| Project/Area Number |
15591026
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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 |
Hematology
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| Research Institution | The University of Tokyo (2004)
Juntendo University (2003) |
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Principal Investigator |
HATTORI Koichi The University of Tokyo, Institute of Medical Science, Project Associate Professor, 医科学研究所, 産学官連携研究員(特任助教授) (10360116)
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| Co-Investigator(Kenkyū-buntansha) |
HEISSIG BEATE 順天堂大学, 医学部, 講師
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | thrombopoiesis / megakaryocyte diffentiation / angiogenesis / thrombopoietin / matrix metalloproteinase-9 / cell mobilization / adhesion molecule / chemokine / Kit-ligand / 血管内皮細胞 / stromal cell-derived factor-1 |
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| Research Abstract |
We reported previously, that cytokines including chemokines or biological stressors like irradiation can promotes the processing of Kit ligand through activation of matrix metalloproteinase-9, mobilization and differentiation of hematopoietic progenitor cells including megakaryocytes. To understand the involvement of platelets in supporting tumor growth we first examined how these cells ncrease under the influence of megakaryocytic-active chemokines such as stromal-cell derived factor-1 (SDF-1). In 2004, we published that chemokine-mediated interactions of megakaryocyte progenitors with bone marrow (BM) endothelial cells promote TPO-independent platelet production. We reported that megakaryocyte-active chemokines, including SDF-1 and fibroblast growth factor-4 (FGF-4), restored thrombopoiesis in TPO-/-mice. FGF-4 and SDF-1 enhanced adhesion molecule-mediated localization of CXCR4+ megakaryocyte progenitors to endothelium, promoting maturation and platelet release. Disruption of BM micr
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oenvironmental "vascular niche" or interference with megakaryocyte motility inhibited thrombopoiesis under physiological conditions. SDF-1 and FGF-4 diminished thrombocytopenia after myelosuppression. These data suggested that TPO supports progenitor cell expansion, whereas chemokine-mediated interaction of progenitors with the BM vascular niche allows progenitors to relocate to a microenvironment that is instructive for megakaryocyte maturation and platelet production. Progenitor-active chemokines offer a new strategy to restore hematopoiesis in a clinical setting.
Others and we have shown that BM-derived hematopoietic cells contribute to tumor angiogenesis and growth. As VEGF-activated platelets release angiogenic factors we hypothesized that thrombopoiesis promotes tumor angiogenesis and growth. We demonstrated that thrombocytes are essential for tumor angiogenesis and growth as tumor growth and angiogenesis was profoundly impaired in thrombocytopoietic mice (TPO-/-and TPO receptor-/-). We now have data showing that neo-angiogenesis is impaired in TPO mice resulting in the formation of defective, disorganized leaky vessels. Our data not only identify a novel mechanism how platelets promote tumor growth, but more importantly challenge the use of non-essential platelet transfusion in cancer patients as transfused platelet might promote tumor growth. Less
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