2006 Fiscal Year Final Research Report Summary
Roles of humoral and neural factors in angiogenesis and lymphangiogenesis in pathological conditions and their significance in molecular targeting therapy
| Project/Area Number |
15390084
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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 |
General pharmacology
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| Research Institution | KITASATO UNIVERSITY |
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Principal Investigator |
MAJIMA Masataka Kitasato university, School of Medicine, Professor, 医学部, 教授 (70181641)
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| Co-Investigator(Kenkyū-buntansha) |
FUJITA Tomoe Kitasato university, School of Medicine, Assistant Professor, 医学部, 講師 (20296510)
KAWAMURA Michiko Kitasato university, School of Medicine, Research Associate, 医学部, 助手 (00154104)
HATANAKA Koh Kitasato university, School of Medicine, Research Associate, 医学部, 助手 (00228470)
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| Project Period (FY) |
2003 – 2006
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| Keywords | angiogenesis / lymphangiogenesis / cancer / chronic inflammation / prostaglandins / angiotensin / receptor signaling / neuropeptide |
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| Research Abstract |
Angiogenesis is also a critical step for development and metastasis of cancers. Proinflammatory mediators, such as PGs may have cell-autonomous effects on tumor cells in autocrine fashion, however, our results from tumor implantation models in knockout mice which lack the host receptor signaling clarified that host stromal signaling of a PGE_2 receptor, EP3 has a crucial role in tumor-associated angiogenesis through the induction of proaniogenic growth factors, and exhibited the landscaping effects on tumor cells. An EP3 antagonist inhibited tumor-associated angiogenesis in wild type mice, but not in EP3 knockout mice, suggesting that host EP3 receptor signaling is important in prevention of tumor-associated angiogenesis. Further, bone marrow transplantation experiment revealed that recruitment of bone marrow cells which express EP3 receptor is critical for angiogenesis in vivo. Relevant PGE2 is generated through the actions of COX-2 and an inducible PGE synthase, mPGES-1. Impressive p
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henotypes of mPGES-1 knockout mice implanted with tumor cells are reduced tumor growth and angiogenesis. Tumor-associated lymphangiogenesis was also suppressed with a COX-2 inhibitor. Thus, control of EP receptor signaling as well as recruitment of EP receptor expressing cells in the tumor microenvironment is likely to be a novel therapeutic approach against malignant solid tumors.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral nervous systems and exhibits numerous biological activities in mammals. Tumor growth was significantly reduced in the sites of sensory nerve denervation. When a CGRP antagonist, CGRP8-37 was given, tumor growth was suppressed compared with vehicle infusion. In CGRP knockout mice, the tumor growth and tumor-associated angiogenesis were significantly reduced compared with wild type mice. In LLC bearing wild type mice, CGRP precursor mRNA levels in dorsal root ganglion were increased compared with non-treated mice. This increase was abolished by sensory nerve denervations. Further, we found that ulcer healing was significantly delayed in CGRP knockout mice with reductions in angiogenesis and VEGF expression. In co-culture system using HUVEC and fiboblasts, CGRP increased tube formation of endothelial cells. These results suggested that CGRP release from sensory nerves stimulated during tumor development and ulcer healing facilitates angiogenesis, and that CGRP may become a target of new treatment for cancers or gastrointestinal mucosal injury. Less
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[Journal Article] Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.2004
Author(s)
Kobayashi T, Tahara Y, Matsumoto M, Iguchi M, ano H, Murama T, Arai H, Qida H, Yurugi-Kobayashi T, Yamashita JK, Katagiri H, ajima M, Yokode M, Kita T, Narumiya S
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Journal Title
J Clin Invest 114(6)
Pages: 784-794
Description
「研究成果報告書概要(和文)」より
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[Journal Article] Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice.2004
Author(s)
Kobayashi T, Tahara Y, Matsumoto M, Iguchi M, Sano H, Murayama T, Arai H, Oida H, Yurugi-Kobayashi T, Yamashita JK, Katagiri H, Majima M, Yokode M, Kita T, Narumiya S.
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Journal Title
J Clin Invest. 114(6)
Pages: 784-794
Description
「研究成果報告書概要(欧文)」より
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