| Project/Area Number |
17390371
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
TANAKA Shinji Tokyo Medical and Dental University, Information Center for Medical Sciences, Associate Professor (Specially Appointed), 情報処理センター, 特任助教授 (30253420)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMADA Mitsuo The University of Tokushima Graduate School, Institute of Health Biosciences, Professor, 大学院ヘルスバイオサイエンス研究部, 教授 (10216070)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥14,900,000 (Direct Cost: ¥14,900,000)
Fiscal Year 2006: ¥7,200,000 (Direct Cost: ¥7,200,000)
Fiscal Year 2005: ¥7,700,000 (Direct Cost: ¥7,700,000)
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| Keywords | angiogenesis / CCN family / TGF-beta / Angiopoietin / Tie2 / prostaglandin E2 / tumor-associated monocytes / Grb7 / CCN / 低酸素 / HIF-1 alpha / 炎症性サイトカイン |
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| Research Abstract |
In vivo progression to malignancy is characterized by the switch to an angiogenic phenotype. The angiogenic switch is a critical control point for tumor expansion. The ability of a tumor to become neovascularized permits rapid expansion of tumor growth and increases the likelihood of metastases. The genetic alterations which accompany the switch to the angiogenic phenotype are unknown. Discoveries of such genes lead to comprehension of molecular mechanisms of the tumor progression, as well as development of novel therapeutic tools. We have isolated a novel "angiogenic switch molecule", Angiopoietin-2, upregulated specifically in hypervascular hepatocellular carcinoma (HCC). Angiopoietin family proteins have been originally identified to be ligands of vascular endothelial receptor of tyrosine kinase Tie2. Ectopic expression of Angiopoietin-2 promotes the rapid development of human HCCs and produces hemorrhage within tumors in nude mice. These results suggest a role for Angiopoietin-2 in
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the neovascularization of HCC. In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Angiopoietin protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells. Tumorigenicity with angiogenesis was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for Angiopoietin/Tie2 signaling in the induction of HCC neovascularization, and disease progression. More important, inhibition of the Angiopoietin/Tie2 signal transduction cascade is a promising approach for HCC treatment. We identified a novel targeting peptide to inhibit signal transduction from Tie2 via Grb7 adaptor protein. Interestingly, Tie2 protein was expressed not only in tumor vessels but also in tumor-associated monocytes. In addition, a new CCN family molecule that regulated TGF-beta angiogenic signaling was identified. The further development of novel antiangiogenic drugs could be a promising approach for the treatment of tumor angiogenesis. Less
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