文章：

血浆纤维连接蛋白通过整合素β3–Tie2轴驱动血凝块中巨噬细胞的伸长

Plasma Fibronectin Drives Macrophage Elongation via Integrin β3–Tie2 Axis in Blood Clots

原文发布日期：26 November 2025

DOI: 10.3390/cancers17233780

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:Plasma fibronectin (pFN) supports lung metastasis by promoting tumor cell invasion and survival in the context of blood clotting. Here, we set out to test if myeloid cells reiterate the clot-invasive mechanisms that have been established for tumor cells.Methods:We analyzed lung tissue sections from transgenic pFN-deficient mice for the co-localization of intravenously injected B16F1 tumor cells and the surrounding fibrin with myeloid cells, granulocytes, and macrophages. We also tested the role of pFN for macrophage differentiation and invasion in a three-dimensional fibrin matrix.Results:B16F1 melanoma cells, entrapped in the lungs of pFN-competent C57BL/6-Fn(fl/fl)Mx-Cre−mice, were surrounded by a fibrin matrix, CD11b-positive myeloid cells, and Gr-1-positive granulocytes within 1 h of intravenous injection, while homing F4/80-positive macrophages to lung-born tumor cells occurred within 16 h. Compared to pFN-competent C57BL/6-Fn(fl/fl)Mx-Cre−mice, the co-localization of CD11b+, Gr-1+, and F4/80+cells with B16F1 cells was significantly reduced in the lungs of pFN-deficient C57BL/6-Fn(fl/fl)Mx-Cre−mice. Mechanistically, we found that fibrin–fibronectin complexes promoted macrophage adhesion, differentiation, and invasion in clotted plasma. The pro-invasive function of fibrin–fibronectin depended on the upregulation of integrin β3 and Tie2 expression in macrophages and was reversed after knocking-down integrin β3 and Tie2 with siRNA.Conclusions:Our results suggest that blood clotting plays an important role in the recruitment of macrophages to circulating tumor cells and that the underlying mechanism of macrophage recruitment involves fibrin–fibronectin complexes, integrin β3, and Tie2.

摘要翻译： 

背景/目的：血浆纤维连接蛋白(pFN)通过促进肿瘤细胞在凝血环境中的侵袭和存活来支持肺转移。本研究旨在验证髓系细胞是否重现了肿瘤细胞已确立的凝血侵袭机制。 方法：我们通过分析转基因pFN缺陷小鼠的肺组织切片，观察静脉注射的B16F1肿瘤细胞及其周围纤维蛋白与髓系细胞、粒细胞和巨噬细胞的共定位情况。同时利用三维纤维蛋白基质模型检测pFN对巨噬细胞分化和侵袭的作用。 结果：在pFN功能正常的C57BL/6-Fn(fl/fl)Mx-Cre−小鼠肺内，静脉注射1小时内即可观察到被捕获的B16F1黑色素瘤细胞周围形成纤维蛋白基质，并聚集CD11b阳性髓系细胞和Gr-1阳性粒细胞；而F4/80阳性巨噬细胞在16小时内向肺内肿瘤细胞归巢。与pFN功能正常小鼠相比，pFN缺陷型C57BL/6-Fn(fl/fl)Mx-Cre−小鼠肺内CD11b+、Gr-1+和F4/80+细胞与B16F1细胞的共定位显著减少。机制研究表明，纤维蛋白-纤维连接蛋白复合物能促进巨噬细胞在凝固血浆中的黏附、分化和侵袭。这种促侵袭功能依赖于巨噬细胞整合素β3和Tie2表达的上调，并通过siRNA敲低整合素β3和Tie2实现功能逆转。 结论：研究结果表明凝血过程在巨噬细胞向循环肿瘤细胞的募集过程中发挥重要作用，其机制涉及纤维蛋白-纤维连接蛋白复合物、整合素β3和Tie2的协同作用。

原文链接：

Plasma Fibronectin Drives Macrophage Elongation via Integrin β3–Tie2 Axis in Blood Clots