Department of Cell Biology, Faculty of Medicine, Complutense University, Madrid, Spain.
Molecular Oncology Unit, CIEMAT-and 12 de Octubre University Hospital, Madrid, Spain.
Clin Cancer Res. 2017 Dec 1;23(23):7388-7399. doi: 10.1158/1078-0432.CCR-17-1004. Epub 2017 Sep 19.
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. 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 by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages. We observed expression is associated and favored type II macrophage differentiation. 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 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 expression. 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 by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth. .
膀胱癌是当前的临床和社会问题。在诊断时，大多数患者表现为非肌肉浸润性肿瘤，其特点是复发率高，可能进展为肌肉浸润性疾病和转移。来自膀胱组织基质的骨形态发生蛋白（BMP）依赖性信号通过促进尿路上皮细胞分化来介导尿路上皮稳态。然而，BMP 配体在膀胱癌中的可能作用仍不清楚。前瞻性收集了 68 例尿路上皮癌患者的肿瘤和正常组织，并分析了 BMP 和巨噬细胞标志物的表达。通过膀胱癌细胞系和外周血单核细胞衍生的巨噬细胞实验评估了作用机制。我们观察到 BMP4 的表达与肿瘤进展和 EMT 标志物呈正相关，并有利于 II 型巨噬细胞分化。实验表明，重组 BMP4 和膀胱癌细胞系的含 BMP4 条件培养基均有利于单核细胞/巨噬细胞向 M2 表型巨噬细胞极化，表现为 IL10 的表达和分泌。使用一系列人类膀胱癌患者样本，我们还观察到在与上皮间质转化（EMT）密切相关的高级和未分化肿瘤中， 表达增加。然而，在显示 EMT 迹象的肿瘤中，p-Smad1、5、8 染色减少，这是由于 miR-21 表达增加导致 表达减少所致。这些发现表明，膀胱癌细胞分泌的 BMP4 提供了有利于肿瘤微环境的 M2 信号。此外，miR-21 对 的抑制作用使肿瘤细胞对 BMP 配体介导的促分化作用产生抗性，有利于肿瘤生长。
