BMP4 Induces M2 Macrophage Polarization and Favors Tumor Progression in Bladder Cancer

Abstract

<b>Purpose:</b> Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.<b>Experimental Design:</b> Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed <i>in vitro</i> by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages.<b>Results:</b> We observed <i>BMP4</i> expression is associated and favored type II macrophage differentiation. <i>In vitro</i> experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of <i>BMP4</i> in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced <i>BMPR2</i> expression.<b>Conclusions:</b> These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of <i>BMPR2</i> by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth. <i>Clin Cancer Res; 23(23); 7388-99. ©2017 AACR</i>.