• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

2006 Fiscal Year Final Research Report Summary

Study of endothelial cell-specific signal transduction pathways and effect of chronic hypoxia. A strategy for the development of an effective antiangiogenic therapy.

Research Project

Project/Area Number 17591686
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionNagasaki University

Principal Investigator

KANDA Shigeru  Nagasaki University, Graduate School of Biomedical Sciences, Department of Molecular Microbiology and Immunology, Research Associate, 大学院医歯薬学総合研究科, 客員研究員 (20244048)

Project Period (FY) 2005 – 2006
KeywordsAntiangiogenic therapy / Molecular targeting therapy / endothelial cells / Src / Fes / HGF / angiopoietin 1 / hypoxia
Research Abstract

Angiogenesis is regulated by a number of proangiogenic factors. It is therefore likely that blockade of signaling molecules that commonly act downsteam of several proangiogenic factor receptors for the regulation of angiogenic cellular responses by endothelial cells must efficiently inhibit tumor angiogenesis driven by several proangiogenic factors simultaneously. To identify such signaling molecules, we investigated the signal trandiuction pathways in endothelial cells and found that ;
a. Fyn played an important roles for FGF-2-induced differentiation of endothelial cells
b. Src was required for HGF-and angiopoietin 1-induced differentiation of endothelial cells
c. Fes was involved in angiopoietin 1 (Ang1)-induced proliferation and FGF-2-directed migration by endothelial cells.
Thus, Src family kinases and Fes would be potential targets for antiangiogenic therapy.
While antiangiogenic strategy potently inhibits tumor growth and progression in xenografted tumor models in animals, antiangiogeic monotherapy failed to attenuate the progression of tumors in clinical trials. One of the reasons of this discrepancy may be that human tumor endothelial cells are chronically exposed to hypoxia. To examine how hypoxia affects the efficacy of antiangiogenic therapy, we cultured the endothelial cells under chronic hypoxia and the effect of a Src family kinase inhibitor PP2 on Ang1-induced capillary morphogenesis. Although downregulation of Src by small interfering RNA (siRNA) inhibited Ang1-induced capillary morphogenesis by endothelial cells cultured under both normoxic and hypoxic conditions, PP2 failed to inhibit it by hypoxic endothelial cells. These cells overexpressed multidrug associated protein 1, of which downregulation by siRNA restored the effect of PP2. This result suggests that combination of small molecular weight protein kinase inhibitors and ABC transporter inhibitos would be beneficial for increase in the efficacy of molecular targeting therapy.

  • Research Products

    (13 results)

All 2007 2006 2005

All Journal Article (12 results) Book (1 results)

  • [Journal Article] Role of Src in angiopoietin 1-induced capillary morphogenesis of endothelial cells : Effect of chronic hypoxia on Src inhibition by PP2.2007

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Cellular Signaling 19(3)

      Pages: 472-480

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Role of Src in angiopoietin 1-induced capillary morphogenesis of endothelial cells : Effect of chronic hypoxia on Src inhibition by PP2.2007

    • Author(s)
      Shigeru Kanda et al.
    • Journal Title

      Cellular Signaling. 19(3)

      Pages: 472-80

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] HGF-induced capillary morphogenesis of endothelial cells is regulated by Src.2006

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 344(2)

      Pages: 617-622

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Elevated expression of ERK 2 in human tumor cells chronically treated with PD98059.2006

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 345(4)

      Pages: 1481-1486

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Fibroblast growth factor-2 induces the activation of Src through Fes, which regulates focal adhesion disassembly.2006

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Experimental Cell Research 312(16)

      Pages: 3015-3022

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Current status and perspective of antioangiogenic therapy for cancer : urinary cancer (REVIEW).2006

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      International Journal of Clinical Oncology 11(2)

      Pages: 90-107

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Fibroblast growth factor-2 induces the activation of Src through Fes, which regulates focal adhesion disassembly.2006

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Experimental Cell Research. 312(16)

      Pages: 3015-22

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Current status and perspective of antiangiogenic therapy for cancer : urinary cancer (REVIEW).2006

    • Author(s)
      Shigeru Kanda et al.
    • Journal Title

      International Journal of Clinical Oncology. 11(2)

      Pages: 90-107

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] T-cell factor-4-dependent up-regulation of fibronectin is involved in fibroblast growth factor-2-induced tube formation by endothelial cells.2005

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Journal of Cellular Biochemistry 94(4)

      Pages: 835-847

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Pigment epithelium-derived factor inhibits fibroblast growth factor-2-induced capillary morphogenesis of endothelial cells through c-Fyn.2005

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Journal of Cell Science 118(Pt 5)

      Pages: 961-970

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Aniopoietin 1 is mitogenic for cultured endothelial cells.2005

    • Author(s)
      Shigeru Kanda, et al.
    • Journal Title

      Cancer Research 65(15)

      Pages: 6820-6827

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Studies of the endothelial cell-specific signal transduction pathways. New paradigm for the development of potent anti-angiogenic therapies.2005

    • Author(s)
      Shigeru Kanda et al.
    • Journal Title

      Trends in Angiogenesis Research. (New York : Nova Science Publishers, Inc)

      Pages: 43-69

    • Description
      「研究成果報告書概要(欧文)」より
  • [Book] Trends in Angiogenesis Research2005

    • Author(s)
      Shigeru Kanda, et al.
    • Total Pages
      254
    • Publisher
      Nova Science Publishers, Inc; New York
    • Description
      「研究成果報告書概要(和文)」より

URL: 

Published: 2008-05-27  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi