gw-4869 and Carcinogenesis

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. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined.. Exosomes 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.. MB49-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.. Our 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. Video Abstract.

Topics: Aniline Compounds; Animals; Benzylidene Compounds; Carcinogenesis; Cell Differentiation; Cell Line, Tumor; Cell Polarity; Cell Proliferation; Disease Progression; Exosomes; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Immunosuppression Therapy; Macrophage Activation; Mice; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; STAT3 Transcription Factor; STAT6 Transcription Factor; Tumor Microenvironment; Urinary Bladder Neoplasms