FIGURE 1.

Schematic representation of the impact of BlCa TME cytokines/chemokines in EMT induction in bladder tumor cells. Bladder tumor microenvironment is comprised by tumor cells and several tumor-infiltrating immune cells, such as, M1 and M2 macrophages, dendritic cells, regulatory T cells, cytotoxic T cells, helper T cells, B cells and NK cells. Furthermore, TME includes stromal cells, like fibroblasts, and non-cellular components, including soluble biological factors or mediators, as cytokines/chemokines. Cytokines/chemokines are mainly produced by several immune cells and fibroblasts, but they also can be produced by tumor cells. Tumor cells present several cytokine/chemokine receptors. IL-8 binds to CXCR1/CXCR2 receptors, CCL2 binds to CCR2/CCR4 receptor, TGF-β1 binds to TGF-βRI/II receptors, CXCL1 binds to CXCR2 receptor, CXCL12 binds to CXCR4/7 receptors and IL-6 binds to IL-6R receptor. Cytokine/receptor binding on tumor cells can drive the deregulation of specific molecules, including the triggering of EMT signaling pathways. Here, are depicted the most relevant signaling pathways involved in driving EMT that have been described to be deregulated in BlCa upon cytokine binding. JAK-STAT, RAS-RAF-ERK and AKT signaling pathways and TGF-β SMAD-dependent pathway are described to play roles in the activation of EMT-related molecules, driving EMT processes in tumor cells. Bladder tumor cells presenting partial EMT demonstrate a higher survival mechanism and a higher tumor-initiating and metastatic potential. In this way, bladder tumor cells are able to metastasize to the bones, lungs and liver (Created with BioRender.com).