Cancer derived exosomes induce macrophages immunosuppressive polarization to promote bladder cancer progression

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.

Aberrant hyperexpression of the RNA binding protein FMRP in tumors mediates immune evasion

“…Therefore, we reasoned that the secreted WT cancer cell-derived exosomes might be involved in macrophage programming, as has been suggested in previous studies (43,44). Accordingly, EVs were isolated from WT and FMRP-KO PDAC cancer cells (fig.…”

Ferroptosis-dependent breast cancer cell-derived exosomes inhibit migration and invasion of breast cancer cells by suppressing M2 macrophage polarization

“…Tumor-derived exosomes can be taken up by macrophages in the tumor microenvironment and then participate in tumor progression and metastasis ( Baig et al, 2020 ). Bladder cancer derived exosomes induced macrophage M2 polarization to facilitate bladder cancer progression ( Jiang et al, 2021 ). Macrophages were reported to exhibit M1 and M2 subtypes.…”

Role of exosomal ncRNAs released by M2 macrophages in tumor progression of gastrointestinal cancers

“…Previous studies suggested that TAMs accumulate in the tissue of GICs due to cancer-released mediators such as CCL-2 and CSF1, which recruit MΦs to infiltrate tumor tissues. 17 , 38 , 39 Several pieces of evidence highlighted the role of Exos released by cancer cells in the intracellular communication between TAMs and tumor cells, thus promoting M2 polarization, 40 , 41 as shown in Figure 1 . Tumor cell-derived Exos transfer many molecules into TAMs such as oncoproteins, miRNAs, lncRNAs, circRNAs, and lipids that actively mediate polarization into M2 and thus enhancing tumor progression.…”