Mechanobiology of Matricellular Proteins in Bladder Cancer: A Narrative Review and Bioinformatics Analysis

The extracellular matrix (ECM) in cancer differs from healthy tissue in structure, composition, and mechanical properties. Matricellular proteins (MCPs) play important roles in shaping ECM architecture during tissue remodeling. This narrative review, combined with a bioinformatics analysis, examines six major MCP families-Fasciclins, Tenascins, Thrombospondins, Small Leucine-Rich Proteoglycans, the SPARC family, and the CCN family-through a mechanobiological lens in bladder cancer. It summarizes current knowledge on the mechanical regulation of MCP expression, their effects on matrix stiffness, and their contributions to bladder cancer progression. Analyses of public datasets reveal that stromal cells are the predominant source of MCPs in the tumor microenvironment. Furthermore, mechanical upregulation and involvement in the formation of stiff ECM highlight MCPs as important players in a mechanotransduction feedback loop. While most MCPs exert pro-tumorigenic effects on bladder cancer cells, several display context-dependent or anti-tumorigenic activities. Existing studies have primarily focused on the isolated effects of MCPs on bladder cancer cell lines in two-dimensional systems or simple subcutaneous xenograft models. Both approaches fail to capture the context-dependent nature of MCPs and their involvement in ECM formation. These findings underscore the need for future studies to investigate the complex effects of MCPs on bladder cancer progression.