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

Abstract

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.

RASAL2, a RAS GTPase-activating protein, inhibits stemness and epithelial–mesenchymal transition via MAPK/SOX2 pathway in bladder cancer

“…5 Therefore, we applied both gain-of-function and loss-of-function strategies to further explore the roles of RASAL2 in BCa stemness. As screening in Figure 2a by quantitative RT-PCR and western blotting assays, RASAL2 is highly expressed in SVHUC-1, an immortalized normal bladder epithelial cell line, whereas a relatively lower expression was detected in all BCa cell lines.…”

“…3, 4 Previous studies have revealed that cancer stemness is responsible for tumorigenicity, therapeutic resistance, relapse and metastasis in BCa. 5, 6 Also, accumulating evidences suggest that epithelial–mesenchymal transition (EMT) has an important role in the enrichment of cells with CSC properties, which are believed to be the origin of cancer progression. 7, 8 Importantly, recent whole-genome studies have discovered the intrinsic basal and luminal MIBC subtypes associated with different chemotherapy sensitivity or patient prognosis, in which a comprehensive molecular alteration involving CSC and EMT has been well characterized.…”

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

“…Recent studies have confirmed the possible origin of normal bladder tissues that have the potential to transform into CSCs through mutations in urothelial stem cells, basal cells, intermediate cells and terminally differentiated umbrella cells . They could also be derived from differentiated progenies after mutational insults and the acquisition of tumorigenic properties …”

Epithelial plasticity in urothelial carcinoma: Current advancements and future challenges

“…Beta-catenin (β-catenin), signal transducer and activator of transcription 3, glioma associated oncogene 1, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), POU domain, class 5, transcription factor 1/ octamer-binding transcription factor 4 (POU5F1/Oct4), sex determining region Y-box 2 (SOX2), Kruppel-like factor 4, v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) and NANOG are the oncogenes/transcription factors that have been observed to be responsible for maintaining the pluripotent properties of stem cells and aggressiveness of tumor invasion [5][6][7] . Studies on the identification of co-expression of keratin 5 and CD44 markers on UroCSCs distinguish them from differentiated tumor cells and support their basal-like phenotype.…”