権番号: 特願2009-176442
  • 出願年月日: 2009-07-29