| Project/Area Number |
17K11149
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
舛森 直哉 札幌医科大学, 医学部, 教授 (20295356)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 前立腺癌 / がん微小環境 / 間質細胞 / 癌関連線維芽細胞 / 肥満細胞 / 細胞外基質 / 去勢抵抗性 / 癌微小環境 |
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| Outline of Final Research Achievements |
To elucidate the tumor microenvironment in prostate cancer for therapy development, we investigated the interaction between cancer-associated fibroblasts, the autogenous extracellular matrix (ECM) they deposit, and mast cells. Patient-derived CAFs induced by estrogen recruited mast cells via chemokine CXCL12 in a CXCR4-dependent manner. CAFs were cultured in three-dimensional melt electrowritten scaffolds where they deposited extensive ECM and promoted significant changes in prostate epithelial morphology, when compared to matched normal prostatic fibroblasts (NPFs).
We demonstrated that mast cell-derived tryptase potentiates CAF-induced morphology changes in adjacent prostate epithelia indirectly via the stromal microenvironment and provides novel insight into the discrete stromal-epithelial interactions. These results suggest that tryptase as an important mediator of these effects, which may be a novel therapeutic target to show or halt prostate tumorigenesis.
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| Academic Significance and Societal Importance of the Research Achievements |
前立腺摘除術検体からCAFとNPFを分離樹立し、pairで使用することによりCAFとNPFの差として得られる結果の意義は大きいと考える。前立腺がん微小環境においてCAFと上皮細胞だけでなく肥満細胞を通じたECMのリモデリングの重要性が明らかとなった。CAFからCXCL12の分泌、肥満細胞の遊走促進、トリプターゼによる細胞外基質の変化が、より一層上皮細胞の形態変化を惹起し、浸潤能の亢進につながる可能性が示唆された。前立腺間質の一連のチェーンを制御することにより去勢抵抗性前立腺がんの革新的な治療法の開発につながることが期待される。
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