Bladder cancer stem cells: clonal origin and therapeutic perspectives

Abstract

In this article, we review the origin and therapeutic perspectives of bladder cancer stem cells (BCSCs), which are integral to the initiation, high recurrence and chemoresistance of bladder cancer. BCSCs are heterogenous and originate from multiple cell types, including urothelial stem cells and differentiated cell types, including basal, intermediate stratum and umbrella cells. Cell surface markers, including CD44, CD67LR, EMA, ALDH1A1 and BCMab1, are used to identify and isolate BCSCs. The Hedgehog, Notch, Wnt and JAK-STAT signaling pathways play key roles in maintaining the stemness, self-renewal and proliferative potential of BCSCs. High expression of ABC transporters, acetaldehyde dehydrogenase, antioxidants and apoptosis resistance proteins in BCSCs play a critical role in chemoresistance. Consequently, a greater understanding of the biology of BCSCs will be important for identifying effective therapeutic targets to improve clinical outcomes for bladder cancer patients.

Emerging Roles of Cancer Stem Cells in Bladder Cancer Progression, Tumorigenesis, and Resistance to Chemotherapy: A Potential Therapeutic Target for Bladder Cancer

“…Identifying predictive markers that have crucial roles in the management of BC helps with better management of this disease. Several CSC surface markers have been identified as responsible for BC development, progression, maintenance of stemness, metastasis, and recurrence [21]. Among them are CD44, CD67LR, EMA, CD133, SOX2, SOX4, ALDH1A1, EZH1, BMI1, MAGE-A3, PD-L1, YAP1, and COX2/PGE2/STAT3, as well as the molecules related to hedgehog, phosphoinositide 3-kinase (PI3K)/AKT, Wnt/β-catenin, Notch [21,22], and c-Myc signaling pathways [23,24].…”

“…The Notch signaling pathway has both oncogenic and tumor-suppressive effects depending on the organ and cellular context [86]. It involves four receptors (Notch1-4) and five ligands and regulates the transcription of multiple target genes [21]. The expression of the Notch1 receptor is decreased in BC and its activation decreases cellular proliferation, suggesting that it has a tumor-suppressive role [86].…”

ALDH1A1 in patient‐derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression

“…On the other hand, coexpression of CD44 and aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) was correlated with CSCs phenotype in melanoma samples . In the case of bladder cancer, CSCs have been isolated using several markers including the ALDH1 family, member A1 (ALDH1A1), cytokeratin 14 (CK14), CD44, CD47 and CD90, and appear to promote tumorigenesis, metastasis and recurrence …”

“…7 In the case of bladder cancer, CSCs have been isolated using several markers including the ALDH1 family, member A1 (ALDH1A1), cytokeratin 14 (CK14), CD44, CD47 and CD90, and appear to promote tumorigenesis, metastasis and recurrence. 8,9 Three-dimensional (3D) culture methods are developing rapidly with the aim of constructing an in vitro culture system that better reflects tumor characteristics and microenvironment. 10 Indeed, 3D culture is assumed to more closely reflect the biological characteristics of tumors than conventional twodimensional (2D) or monolayer culture.…”

Hope and challenge: Precision medicine in bladder cancer

“…BC is the most prevalent urinary cancer in China, the ratio of the incidence BC for males to females and cities to rural areas is 3.3 and 2.4, respectively. For the past few years, the overall incidence and mortality of BC have shown a gradual upward trend and become a serious threat to the health of people …”