Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer

Urothelial carcinoma is a highly heterogeneous disease that develops along two distinct biological tracks as evident by candidate gene analysis and genome-wide screening and therefore, offers different challenges for clinical management. Tumors representing the truly distinct molecular entities express molecular markers characteristic of a developmental process and a major mechanism of cancer metastasis, known as epithelial-to-mesenchymal transition (EMT). Recently identified subset of cells known as urothelial cancer stem cells (UroCSCs) in urothelial cell carcinoma (UCC) have self-renewal properties, ability to generate cellular tumor heterogeneity via differentiation and are ultimately responsible for tumor growth and viability. In this review paper, PubMed and Google Scholar electronic databases were searched for original research papers and review articles to extract relevant information on the molecular mechanisms delineating the relationship between EMT and cancer stemness and their clinical implications for different subsets of urothelial cell carcinomas. Experimental and clinical studies over the past few years in bladder cancer cell lines and tumor tissues of different cancer subtypes provide evidences and new insights for mechanistic complexity for induction of EMT, tumorigenicity, and cancer stemness in malignant transformation of urothelial cell carcinomas. Differentiation and elimination therapies targeting EMT-cancer stemness pathway have been proposed as cynosure in the molecular biology of urothelial cell carcinomas and could prove to be clinically beneficial in an ability to reverse the EMT phenotype of tumor cells, suppress the properties of UroCSCs, inhibit bladder cancer progression and tumor relapse, and provide rationale in the treatment and clinical management of urothelial cancer.