Abstract
BackgroundExosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined.MethodsExosomes were extracted from bladder cancer cells MB49 conditioned medium by ultracentrifugation. The effects of MB49-derived exosomes on macrophages polarization were analyzed by qPCR, flow cytometry, and Western blot. The immunosuppressive phenotype and function of MB49-derived exosomes stimulated macrophages were verified by tumor xenograft assays and T cell co-culture experiments. Exosomal miRNAs were analyzed by microarray to identify potential targets regulating macrophage polarization.ResultsMB49-derived exosomes could be ingested by macrophages, consequently promoting macrophages immunosuppressive polarization. Mechanically, the MB49-derived exosomes induced macrophage M2 polarization was mediated by down-regulation of PTEN and activation of AKT/STAT3/6 signaling. Moreover, hindrance of the generation or secretion of exosomes by GW4869 inhibited macrophages differentiation into immunosuppressive phenotype and function, thereby suppressed tumor growth in a mouse subcutaneous tumor model.ConclusionOur study confirmed the contribution of bladder cancer derived exosomes on the establishment of immunosuppressive TME and provided a potential therapeutic target for bladder cancer treatment.2e86TcVernrUPgLLsbgfc9Video
Highlights
Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression
In order to investigate the effect of bladder cancer cells secreted factors on macrophage polarization, mouse bone marrow-derived macrophages (BMDM) were treated with bladder cancer cell MB49 cells culture supernatant and gene expression was analyzed by RT-qPCR
B BMDM were stimulated with MB49 conditioned medium for 48 h, and the proportion of F4/80+Cluster of differentiation 206 (CD206)+ cells was detected by flow cytometry
Summary
Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. Jiang et al Cell Commun Signal (2021) 19:93 and the extracellular matrix, which plays an essential role in cancer development, progression and control [5]. Tumor associated macrophages (TAM), a major component of immune cells in TME, have been suggested to play a central role in tumor progression [7,8,9]. Increasing evidence indicates that TAM could increase tumor invasion and metastasis by taming host adaptive immunity [12, 13]. It is urgent need to understand how TAM polarization in bladder TME during tumor progression
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