Molecular pathways of urothelial development and bladder tumorigenesis

Castillo-Martin, Mireia; Domingo-Domènech, Josep; Karni-Schmidt, Orit; Matos, Tulio; Cordon‐Cardo, Carlos

doi:10.1016/j.urolonc.2009.04.019

Cited by 229 publications

(196 citation statements)

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“…We now show that neither loss of p53 nor p16 function had any direct effect on differentiation, in agreement with the normal differentiation potential of keratinocytes with inactivated p16 function [25]. Less expected was the lack of any association between loss of p53 and differentiation, as changes in p53 have been associated with carcinoma in situ [5], thus implying that other changes may contribute to the dysplastic phenotype.…”

Section: Discussionsupporting

confidence: 68%

“…As a result, FGFR3 enhances proliferation by activating Ras-Raf-Extracellular signal-Related Kinase (ERK), Phosphatidylinositol 3-Kinase (PI3-K) and Signal Transducer and Activator of Transcription (STAT) proteins [4]. The p53/p21 and p16/Retinoblastoma (Rb) tumour suppressor pathways are frequently altered in muscle-invasive disease, with p53 loss associated with muscle-invasive disease and p16/Rb loss linked to tumours of higher metastatic potential (reviewed in [5]). …”

Section: Introductionmentioning

confidence: 99%

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Immortalisation of Normal Human Urothelial Cells Compromises Differentiation Capacity

et al. 2011

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Immortalisation of Normal Human Urothelial Cells Compromises Differentiation Capacity

et al. 2011

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“…Mouse urothelium displays histological features similar to human urothelium despite having only up to three layers in the mucosa, 19 which comprise a basal, an intermediate, and a superficial layer of umbrella cells. Basal and intermediate urothelial cells displayed nuclear positivity for all p63 antibodies analyzed, which validated the use of these antibodies in mouse tissue samples (Figure 2A).…”

Section: Tap63 and ⌬Np63 Counterbalance Is Important For Urothelium Dmentioning

confidence: 96%

“…There are up to seven layers in human bladder urothelium and only up to three layers in the mouse bladder urothelium. 19 It is well documented that the basal and intermediate cell layers are characterized by a nuclear p63-positive phenotype, along with the expression of high molecular weight cytokeratins (CKs), such as CK5 and CK14. In contrast, umbrella cells of the superficial layer display a distinct phenotype characterized by lack of p63 expression and presence of certain low molecular weight CKs, such as CK20 and CK18, as well as uroplakins [eg, uroplakin II (UPII) 19,20 ].…”

mentioning

confidence: 99%

“…19 It is well documented that the basal and intermediate cell layers are characterized by a nuclear p63-positive phenotype, along with the expression of high molecular weight cytokeratins (CKs), such as CK5 and CK14. In contrast, umbrella cells of the superficial layer display a distinct phenotype characterized by lack of p63 expression and presence of certain low molecular weight CKs, such as CK20 and CK18, as well as uroplakins [eg, uroplakin II (UPII) 19,20 ]. Our group and others previously found that p63 is essential for urothelial differentiation 21 and that p63-null mice developed a nontransitional default simple cubical epithelium.…”

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confidence: 99%

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Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Karni-Schmidt

Castillo-Martín

HuaiShen

et al. 2011

The American Journal of Pathology

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The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ⌬Np63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ⌬Np63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ⌬Np63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ⌬Np63 acting as an oncogene in certain invasive bladder tumors.

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Nexgen Pathology: Predicting Clinical Course and Targeting Disease Causation

Cordon‐Cardo

Firpo-Betancourt

2017

Holland‐Frei Cancer Medicine

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Overview Pathology is a bridging discipline involving basic and clinical biomedical sciences. This context includes both descriptive and mechanistic approaches, with the goals of understanding the anatomical changes and underlying molecular events involved in disease‐related processes. Neoplastic disorders are a focal point for the further development of this chapter. The two main objectives of pathology are to define disease causation [from “Pathos” (Greek) “Disease”] and categorize disease states to render clinical diagnostic services. A modern academic Department of Pathology encompasses education activities, including teaching students, training residents and fellows, and mentoring faculty; and hospital‐based clinical services usually under three divisions, comprising anatomic pathology (surgical pathology, cytology, and autopsy services); clinical pathology (embodying a variety of laboratory services from blood bank and coagulation to chemistry and microbiology, among others); and molecular pathology (commonly housing somatic genetics, cytogenomics, and flow cytometry). During the past two decades, we have witnessed the transition from descriptive analysis of tissue histology and analyte variables that categorized patients and broad disease stages to more objective and quantitative multidimensional studies aimed at defining individual patient signatures. More traditional population and cohort‐based classifications are turning into patient‐specific profiles that optimize treatment efficacy and outcome: from diagnostic and prognostic approaches that group patients into disease categories to the development of a more precise, predictive, and individualized patient assessment. Such an integrated care model drives selection of evidence‐based treatment protocols to optimize clinical outcome, engendering a cost‐effective and personalized healthcare. Disease classification and assistance in selection of therapy is the focus of this “patient‐centric” pathology approach, expanding into monitoring of therapy (such as assessing therapeutic index and mutational load through tumor genotypes) and managing high‐risk patients through early diagnosis of their disease condition. The ultimate goals are to move from treating symptomatology to treating disease causation once origin of the disease is better understood and to move from a fee‐for‐service to population‐based accountable healthcare management.

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Molecular pathways of urothelial development and bladder tumorigenesis

Cited by 229 publications

References 50 publications

Immortalisation of Normal Human Urothelial Cells Compromises Differentiation Capacity

Immortalisation of Normal Human Urothelial Cells Compromises Differentiation Capacity

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Nexgen Pathology: Predicting Clinical Course and Targeting Disease Causation

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