Tumor microenvironment and epithelial-mesenchymal transition in bladder cancer: Cytokines in the game?

Abstract

Bladder cancer (BlCa) is a highly immunogenic cancer. Bacillus Calmette-Guérin (BCG) is the standard treatment for non-muscle invasive bladder cancer (NMIBC) patients and, recently, second-line immunotherapies have arisen to treat metastatic BlCa patients. Understanding the interactions between tumor cells, immune cells and soluble factors in bladder tumor microenvironment (TME) is crucial. Cytokines and chemokines released in the TME have a dual role, since they can exhibit both a pro-inflammatory and anti-inflammatory potential, driving infiltration and inflammation, and also promoting evasion of immune system and pro-tumoral effects. In BlCa disease, 70-80% are non-muscle invasive bladder cancer, while 20-30% are muscle-invasive bladder cancer (MIBC) at the time of diagnosis. However, during the follow up, about half of treated NMIBC patients recur once or more, with 5-25% progressing to muscle-invasive bladder cancer, which represents a significant concern to the clinic. Epithelial-mesenchymal transition (EMT) is one biological process associated with tumor progression. Specific cytokines present in bladder TME have been related with signaling pathways activation and EMT-related molecules regulation. In this review, we summarized the immune landscape in BlCa TME, along with the most relevant cytokines and their putative role in driving EMT processes, tumor progression, invasion, migration and metastasis formation.

Keywords: bladder cancer; cytokines/chemokines; epithelial-mesenchymal transition (EMT); immune cells; tumor microenvironment (TME).

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).