Stem cells in the biology of normal urothelium and urothelial carcinoma

Abstract

Urothelium is a special type of stratified epithelium that lines the distal portion of the urinary tract. For a long time, basal urothelial cells have been suspected to include a population of urothelial stem cells. Recent experiments identifying label-retaining cells as well as lineage tracing analyses corroborate this notion. There are striking morphological and antigenic similarities between basal or differentiated urothelial cells and the corresponding cells in some urothelial carcinomas. In this respect, basal cell-specific markers provide good candidates to identify urothelial carcinoma stem cells, e.g. specific cytokeratins (CK5, CK14, CK17) or adhesion molecules (specific integrin subspecies, CD44). Common properties of the stem cells of normal urothelium and urothelial cancer have thus emerged. Both are characterized by a remarkable plasticity and both rely on reciprocal interactions with stromal fibroblasts. However, the stem cells of individual urothelial carcinomas appear to differ considerably and may contribute to the heterogeneity of this disease. The presence, quantity, and particular biological nature of urothelial carcinoma stem cells in each case may thus carry important clinical information that might allow a rationale stratification of urothelial cancer patients for treatment in the near future.

Prognostic Implication of Urothelial Stem Cell Markers Differs According to Primary Tumour Location in Non-Muscle-Invasive Bladder Cancer

“…Urothelial stem cells (USC) have attracted considerable attention due to their possible roles in urothelium homoeostasis and tissue repair as well as their potential in tumor initiation [7,8]. In line with this notion, recent experiments have shown striking morphological and antigenic similarities between basal and intermediate differentiated cells and the corresponding cells in urothelial carcinomas [9]. Signalling pathways involved in USC self-renewing and cell differentiation are also implicated in the malignant transformation of urothelial carcinomas [10,11].…”

ALDH1 in Combination with CD44 as Putative Cancer Stem Cell Markers are Correlated with Poor Prognosis in Urothelial Carcinoma of the Urinary Bladder

“…Among various and proposed cancer stem cell surface markers used to isolate different subtypes of urothelial carcinomas, ALDH1A1 is one of the promising prognostic markers for CSCs of UCUB (Hatina and Schulz, 2012;Ho et al, 2012). In the present study, we examined the immunohistochemical expression of two putative cancer stem cell markers, CD44 and ALDH1A1, using tissue microarray method for the first time among 159 Iranian patients suffering from UCUB and then we evaluated the correlation between expressions of each marker with clinicopathological parameters.…”

“…Two different carcinogenic pathways also called dual track carcinogenesis are involved in the pathogenesis of UC including low-grade noninvasive papillary and high-grade flat-invasive sub-types (Brandt et al, 2009;Hatina and Schulz, 2012). Low-grade (G1, G2) noninvasive papillary (pTa and pT1/pTis) UC account for approximately 70-80% of all bladder cancers which are caused by mutations in the fibroblast growth receptor (FGFR3) gene which causes activation of receptor tyrosine kinase-Ras pathway (Harvey Rasor PI3-kinase) (Billerey et al, 2001;van Rhijn et al, 2002;Wu, 2005;.…”

“…Cancer stem cell markers including basal urothelial cell cytokeratins (CK5, CK14, CK17) (Ho et al, 2012) or adhesion molecules (CD44) (Immervoll et al, 2011;Ho et al, 2012), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) (Ho et al, 2012), and tumor protein 63 (p63) (Ho et al, 2012) have been previously used as prognostic factors and applied to identify urothelial carcinoma stem cells (Hatina and Schulz, 2012;Ho et al, 2012). Further studies suggest that CSCs markers are composed of CD133 (Immervoll et al, 2008;Jaggupilli and Elkord, 2012), CD24 (Jaggupilli and Elkord, 2012), CD90, CD34, CD117 and CD20 as other potential CSC markers in bladder carcinomas (Komuro et al, 2007;Mehrazma et al, 2013).…”

Optimization of the current self-assembled urinary bladder model: Organ-specific stroma and smooth muscle inclusion

“…Due to slow turnover of the umbrella cells, postinjury inflammation and hyperplasia, ethical drawbacks and animal cost, the in vivo study of urothelial differentiation and development is difficult. [1][2][3][4] The investigation of preor postnatal differentiation in rodents does not follow the same pathways in human. 5 In vitro studies can avoid these obstacles; however, these studies have limitations.…”