| 研究領域 | がん微小環境ネットワークの統合的研究 |
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| 研究課題/領域番号 |
22112007
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| 研究機関 | 東京大学 |
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研究代表者 |
HEISSIG Beate 東京大学, 医科学研究所, 准教授 (30372931)
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| 研究期間 (年度) |
2010-06-23 – 2015-03-31
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| キーワード | がん / 酵素 / 細胞・組織 / 発生・分化 / 生体・分子 |
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| 研究概要 |
Extracellular matrix breakdown accomplished by e.g. the serine protease plasmin is crucial for cancer metastasis. We had demonstrated that the fibrinolytic pathway regulates myeloid cell influx necessary for lymphoma growth (Ishihara et al. Leukemia 2011). In 2013, we were able to demonstrate that BM-derived CD11b+Jagged2+ cells regulate the epithelial-to-mesenchymal transition (EMT) (Caidado et al. Cancer Res. 2013). As the EMT is a process by which epithelial cells lose their cell polarity and cell-cell adhesion, and gain migratory and invasive properties to become mesenchymal stem cells, this process has very important implications for the initiation of metastasis for cancer progression. We propose that blockade of myeloid cell influx can prevent EMT and reduce tumor metastasis. In addition, we were able to show that the fibrinolytic system controls the myeloid cell-mediated cytokine storm in leukemic patients undergoing bone marrow transplantation (Sato et al. Leukemia, 2014 accepted). The clinical implications of this study are numerous: Tumor associated inflammatory cells as part of the microenvironment are known to control the tumor growth. Therefore,controlling the inflammatory response by modulating the tumor microenvironment with the use of plasmin inhibitors is a novel therapeutic concept for cancer treatment. In addition, we generated data implying that the fibrinolytic pathway can regulate colitis progression, a disease known to be precancerous (Munakata et al. Gastroenterology, in Revision).
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
Last year we studied inflammatory cells as part of the microenvironment. We were able to show that the influx of inflammatory cells within cancer or inflammatory tissues is regulated by the fibrinolytic system, and that the use of plasmin inhibitors or genetic deficiency in plm prevented the influx of inflammatory cells. But not only their migratory ability was altered, we were able to show that plasmin by activating e.g. the NFkb pathway can directly modulate the gene expression of various proinflammatory cytokines, which are known to be involved in tumor growth progression. We also established that important chemokines released form endothelial cells, like MCP-1, can be activated by plasmin, and that the use of a plasmin inhibitor in vitro and in vivo prevented the migration of CCR2+ cells. CCR2+ monocytes/macrophages are known to play a pivotal role in the tumor progression and metastasis of solid cancers like breast cancer. Therefore, our data have important clinical relevance for the treatment of MCP-1 associated diseases, but also non-cancerous disease like adipositas. Controlling monocyte influx into cancer tissues by indirectly blocking plasmin might be a novel therapeutic strategy to modulate tumor growth progression.
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| 今後の研究の推進方策 |
We have established that plasmin is required for myeloid cell and hematopoietic progenitor expansion in the bone marrow and results in the release of myeloid cells into circulation (Heissig et al. Cell Stem Cell 2007). Following up on these observations, we currently study whether plm activation can expand mesenchymal stem cells in the bone marrow/within the tumor, thereby promoting/altering tumor growth. We will use rec. tissue type plasminogen activator or urokinase to show that MSC expansion occurs after plasmin activation. Then we will determine whether pharmacological and genetic plasmin/plasminogen deficiency prevents MSC expansion within tumor tissues or the bone marrow. We also will test whether the proteolytic activity of the tested plasminogen activators is required for the MSC expansion process. Then we will determine whether MSC-prone tumors like melanoma cells use a plm-driven mechanism to recruit MSC/or expand MSCs within the tumor tissues. MSCs have been shown to promote neoangiogenesis. Therefore, we will study the role of PAs/PAI-1 secreting niche cells (e.g. MSCs) for the recruit myeloid cells and the induction of angiogenesis. We will determine the role of fibrinolytic factor expressing cancer-associated fibroblasts (CAFs) or mesenchymal stem cells (MSCs) for tumor growth and neoangiogenesis. We also will examine whether chemotherapy can induces fibrinolytic factor expression in microenvironmental cells including fibroblasts, MSCs or myeloid or endothelial cells thereby accelerating their angiogenic potential.
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