Cancer stem cells and epithelial–mesenchymal transition in urothelial carcinoma: Possible pathways and potential therapeutic approaches

There is growing evidence of the presence of cancer stem cells in urothelial carcinoma. Cancer stem cells have the ability to self-renew and to differentiate into all cell types of the original heterogeneous tumor. A panel of diverse cancer stem cell markers might be suitable for simulation studies of urothelial cancer stem cells and for the development of optimized treatment protocols. The present review focuses on the advances in recognizing the markers of urothelial cancer stem cells and possible therapeutic targets. The commonly reported markers and pathways that were evaluated include CD44, CD133, ALDH1, SOX2 & SOX4, BMI1, EZH1, PD-L1, MAGE-A3, COX2/PGE2/STAT3, AR, and autophagy. Studies on the epithelial–mesenchymal transition-related pathways (Shh, Wnt/β-catenin, Notch, PI3K/Akt, TGF-β, miRNA) are also reviewed. Most of these markers were recognized through the expression patterns of cancer stem cell-rich side populations. Their regulative role in the development and differentiation of urothelial cancer stem cells was confirmed in vitro by functional analyses (e.g. cell migration, colony formation, sphere formation), and in vivo in xenograft experiments. Although a small number of these pathways are targeted by currently available drugs or drugs that are the currently being tested in clinical trials, a clear treatment approach has not been developed for most pathways. A greater understanding of the mechanisms that control the proliferation and differentiation of cancer stem cells is expected to lead to improvements in targeted therapy.