Tumor-Associated Macrophages Promote Malignant Progression of Breast Phyllodes Tumors by Inducing Myofibroblast Differentiation
Tumor-Associated Macrophages Promote Malignant Progression of Breast Phyllodes Tumors by Inducing Myofibroblast Differentiation
复制标题
肿瘤相关巨噬细胞通过诱导肌成纤维细胞分化促进乳腺叶状肿瘤的恶性进展
DOI：
10.1158/0008-5472.can-16-2709
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发表时间：
2017-07-01
期刊：
影响因子：
11.2
通讯作者：
Song, Erwei
中科院分区：
文献类型：
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作者：
Nie, Yan;Chen, Jianing;Song, Erwei
肌成纤维细胞分化在叶状肿瘤的恶性进展中起着重要作用，叶状肿瘤是一种快速生长的肿瘤，来源于乳腺导管周围基质细胞。巨噬细胞经常与肌成纤维细胞密切相关，但不确定它们是否参与叶状肿瘤进展期间的肌成纤维细胞分化。我们发现肿瘤相关巨噬细胞（TAM）密度的增加与叶状肿瘤的恶性进展相关。我们发现TAMs刺激肌成纤维细胞分化，促进叶状肿瘤细胞的增殖和侵袭。此外，我们发现TAM中趋化因子CCL 18的水平是叶状肿瘤的独立预后因素。机制研究表明，CCL 18促进α-平滑肌肌动蛋白的表达，这是肌成纤维细胞的标志，沿着叶状肿瘤细胞的增殖和侵袭，并且CCL 18驱动的肌成纤维细胞分化由NF-κ B/miR-21/PTEN/AKT信号轴介导。在人类叶状肿瘤的小鼠异种移植模型中，CCL 18加速肿瘤生长，诱导肌成纤维细胞分化，并促进转移。综上所述，我们的研究结果表明，TAM驱动肌成纤维细胞分化和叶状肿瘤的恶性进展，通过CCL 18驱动的信号级联服从抗体破坏。
Myofibroblast differentiation plays an important role in the malignant progression of phyllodes tumor, a fast-growing neoplasm derived from periductal stromal cells of the breast. Macrophages are frequently found in close proximity with myofibroblasts, but it is uncertain whether they are involved in the myofibroblast differentiation during phyllodes tumor progression. Here we show that increased density of tumor-associated macrophage (TAM) correlates with malignant progression of phyllodes tumor. We found that TAMs stimulated myofibroblast differentiation and promoted the proliferation and invasion of phyllodes tumor cells. Furthermore, we found that levels of the chemokine CCL18 in TAM was an independent prognostic factor of phyllodes tumor. Mechanistic investigations showed that CCL18 promoted expression of alpha-smooth muscle actin, a hallmark of myofibroblast, along with the proliferation and invasion of phyllodes tumor cells, and that CCL18-driven myofibroblast differentiation was mediated by an NF-kappa B/miR-21/PTEN/AKT signaling axis. In murine xenograft models of human phyllodes tumor, CCL18 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. Taken together, our findings indicated that TAM drives myofibroblast differentiation and malignant progression of phyllodes tumor through a CCL18driven signaling cascade amenable to antibody disruption.