The role of microbiota in tumorigenesis, progression and treatment of bladder cancer

Abstract

For decades, the urinary system was regarded as a sterile environment due to the absence of any bacterial growth in clinical standard urine cultures from healthy individuals. However, a diverse array of microbes colonizes the urinary system in small quantities, exhibiting a variable compositional signature influenced by differences in sex, age, and pathological state. Increasing pieces of evidence suggest microbiota exists in tumor tissue and plays a crucial role in tumor microenvironment based on research in multiple cancer models. Current studies about microbiota and bladder cancer have preliminarily characterized the bladder cancer-related microbiota, but how the microbiota influences the biological behavior of bladder cancer remains unclarified. This review summarizes the characteristics of microbiota in bladder cancer, aims to propose possible mechanisms that microbiota acts in tumorigenesis and progression of bladder cancer based on advances in gut microbiota, and discusses the potential clinical application of microbiota in bladder cancer.

Keywords: Microbiota; bladder cancer; mechanism; microbial metabolites; tumor microenvironment.

Figure 1

Possible mechanisms that microbiota promotes initiation of bladder cancer. Lesion starts with invasion of microbiota, which usually damages epithelial barrier through multiple virulence factors^[31,40] and increases the chance that microbiota interacts with bladder cells. Formation of intracellular bacteria and incomplete clearance^[41] from innate immune cells leads to chronic infection with an inflammatory environment characterized by various inflammatory mediators and immune cells. Chronic barrier destruction leads to more interactions between microbes and host, and persistent damage-repair loop (an inappropriate host response) of bladder epithelium plus inflammation environment increases the possibility of gene mutation and disrupts the intracellular signaling pathways^[36]. Overall, multiple microbiota-mediated hits may contribute to the carcinogenesis of bladder cancer and further research needs to evaluate this relevance.

Figure 2

Possible overview of microbiota in the TME of bladder cancer. Extracellular microbiota may directly influence tumor cells through metabolites^[53] or ECM remodeling^[54]. Gut microbiota is able to produce a remote effect through systemic microbial metabolites^[55-58]. Furthermore, the microbiota can interplay with the immune compartment in the TME and result in immunomodulation^[59]. Notably, the intracellular microbiota may influence the gene expression or intracellular signal pathways to manipulate the behavior of tumor cells^[52]. The blue metabolites refer to the systemic microbiota metabolites. ECM: Extracellular matrix; TME: tumor microenvironment.