The cytokeratins are the intermediate filament proteins characteristic of epithelial cells. In human cells, some 20 different cytokeratin isotypes have been identified. Epithelial cells express between two and ten cytokeratin isotypes and the consequent profile which reflects both epithelial type and differentiation status may be useful in tumour diagnosis. The transitional epithelium or urothelium of the urinary tract shows alterations in the expression and configuration of cytokeratin isotypes related to stratification and differentiation. In transitional cell carcinoma, changes in cytokeratin profile may provide information of potential diagnostic and prognostic significance. The intensification of immunolabelling with some CK8 and CK18 antibodies may underly an active role in tumour invasion and foci of CK17-positive cells may represent proliferating populations. Loss of CK13 is a marker of grade and stage and de novo expression of CK14 is indicative of squamous differentiation and an unfavourable prognosis. However, perhaps the most important recent finding is the demonstration that a normal CK20 expression pattern is predictive of tumour non-recurrence and can be used to make an objective differential diagnosis between transitional cell papilloma and carcinoma. This review will consider cytokeratin expression in urothelium and discuss the application of cytokeratin typing to the diagnosis and prognosis of patients with TCC.
"According to our own data KRT13 is less expressed in UCB. Other studies [15–18] show a downregulation of KRT13 expression in more advanced stages and in high grade UCB. Recent findings suggested an epigenetic alteration of KRT13 gene due to hypermethylation leading to diminished expression of this gene in aggressive UCB . "
[Show abstract][Hide abstract] ABSTRACT: Purpose. To validate microarray data on cytokeratin 13 (KRT13) and interleukin-1 receptor antagonist (IL1RN) expression in urothelial carcinoma of the urinary bladder (UCB) and to correlate our findings with pathologic characteristics and tobacco smoking.
Methods. UCB tissue samples (n = 109) and control samples (n = 14) were obtained from transurethral resection and radical cystectomy specimens. Immunohistochemical staining of KRT13 and IL1RN was performed and semiquantitative expression scores were assessed. Smoking status was evaluated using a standardized questionnaire. Expression scores were correlated with pathologic characteristics (tumor stage and grade) and with smoking status. Results. Loss of KRT13 and IL1RN expression was observed in UCB tissue samples when compared to controls (P = 0.007, P = 0.008) in which KRT13 and IL1RN expression were high. IL1RN expression was significantly reduced in muscle-invasive tumors (P = 0.003). In tissue samples of current smokers, a significant downregulation of IL1RN was found when compared to never smokers (P = 0.013). Conclusion. Decreased expressions of KRT13 and IL1RN are common features of UCB and are associated with aggressive disease. Tobacco smoking may enhance the loss of IL1RN, indicating an overweight of proinflammatory mediators involved in UCB progression. Further validation of the influence of smoking on IL1RN expression is warranted.
Advances in Urology 07/2014; 2014:184602. DOI:10.1155/2014/184602
"Both urothelial cells and detrusor muscle cells are relatively straightforward to isolate and propagate in culture (Birder et al., 2003; Sun and Chai, 2002). AE1/AE3 is a marker for urothelial cells known to react against an antigenic determinant present on the majority of the subfamily A and B cytokeratins (Eichner et al., 1984; Sun et al., 1984), and has previously been employed in studies of the urothelium (Trifillis et al., 1995; Southgate et al., 1999). Smooth muscle actin (α-SMA) is a contractile protein present in both smooth muscle (Roholl et al., 1990) and myofibroblasts (Drake et al., 2006; Sadananda et al., 2008; Iwanaga et al., 2010; McCloskey, 2010). "
[Show abstract][Hide abstract] ABSTRACT: ATP is released from the bladder mucosa in response to stretch, but the cell types responsible are unclear. Our aim was to isolate and characterize individual populations of urothelial, myofibroblast, and detrusor muscle cells in culture, and to examine agonist-stimulated ATP release. Using female pig bladders, urothelial cells were isolated from bladder mucosa following trypsin-digestion of the luminal surface. The underlying myofibroblast layer was dissected, minced, digested, and cultured until confluent (10-14 days). A similar protocol was used for muscle cells. Cultures were used for immunocytochemical staining and/or ATP release investigations. In urothelial cultures, immunoreactivity was present for the cytokeratin marker AE1/AE3 but not the contractile protein α-smooth muscle actin (α-SMA) or the cytoskeletal filament vimentin. Neither myofibroblast nor muscle cell cultures stained for AE1/AE3. Myofibroblast cultures partially stained for α-SMA, whereas muscle cultures were 100% stained. Both myofibroblast and muscle stained for vimentin, however, they were morphologically distinct. Ultrastructural studies verified that the suburothelial layer of pig bladder contained abundant myofibroblasts, characterized by high densities of rough endoplasmic reticulum. Baseline ATP release was higher in urothelial and myofibroblast cultures, compared with muscle. ATP release was significantly stimulated by stretch in all three cell populations. Only urothelial cells released ATP in response to acid, and only muscle cells were stimulated by capsaicin. Tachykinins had no effect on ATP release. In conclusion, we have established a method for culture of three cell populations from porcine bladder, a well-known human bladder model, and shown that these are distinct morphologically, immunologically, and pharmacologically.
"It is known that normal urothelium is characterised by terminally differentiated superficial cells, which express cytokeratin 20 [44-46]. While our early primary cultures derived from bladder biopsies contained some cells that were positive for CK20, this marker was soon lost in culture. "
[Show abstract][Hide abstract] ABSTRACT: The functional role of the bladder urothelium has been the focus of much recent research. The bladder mucosa contains two significant cell types: urothelial cells that line the bladder lumen and suburothelial interstitial cells or myofibroblasts. The aims of this study were to culture these cell populations from human bladder biopsies and to perform immunocytochemical characterisation.
Primary cell cultures were established from human bladder biopsies (n = 10). Individual populations of urothelial and myofibroblast-like cells were isolated using magnetic activated cell separation (MACS). Cells were slow growing, needing 3 to 5 weeks to attain confluence.
Cytokeratin 20 positive cells (umbrella cells) were isolated at primary culture and also from patients' bladder washings but these did not proliferate. In primary culture, proliferating cells demonstrated positive immunocytochemical staining to cytokeratin markers (AE1/AE3 and A0575) as well fibroblasts (5B5) and smooth muscle (αSMA) markers. An unexpected finding was that populations of presumptive urothelial and myofibroblast-like cells, isolated using the MACS beads, stained for similar markers. In contrast, staining for cytokeratins and fibroblast or smooth muscle markers was not co-localised in full thickness bladder sections.
Our results suggest that, in culture, bladder mucosal cells may undergo differentiation into a myoepithelial cell phenotype indicating that urothelial cells have the capacity to respond to environmental changes. This may be important pathologically but also suggests that studies of the physiological function of these cells in culture may not give a reliable indicator of human physiology.
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