期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 21, 期 11, 页码 3153-3165出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jtha.2023.07.005
关键词
cancer-associated fibroblasts; cancer-associated thrombosis; CLEC-2; platelets; podoplanin
This study reveals that cancer-associated fibroblasts (CAFs) and their released extracellular vesicles (EVs) can induce CLEC-2-dependent platelet aggregation, exacerbating venous thrombosis.
Background: Cancer-associated thrombosis (CAT) is the leading cause of morbidity and mortality. Cancer-associated fibroblasts (CAFs) are a prominent component of the tumor microenvironment that contributes to cancer progression through direct cell- cell interactions and the release of extracellular vesicles (EVs). However, the role of CAFs in CAT remains unclear.Objective: This study aims to investigate whether CAFs aggravate CAT and the underlying molecular mechanism using a preclinical mouse lung cancer model. Methods: We designed a Lewis lung carcinoma (LLC) tumor-bearing mouse model. CAFs were characterized using fluorescence immunohistostaining. The presence of podoplanin, a platelet-activating membrane protein through C-type lectin-like receptor 2 (CLEC-2), in EVs isolated from primary CAFs or LLC tumor tissues was assessed by immunoblotting. The platelet activation and aggregation abilities of the EVs were quantified using flow cytometry. Podoplanin plasma levels were measured by enzyme-linked immunosorbent assay. Venous thrombosis was induced in the femoral vein using 2.5% ferric chloride. The anti-CLEC-2 monoclonal antibody 2A2B10 was used to deplete CLEC-2 on the surface of the platelets.Results: CAFs expressing CD90, PDGFR beta, HSP47, CD34, and vimentin, co-expressed podoplanin and induced platelet activation and aggregation in a CLEC-2-dependent manner. Tumor-bearing mice showed elevated podoplanin plasma levels. CAF-EV injec-tion and tumor-bearing mice showed shorter occlusion time in the venous thrombosis model. Although tumor growth was not altered, antibody-induced CLEC-2 depletion suppressed venous thrombosis in the tumor-bearing state but not in the healthy condition. Conclusion: CAFs and CAF-derived EVs induce CLEC-2-dependent platelet aggregation and aggravate venous thrombosis.
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