Signaling mechanism of tumor angiogenesis.

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014020
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tokyo Medical and Dental University (2007-2009); The University of Tokyo (2005-2006)
• Principal Investigator: SHIBUYA Masabumi Tokyo Medical and Dental University, 医学部, 非常勤講師 (10107427)
• Project Period (FY): 2005 – 2009
• Keywords: 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

Research Abstract

We demonstrated that (1) vascular endothelial growth factorreceptor-2 (VEGFR-2) utilizes unique signaling via a single tyrosine by using mutantmouse model, and (2) VEGFR-1 plays an important role in growth of tumors includingbrain tumor in vivo mostly via activation of VEGFR-1+ bone-marrow-derived cells.Furthermore, we showed that resistance of tumors against antiangiogenic therapy is partlydependent on a metabolic shift under stresses. In addition, we found new pathway for thefunction of endogenous antiangiogenic protein TSP1.

Research Products

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