Altered expression of CKs 14/20 is an early event in a rat model of multistep bladder carcinogenesis

Costa, Rui M. Gil da; Oliveira, Paula A.; Nóbrega, Cármen; Arantes‐Rodrigues, Regina; Pinto‐Leite, Rosário; Colaço, Aura; Cruz, L. F. De La; Lopes, Carlos

doi:10.1111/iep.12145

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…Both CK14 and CK20 were suggested to direct the aggravation of early urothelial carcinoma via the carcinoma in situ-driven pathway (13,17,21). In an animal model, altered expression of CK14 and CK20 corresponded to an early tumorigenic step of papillary urothelial carcinoma (22). Taken together, it would be reasonable to speculate that CK5/6negative/CK20-positive expression may represent a "second hit" to a primitive and aggressive CK14-positive papillary NMIUTUC.…”

Section: Discussionmentioning

confidence: 96%

“…Consistent with this observation, Volkmer et al (19) and Ho et al (21) demonstrated that CK14 defined the most primitive/least differentiated basal-type urothelial carcinoma, which preceded the emergence of cancer cells expressing CK5 (intermediately differentiated) or CK20 (well-differentiated); further, CK14 expression marked the highly tumorigenic stem cell population. The increase in CK14 immunoreactivity was also observed at an early carcinogenesis stage, initiating the appearance of malignant lesions of the urinary bladder in a rat model (22). Moreover, CK14-positive urothelial carcinoma cells might have a predilection for chemoresistance (23).…”

Section: Introductionmentioning

confidence: 83%

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CK14 Expression Identifies a Basal/Squamous-Like Type of Papillary Non-Muscle-Invasive Upper Tract Urothelial Carcinoma

et al. 2020

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Object: CK14 expression is an important marker of basal/squamous-like (BASQ)-type muscle-invasive bladder carcinoma, and this molecularly defined subtype has a poor prognosis and a distinct response to chemotherapy. However, CK14 expression and its clinicopathological and molecular significance in papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) remain unknown. Herein, we investigated the prognostic implications of immunohistochemical (IHC) staining for CK14 and the transcriptional characteristics associated with CK14 expression in papillary NMIUTUC. Materials and Methods: IHC staining for CK14 was conducted in 204 papillary NMIUTUC specimens. Positive CK14 IHC staining was defined as a positive signal in >0% of tumor cells. RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors. Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003). Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780). Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor α-nuclear factor-κB, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype. In addition, with a p < 0.05 and |fold change| ≥2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors. Functional analysis of these genes revealed several networks and gene ontology terms related to the positive regulation of cellular proliferation in CK14-positive tumors. Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002). Jung et al. CK14 and BASQ-Type Papillary NMIUTUC Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity. We propose that CK14 IHC staining can be a useful biomarker of BASQ-type papillary NMIUTUC that can be applied in daily practice with the aim of precision oncology.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 83%

CK14 Expression Identifies a Basal/Squamous-Like Type of Papillary Non-Muscle-Invasive Upper Tract Urothelial Carcinoma

et al. 2020

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“…12,21 The BBN-induced bladder tumors in mice or rat provide an opportunity to study the entire cascade of bladder cancer histogenesis in an immunocompetent context. 17 In comparison, xenograft experiments using in vitro cell lines can be done only in the context of immunodeficient animals and thus does not allow the same depth or detail into the pathogenesis of bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

“…nitrosamine (BBN)-induced model is one of the most universally used model to study bladder carcinogenesis. 16,17 This model largely reminisces the multistep process that results in papillary urothelial neoplasms, 16,17 and allows in-depth study of the various steps of the process. In addition, the entire time span is short and thus feasible.…”

Section: Impact Statementmentioning

confidence: 99%

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Differential expression of cytokeratin 14 and 18 in bladder cancer tumorigenesis

Liu

Jia

Jiang

et al. 2018

Exp Biol Med (Maywood)

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It has been previously suggested that cytokeratins (CKs) are important diagnostic and prognostic biomarkers for urothelial lesions. Hence it is imperative to understand the expression pattern of cytokeratins during formation of papillary bladder cancer, which was the objective of the current study. Expression pattern of CK14 and CK18 were examined using immunohistochemical staining in a mice model of papillary bladder cancer. Twenty female mice were divided into two groups-group 1 (NT) and group 2, which received N-butyl- N-(4-hydroxybutyl) nitrosamine (BBN) for 20 weeks plus one week without treatment. Following histological classification of bladder lesions, CK14 and CK18 immunostaining was assessed according to its distribution and intensity. In NT animals, both basal cells and umbrella cells showed sporadic positive staining for CK14 and CK18, respectively. In BBN group, hyperplastic lesions showed significantly more CK14 and significantly less CK18 staining ( P < 0.05 in each case). Invasive carcinomas showed increased CK14 immunostaining in all epithelial layers. Cumulatively, our data indicate that altered CK14 (high) and CK18 (low) expression is perhaps an early event in bladder cancer tumorigenesis in females at least and is characteristic of both urothelial superficial pre-neoplastic and neoplastic lesions. Impact statement Studies have shown that expression of cytokeratins (CKs) or their altered distribution affects the bladder cancer pathogenesis and disease outcome, while the underlying mechanisms are not clear. The present study aims to explore the expression pattern of CK14 and CK18 during formation of papillary bladder cancer. The results showed that hyperplastic lesions showed significantly more CK14 and significantly less CK18 staining and invasive carcinomas showed increased CK14 immunostaining in all epithelial layers in N-butyl- N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse model. The results indicate that altered CK14 (high) and CK18 (low) expression is perhaps an early event in bladder cancer tumorigenesis and is characteristic of both urothelial superficial pre-neoplastic and neoplastic lesions, which may provide the early diagnosis index.

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The N-butyl-N-4-hydroxybutyl Nitrosamine Mouse Urinary Bladder Cancer Model

Oliveira

Nóbrega

Costa

et al. 2017

Urothelial Carcinoma

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Urinary bladder cancer (UBC) is a common and complex malignancy, with a multifactorial etiology, like environmental factors, such as cigarette smoking, occupational exposure, and genetic factors.UBC exhibits considerable genotypic and phenotypic heterogeneity. Among all UBC lesions, urothelial carcinoma is the most frequently observed histological type. Despite all the developments made in urologic oncology field, therapeutic options remain inadequate. There is urgency for the identification and development of new antineoplastic drugs to replace or improve current protocols and in vivo models have been proven to be essential for this step. There are different animal models of UBC: Spontaneous and experimentally induced models (genetically engineered, transplantable-xenograft and syngeneic animals- and chemically induced models). N-butyl-N(4-hydroxybutil)nitrosamine (BBN) is the most suitable reagent to generate chemically induced in vivo models of UBC and to study bladder carcinogenesis. BBN has proven, over the years, to be very realistic and reliable. It is bladder specific, and induces high tumor incidence.

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Altered expression of CKs 14/20 is an early event in a rat model of multistep bladder carcinogenesis

Cited by 10 publications

References 22 publications

CK14 Expression Identifies a Basal/Squamous-Like Type of Papillary Non-Muscle-Invasive Upper Tract Urothelial Carcinoma

CK14 Expression Identifies a Basal/Squamous-Like Type of Papillary Non-Muscle-Invasive Upper Tract Urothelial Carcinoma

Differential expression of cytokeratin 14 and 18 in bladder cancer tumorigenesis

The N-butyl-N-4-hydroxybutyl Nitrosamine Mouse Urinary Bladder Cancer Model

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