The interplay of extracellular matrix and microbiome in urothelial bladder cancer

Abstract

Many pathological changes in solid tumours are caused by the accumulation of genetic mutations and epigenetic molecular alterations. In addition, tumour progression is profoundly influenced by the environment surrounding the transformed cells. The interplay between tumour cells and their microenvironment has been recognized as one of the key determinants of cancer development and is being extensively investigated. Data suggest that both the extracellular matrix and the microbiota represent microenvironments that contribute to the onset and progression of tumours. Through the introduction of omics technologies and pyrosequencing analyses, a detailed investigation of these two microenvironments is now possible. In urological research, assessment of their dysregulation has become increasingly important to provide diagnostic, prognostic and predictive biomarkers for urothelial bladder cancer. Understanding the roles of the extracellular matrix and microbiota, two key components of the urothelial mucosa, in the sequelae of pathogenic events that occur in the development and progression of urothelial carcinomas will be important to overcome the shortcomings in current bladder cancer treatment strategies.

Figure 1. Dysbiosis and ECM modifications.

a | In many tissues, homeostasis depends on ecological community with microbial organisms (eubiosis). Disruption of this balance (dysbiosis) and extracellular matrix (ECM) remodelling are associated with a variety of diseases, for example, colorectal carcinoma. Future studies are likely to also establish associations between the functions of the microbiota and the urothelium, connecting dysbiosis with the onset, progression and relapse of urothelial bladder cancer. b | These associations have been mainly viewed as dysbiosis inducing ECM remodelling, for example, through the release of bacterial enzymes that degrade ECM components or introduce post-translational modifications (PTMs), activation of inflammatory pathways and epigenetic modifications of fibroblasts. Microbial translocation can occur during this process and exacerbate ECM dysregulation. Interaction between the microbiome and sex hormones can also regulate ECM features^,. c | However, dysbiosis can also follow ECM remodelling at the onset of disease; for example, a solid tumour can establish a new niche for the growth of bacterial strains by creating hypoxic and/or acidic conditions or changing the ECM composition^,. Dysregulation of the ECM composition can also follow nontumoural conditions, for example, through epigenetic modifications of fibroblasts induced by toxins, irradiation and chronic inflammatory responses, an imbalance between sex hormones and/or their receptors, and ageing. Changes in the ECM composition provide conditions for altered binding of bacterial strains, thus, favouring dysbiosis and microbial translocation. PAMPs, pathogen-associated molecular patterns; TLRs, Toll-like receptors. PowerPoint slide