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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
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsAntiangiogenic therapy / Molecular targeting therapy / endothelial cells / Src / Fes / HGF / angiopoietin 1 / hypoxia / angiopoietin 1 / 血管新生 / FGF-2 / 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.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (23 results)

All 2007 2006 2005

All Journal Article (21 results) Book (2 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

    • NAID

      120006983943

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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

    • NAID

      120006983943

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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)
      Kanda S, Kanetake H, Miyata Y.
    • Journal Title

      Cellular Signaling 19(3)

      Pages: 472-80

    • NAID

      120006983943

    • Related Report
      2006 Annual Research Report
  • [Journal Article] シグナル伝達分子に対する分子標的療法の現況と将来の展望2007

    • Author(s)
      神田 滋, 正野武文, 宮田康好, 金武洋
    • Journal Title

      西日本泌尿器科 69(3)(印刷中)

    • Related Report
      2006 Annual Research Report
  • [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

    • NAID

      120006983940

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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

    • NAID

      120006983941

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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

    • NAID

      120006983942

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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

    • NAID

      120006983942

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

    • Author(s)
      Kanda S, Kanetake H, Miyata Y.
    • Journal Title

      Biochemical and Biophysical Research Communications 344(2)

      Pages: 617-22

    • Related Report
      2006 Annual Research Report
  • [Journal Article] levated expression of ERK 2 in human tumor cells chronically treated with PD98059.2006

    • Author(s)
      Kanda S, Kanetake H, Miyata Y.
    • Journal Title

      Biochemical and Biophysical Research Communications 345(4)

      Pages: 1481-6

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Fibroblast growth factor-2 induces the activation of Src through Fes, which regulates focal adhesion disassembly.2006

    • Author(s)
      Kanda S, Miyata Y, Kanetake H, Smithgall TE.
    • Journal Title

      Experimental Cell Research 312(16)

      Pages: 3015-22

    • NAID

      120006983942

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Current status and perspective of antiangiogenic therapy for cancer : urinary cancer.2006

    • Author(s)
      Kanda S, Miyata Y, Kanetake H.
    • Journal Title

      International Journal of Clinical Oncology 11(2)

      Pages: 90-107

    • NAID

      10018174756

    • Related Report
      2006 Annual Research Report
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [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

      Pages: 835-847

    • Related Report
      2005 Annual Research Report
  • [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

      Pages: 961-970

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Aniopoietin 1 is mitogenic for cultured endothelial cells.2005

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

      Cancer Research 65

      Pages: 6820-6827

    • Related Report
      2005 Annual Research Report
  • [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
    • Related Report
      2006 Final Research Report Summary
  • [Book] Trends in Angiogenesis Research.2005

    • Author(s)
      Kanda, S., Miyata, Y., Kanetake, H.
    • Publisher
      Studies of the endothelial cell-specific signal transduction pathways. New paradigm for the development of potent anti-angiogenic therapies.
    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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