American Association for Cancer Research
10780432ccr171004-sup-181622_3_supp_4242141_5vhsp8.pdf (1.21 MB)

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

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posted on 2023-03-31, 20:00 authored by Víctor G. Martínez, Carolina Rubio, Mónica Martínez-Fernández, Cristina Segovia, Fernando López-Calderón, Marina I. Garín, Alicia Teijeira, Ester Munera-Maravilla, Alberto Varas, Rosa Sacedón, Félix Guerrero, Felipe Villacampa, Federico de la Rosa, Daniel Castellano, Eduardo López-Collazo, Jesús M. Paramio, Ángeles Vicente, Marta Dueñas

Supplementary Table 1. Bladder Cancer cell lines. Supplementary Table 2. Primers and TaqMan probes used for qPCR. Supplementary Figure 1.Characterization of monocyte/macrophage polarization. Supplementary Figure 2. Resistance of BCCs to monocyte-induced apoptosis Supplementary Figure 3. Macrophage marker evaluation toward tumorigenesis and recurrence Supplementary Figure 4. Analyses of different factors that may influence time to recurrence Supplementary Figure 5.CD 163 expression in Tissue microarrays. Representative positive (A) and negative (B) tumors are shown. Supplementary Figure 6.BMP4 expression on NMIBC and MIBC


Fondo Europeo de Desarrollo Regional

Comunidad Autónoma de Madrid




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.