2007 Fiscal Year Final Research Report Summary
Endostatin contributes to low-dose paclitaxel-mediated tumor growth and angiogenesis suppression
| Project/Area Number |
18590364
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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 |
Experimental pathology
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| Research Institution | Chiba University |
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Principal Investigator |
HAMANO Yuki Chiba University, University Hospital, Assistant Professor (90396680)
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| Co-Investigator(Kenkyū-buntansha) |
MIKI Yoshio Tokyo Medical and Dental University, Medical Research Institute, Professor (10281594)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Endostatin / Low-dose chemotherapy / HIF-1α / Paclitaxel / Metastatic tumor / Endogenous angiogenesis inhibitor / Angiogenesis |
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| Research Abstract |
Progression of cancer is dependent on angiogenesis. Anti-angiogenic (metronomic or low-dose) chemotherapy is a strategy for optimizing the effects of chemotherapeutics by administrating traditional cytotoxic drugs at lower concentrations without a rest period. We and others have shown that an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis in the tumor microenvironment. Here, we investigate whether endogenous endostatin serves as an angiogenic inhibitor in low-dose chemotherapy. Low-dose paclitaxel treatment predominantly induced the expression of endostatin in Lewis lung carcinoma cells (LLC), but not in B16F10 melanoma cells (B16F10), endothelial cells or fibroblasts. Low-dose paclitaxel treatment also upregulated the production of endostatin in the circulation of LLC-bearing mice and further reduced the mean tumor volume and blood vessel density. In contrast, sFlt-l, TSP-1 and tumstatin were not affected in the same setting. Lack of endostatin in mice led to the diminished capacity of low-dose paclitaxel to suppress tumor growth. In addition, hypoxia blocked the paclitaxel-mediated upregulation of endostatin while the disruption of HIF-1α significantly increased the expression of endostatin, suggesting that the production of endogenous endostatin is controlled by HIF-1α in the tumor cells. Theses studies demonstrate that endostatin is a key mediator of anti-angiogenic effects observed with low-dose paclitaxel treatment.
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Research Products
(2 results)
