Abstract
Purpose: 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.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 bladder cancer cell lines and peripheral blood monocyte-derived macrophages.Results: We observed BMP4 expression is associated and favored type II macrophage differentiation. In vitro 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 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 bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of BMPR2 by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth. Clin Cancer Res; 23(23); 7388-99. ©2017 AACR.
Highlights
Bladder cancer is an important health problem, causing approximately 150,000 deaths worldwide [1]
In vitro 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
The p-Smad 1,5,8 staining in tumors showing epithelial–mesenchymal transition (EMT) signs was reduced, due to the increased miR21 expression leading to reduced BMPR2 expression
Summary
Bladder cancer is an important health problem, causing approximately 150,000 deaths worldwide [1]. This generates multiple immune reactions that diminish the recurrence and progression rate of responder patients This reduction is accomplished, in part, through the generation of an antitumor stroma, mediated by various immune cells and soluble factors [7]. One of these responses consists of BCG-induced macrophage cytotoxicity toward bladder cancer cells mediated by both cell contact and soluble factors, including IL6, IL12, and TNFa [8]. The anti-inflammatory or M2 phenotype in TAMs is normally associated with a poor response to BCG [10, 11] These M2-like TAMs favor tumor growth and angiogenesis, suppress adaptive immunity, and promote tumor cell migration, invasion, and metastasis [12]. The understanding of how macrophage polarization is regulated in bladder cancer is of great importance for the development of novel therapies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
