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.
| Project/Area Number |
17591686
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Nagasaki University |
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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)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Antiangiogenic therapy / Molecular targeting therapy / endothelial cells / Src / Fes / HGF / angiopoietin 1 / hypoxia |
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| 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.
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