Abstract
<div>Abstract<p><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.</p><p><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.</p><p><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.</p><p><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>.</p></div>
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