The role of the tumor microenvironment in bladder cancer development and progression

Urothelial cell carcinoma (UCC) of the bladder comprises a mixture of heterogeneous tumor cell populations, the surrounding stroma (which is populated by different types of mesenchymal cells), and the extracellular matrix (ECM). Bladder cancer (BC) has certain characteristics that distinguish it from other cancers. First, BCs are categorized into two groups: non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). The overall survival rate of patients with NMIBC is excellent compared with that of patients with other malignancies; however, some patients have a high risk of recurrence and a variable risk of progression despite administration of local therapies. The oft-cited “50% overall survival at 5 years” for MIBC has remained relatively unchanged over the last 20 years. Second, BC is a highly immunogenic cancer that shows a high rate of mutation due to the fact that more mutations are associated with a higher chance of tumor antigens triggering an appropriate immune response. The host immune response to tumor cells is based on the interactions that take place within the tumor microenvironment (TME). Intravesical bacillus Calmette-Guerin (BCG) therapy is the first U.S. Food and Drug Administration (FDA)-approved immunotherapy for BC and is the most successful immunotherapy for any established human neoplasm. Recently, the FDA approved the use of atezolizumab (Tecentriq^®) and nivolumab (Opdivo^®), which mimic programmed cell death ligand-1 inhibitor, to treat patients with locally advanced or metastatic UCC. Combination therapies involving cytotoxic chemotherapy, antiangiogenic agents, alternative immune checkpoint inhibitors, immunostimulatory cytokines, and cancer vaccines are currently under clinical investigation. This review summarizes recent studies of tumor-stromal crosstalk during pathogenesis of UCC of the bladder, and discusses the emerging roles of functionally important cellular components that interact within the cancer cell-TME. In addition, TME-targeted anticancer strategies such as chemotherapy, chemo-immunotherapy, and immunotherapy are briefly reviewed.