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Normal and neoplastic urothelial stem cells: getting to the root of the problem

Abstract

Most epithelial tissues contain self-renewing stem cells that mature into downstream progenies with increasingly limited differentiation potential. It is not surprising that cancers arising from such hierarchically organized epithelial tissues retain features of cellular differentiation. Accumulating evidence suggests that the urothelium of the urinary bladder is a hierarchically organized tissue, containing tissue-specific stem cells that are important for both normal homeostasis and injury response. The phenotypic and functional properties of cancer stem cells (CSCs; also known as tumour-initiating cells) from bladder cancer tissue have been studied in detail. Urothelial CSCs are not isolated by a 'one-marker-fits-all' approach; instead, various cell surface marker combinations (possibly reflecting the cell-of-origin) are used to isolate CSCs from distinct differentiation subtypes of urothelial carcinomas. Additional CSC markers, including cytokeratin 14 (CK14), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and tumour protein 63 (p63), have revealed prognostic value for urothelial carcinomas. Signalling pathways involved in normal stem cell self-renewal and differentiation are implicated in the malignant transformation of different subsets of urothelial carcinomas. Early expansion of primitive CK14+ cells—driven by genetic pathways such as STAT3—can lead to the development of carcinoma in situ, and CSC-enriched urothelial carcinomas are associated with poor clinical outcomes. Given that bladder CSCs are the proposed root of malignancy and drivers of cancer initiation and progression for urothelial carcinomas, these cells are ideal targets for anticancer therapies.

Key Points

  • Normal slow-cycling urothelium demonstrates rapid regenerative potential and the ability to transdifferentiate into multiple cell types; characteristics that support the existence of normal urothelial stem cells

  • Evidence suggests that urothelial stem cells primarily originate from basal cells, whereas an alternative pool of stem cells might exist that could give rise to umbrella cells within the urothelium

  • Tumorigenic subpopulations of cancer stem cells (CSCs) with basal cell characteristics and phenotypic markers are evident in primary bladder cancers, xenografts, and immortalized cell lines

  • Signalling pathways implicated in normal stem cell self-renewal and lineage differentiation have major roles in bladder cancer development; heterogeneity in their activation status is evident among patients

  • Bladder cancers can be categorized into subtypes on the basis of differentiation status; the most primitive basal subtypes and cell markers correlate with poor clinical outcomes

  • Novel targeted approaches for treating bladder CSCs might improve the efficacy of current standard-of-care treatment regimens when administered as combination therapy

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Figure 1: Markers and signalling pathways associated with urothelial cellular differentiation.
Figure 2: Clinical relevance of urothelial CSCs.

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Acknowledgements

The authors would like to thank the National Cancer Institute (CA129640), V Foundation for Cancer Research (V Scholar Award), L E. Gordy and Josephine S. Gordy Memorial Cancer Research Fund, the Curtis Hankamer Basic Research Fund, the ARCO Foundation Young Teacher-Investigator Fund, and the CPRIT pre-doctoral fellowship for their funding support.

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P. L. Ho and K. S. Chan both contributed towards researching, writing, and editing the manuscript, as well as discussions of content. A. Kurtova contributed to editing and discussions of content.

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Correspondence to Keith Syson Chan.

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Ho, P., Kurtova, A. & Chan, K. Normal and neoplastic urothelial stem cells: getting to the root of the problem. Nat Rev Urol 9, 583–594 (2012). https://doi.org/10.1038/nrurol.2012.142

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