Tumor-associated macrophages promote malignant progression of breast phyllodes tumors by inducing myofibroblast differentiation

Myofibroblast differentiation plays an important role in the malignant progression of phyllodes tumor (PT), 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 PT progression. Here we show that increased density of tumor associated macrophage (TAM) correlates with malignant progression of PT. We found that TAM stimulated myofibroblast differentiation and promoted the proliferation and invasion of PT cells. Furthermore, we found that levels of the chemokine CCL18 in TAM was an independent prognostic factor of PT. Mechanistic investigations showed that CCL18 promoted expression of α-smooth muscle actin, a hallmark of myofibroblast, along with the proliferation and invasion of PT cells, and that CCL18-driven myofibroblast differentiation was mediated by an NF-κB/miR-21/PTEN/AKT signaling axis. In murine xenograft models of human PT, CCL18 accelerated tumor growth, induced myofibroblast differentiation and promoted metastasis. Taken together, our findings indicated that TAM drives myofibroblast differentiation and malignant progression of PT through a CCL18-driven signaling cascade amenable to antibody disruption.

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