The human urothelium consists of multiple clonal units, each maintained by a stem cell

Gaisa, Nadine T.; Graham, Trevor A.; McDonald, Stuart; Cañadillas-Lopez, Sagrario; Poulsom, Richard; Heidenreich, Axel; Jakse, G.; Tadrous, Paul J.; Knuechel, Ruth; Wright, Nicholas

doi:10.1002/path.2945

Cited by 61 publications

(43 citation statements)

References 37 publications

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“…Further evidence supporting the hypothesis that a small portion of the basal cell layer contains putative urothelial stem cells was recently provided by the identification of clonal patches of cells in the human urothelium that are maintained by a single stem cell (21).…”

Section: Urothelial Stem Cellsmentioning

confidence: 84%

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Horst

Bos

Pluijm

2012

Molecular Cancer Research

139

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High recurrence rates and poor survival rates of metastatic bladder cancer emphasize the need for a drug that can prevent and/or treat bladder cancer progression and metastasis formation. Accumulating evidence suggests that cancer stem/progenitor cells are involved in tumor relapse and therapy resistance in urothelial carcinoma. These cells seem less affected by the antiproliferative therapies, as they are largely quiescent, have an increased DNA damage response, reside in difficult-to-reach, protective cancer stem cell niches and express ABC transporters that can efflux drugs from the cells. Recent studies have shown that epithelial-to-mesenchymal transition (EMT), a process in which sessile, epithelial cells switch to a motile, mesenchymal phenotype may render cancer cells with cancer stem cells properties and/or stimulate the expansion of this malignant cellular subpopulation. As cancer cells undergo EMT, invasiveness, drug resistance, angiogenesis, and metastatic ability seem to increase in parallel, thus giving rise to a more aggressive tumor type. Furthermore, the tumor microenvironment (tumor-associated stromal cells, extracellular matrix) plays a key role in tumorigenesis, tumor progression, and metastasis formation. Taken together, the secret for more effective cancer therapies might lie in developing and combining therapeutic strategies that also target cancer stem/progenitor cells and create an inhospitable microenvironment for highly malignant bladder cancer cells. This review will focus on the current concepts about the role of cancer stem cells, epithelial plasticity, and the supportive stroma in bladder carcinoma. The potential implications for the development of novel bladder cancer therapy will be discussed. Mol Cancer Res; 10(8); 995-1009. Ó2012 AACR. Bladder CancerWorldwide, an estimated number of 386,300 new cases and 150,200 deaths from bladder cancer occurred in 2008, with the majority of cases (77%) occurring in men. Thereby, bladder cancer is the seventh most common cancer and the ninth most common cause of cancer-related death in men. Bladder cancer is most common in developed countries, where 63% of the cases occurred in 2002. In Europe and the United States, for example, bladder cancer is the fourth most common cancer in males. Overall, the 5-year survival rate of bladder cancer is approximately 80%, and it varies with the stage of the tumor, ranging from 97% for carcinoma in situ to 6% for metastatic disease.Urothelial carcinoma is a heterogeneous disease and multifocal tumors can develop in the same patient. Multifocality can be explained by the monoclonal theory, that is, multiple tumors arise from a single transformed cell or by the field cancerization theory (1). In the latter, exposure of the urothelium to important risk factors for bladder cancer, such as occupational carcinogens induces changes at different sites of the urothelium. As described by Cheng and colleagues (1), urothelial carcinoma in situ is a well-established precursor of invasive bladder cancer and may be...

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Section: Urothelial Stem Cellsmentioning

confidence: 84%

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Horst

Bos

Pluijm

2012

Molecular Cancer Research

139

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“…Furthermore, analyses of mice harboring a germline deletion of p63 , which is expressed in basal but not umbrella cells, lack basal and intermediate cells but have a superficial cell layer 22, 23 . In addition to these studies of mouse bladder, analyses of clonal relationships in human bladder, inferred from analyses of mitochondrial DNA, also support the model that that the bladder has multiple progenitors 24 . Clearly, lineage relationships within the bladder urothelium are far from resolved.…”

Section: Biology Of the Bladder And Lineage Relationships Of Its Epitmentioning

confidence: 56%

Modelling bladder cancer in mice: opportunities and challenges

et al. 2014

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The prognosis and treatment of bladder cancer have hardly improved in the last 20 years. Bladder cancer remains a debilitating and often fatal disease, and among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as impact its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described and particularly few that develop invasive cancer phenotypes. This review focuses on opportunities for improving the landscape of mouse models of bladder cancer.

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“…On the other hand, the slow cycling of urothelium and especially the urothelial stem cells has made it possible to map the unit of proliferative succession by mutational analysis as well. Both X-inactivation based [7] and mitochondrial mutation-based [8] studies gave, principally, identical results -monoclonal proliferative units (i.e. subpopulations of cells sharing the same copy of inactivated X chromosome or the same mutation in the mitochondrial DNA) could be identified in urothelium.…”

mentioning

confidence: 76%

Stem cells in the biology of normal urothelium and urothelial carcinoma

Hatina¹,

Schulz²

2012

neo

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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.

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The human urothelium consists of multiple clonal units, each maintained by a stem cell

Cited by 61 publications

References 37 publications

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Epithelial Plasticity, Cancer Stem Cells, and the Tumor-Supportive Stroma in Bladder Carcinoma

Modelling bladder cancer in mice: opportunities and challenges

Stem cells in the biology of normal urothelium and urothelial carcinoma

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