Urothelial Cancer Stem Cell Heterogeneity

  • Michaela Kripnerova
  • Hamendra Singh Parmar
  • Martin Pesta
  • Michaela Kohoutova
  • Jitka Kuncova
  • Karel Drbal
  • Marie Rajtmajerova
  • Jiri HatinaEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1139)


Urothelial carcinoma is a tumor type featuring pronounced intertumoral heterogeneity and a high mutational and epigenetic load. The two major histopathological urothelial carcinoma types – the non-muscle-invasive and muscle-invasive urothelial carcinoma – markedly differ in terms of their respective typical mutational profiles and also by their probable cells of origin, that is, a urothelial basal cell for muscle-invasive carcinomas and a urothelial intermediate cell for at least a large part of non-muscle-invasive carcinomas. Both non-muscle-invasive and muscle-invasive urothelial carcinomas can be further classified into discrete intrinsic subtypes based on their typical transcriptomic profiles. Urothelial carcinogenesis shows a number of parallels to a urothelial regenerative response. Both of these processes seem to be dominated by specific stem cell populations. In the last years, the nature and location of urothelial stem cell(s) have been subject to many controversies, which now seem to be settled down, favoring the existence of a largely single urothelial stem cell type located among basal cells. Basal cell markers have also been amply used to identify urothelial carcinoma stem cells, especially in muscle-invasive disease, but they proved useful even in some non-muscle-invasive tumors. Analyses on molecular nature of urothelial carcinoma stem cells performed till now point to their great heterogeneity, both during the tumor development and upon intertumoral comparison, sexual dimorphism providing a special example of the latter. Moreover, urothelial cancer stem cells are endowed with intrinsic plasticity, whereby they can modulate their stemness in relation to other tumor-related traits, especially motility and invasiveness. Such transitional modulations suggest underlying epigenetic mechanisms and, even within this context, inter- and intratumoral heterogeneity becomes apparent. Multiple molecular aspects of urothelial cancer stem cell biology markedly influence therapeutic response, implying their knowledge as a prerequisite to improved therapies of this disease. At the same time, the notion of urothelial cancer stem cell heterogeneity implies that this therapeutic benefit would be most probably and most efficiently achieved within the context of individualized antitumor therapy.


Urothelium Urothelial stem cells Urothelial regenerative response Lineage-tracing Lineage-depletion Urothelial carcinoma Urothelial carcinoma heterogeneity Non-muscle-invasive bladder cancer Muscle-invasive bladder cancer Intrinsic subtypes Urothelial carcinoma sexual dimorphism Urothelial carcinoma stem cells Stemness signaling pathway Sonic hedgehog Wnt/β-catenin pathway SOX-2 STAT-3 COX-2 YAP-1 Epithelial-mesenchymal transition Epigenetic plasticity DNMT-1 



The original studies cited are supported by the Charles University Research Fund (Progres Q39), National Sustainability Program I (NPUI) Nr. LO1503 provided by the Ministry of Education, Youth and Sports of the Czech Republic (M.Kr., M.Ko, and J.K) and by Charles University Specific Student Research Projects Nr. 260394/2017, Nr. 260393/2017 (J.H.,M.K., M.P., J.K.)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Michaela Kripnerova
    • 1
  • Hamendra Singh Parmar
    • 1
    • 2
  • Martin Pesta
    • 1
  • Michaela Kohoutova
    • 3
  • Jitka Kuncova
    • 3
  • Karel Drbal
    • 4
  • Marie Rajtmajerova
    • 4
  • Jiri Hatina
    • 1
    Email author
  1. 1.Charles University, Faculty of Medicine in Pilsen, Institute of BiologyPilsenCzech Republic
  2. 2.School of Biotechnology, Devi Ahilya UniversityIndoreIndia
  3. 3.Charles University, Faculty of Medicine in Pilsen, Institute of PhysiologyPlzenCzech Republic
  4. 4.Charles University, Faculty of Science, Department of Cell BiologyPragueCzech Republic

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