WNT/β-catenin signaling in urothelial carcinoma of bladder

Abstract

Urothelial carcinoma of bladder is the second most prevalent genitourinary disease. It is a highly heterogeneous disease as it represents a spectrum of neoplasms, including non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and metastatic lesions. Genome-wide approaches and candidate gene analysis suggest that malignant transformation of the bladder is multifactorial and a multitude of genes are involved in the development of MIBC or NMIBC phenotypes. Wnt signaling is being examined to control and maintain balance between stemness and differentiation in adult stem cell niches. Owing to its participation in urothelial development and maintenance of adult urothelial tissue homeostasis, the components of Wnt signaling are reported as an important diagnostic and prognostic markers as well as novel therapeutic targets. Mutations/epigenetic alterations in the key molecules of Wnt/β-catenin canonical pathway have been linked with tumorigenesis, development of drug resistance and enhanced survival. Present review extends our understanding on the functions of key regulatory molecules of canonical Wnt/β-catenin pathway in urothelial tumorigenesis by inducing cancer stem cell phenotype (UCSCs). UCSCs may be responsible for tumor heterogeneity, high recurrence rates and complex biological behavior of bladder cancer. Therefore, understanding the role of UCSCs and the regulatory mechanisms that are responsible for high relapse rates and metastasis could help to develop pathway inhibitors and augment current therapies. Potential implications in the treatment of urothelial carcinoma of bladder by targeting this pathway primarily in UCSCs as well as in bulk tumor population that are responsible for high relapse rates and metastasis may facilitate potential therapeutic avenues and better prognosis.

Keywords: Chemoresistance; Therapeutic approaches; Urothelial carcinoma of bladder; Urothelial cancer stem cells; Wnt/β-catenin

Core tip: Wnt/β-catenin signaling pathway plays significant role in maintaining balance between stemness and differentiation in adult stem cell niches. Mutations/epigenetic alterations in the regulatory components of Wnt/β-catenin signaling lead to acquisition of urothelial cancer stem cell phenotype, chemoresistance and enhanced survival. Key regulatory molecules of Wnt/β-catenin pathways are being examined as diagnostic/ prognostic markers as well as novel therapeutic targets in urothelial tumorigenesis.