Purpose: Bladder cancer (BC) is a current clinical and social problem. At diagnosis, most patients present non-muscle 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 BC is still unclear. Experimental Design: 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 in vitro by experiments with BC cell lines and peripheral blood monocyte-derived macrophages. Results: We observed BMP4 expression is associated and favored type-2 macrophage differentiation. In vitro experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from BC cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL-10. Using a series of human BC patient samples we also observed increased expression of BMP4 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 BMPR2 expression. Conclusions: These findings suggest that BMP4 secretion by BC cells provides the M2 signal necessary for a pro-tumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the pro-differentiating actions mediated by BMP ligands, favoring tumor growth.
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