2022 Fiscal Year Final Research Report
Contribution of platelet-activating receptor CLEC-2 in the pathogenesis of cancer-associated thrombosis.
| Project/Area Number |
20K17374
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Yamanashi |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 血小板 / CLEC-2 / 癌関連血栓症 |
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| Outline of Final Research Achievements |
Three cancer cell lines (LLC, Pan02, MC-38) were transplanted into mice. Immunohistological analysis revealed abundant podoplanin-positive cancer-associated fibroblasts (CAFs) in tumors. Extracellular vesicles (EVs) isolated from cultured CAFs from LLC tumors revealed the presence of podoplanin in the EVs and that CAF-EVs activate platelets in a CLEC-2-dependent manner.
Plasma podoplanin levels were elevated in LLC-bearing mice. In a model of femoral vein thrombosis induced by ferric chloride injury, CAF-EVs administration and LLC tumorigenesis shortened the vascular occlusion time. Antibody-induced CLEC-2 depletion inhibited the exacerbating effects of CAF-EVs and tumor in venous thrombosis.
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| Free Research Field |
血栓止血学
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| Academic Significance and Societal Importance of the Research Achievements |
CLEC-2は血小板・巨核球にほぼ特異的に発現している。そのリガンドのポドプラニンは正常状態では血管内に存在しない。したがって、CLEC-2の止血機能への寄与は非常に小さく、実際にCLEC-2欠損マウスは出血傾向を示さない。しかし腫瘍が形成されると、癌細胞やCAFsからポドプラニンが発現し、細胞間相互作用あるいはEVsによってCLEC-2依存的な血小板活性化を惹起する。すなわち、ポドプラニン/CLEC-2はCAT特異的な血栓形成機序である。すなわち、抗CLEC-2療法は、従来の抗血小板薬よりも安全に使用できる抗CAT戦略と考えられる。
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