Liposomal inhibition of acrolein-induced injury in rat cultured urothelial cells.

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Nirmal, J; Wolf-Johnston, A S; Chancellor, M B; Tyagi, P; Anthony, M; Kaufman, J; Birder, L A

2014-10-01

To study the protection offered by empty liposomes (LPs) alone against acrolein-induced changes in urothelial cell viability and explored uptake of LPs by primary (rat) urothelial cells. Acrolein was used as a means to induce cellular damage and reduce urothelial cellular viability. The effect of acrolein or liposomal treatment on cellular proliferation was studied using 5-bromo-2'-deoxy-uridine assay. Cytokine release was measured after urothelial cells were exposed to acrolein. Temperature-dependent uptake study was carried out for fluorescent-labeled LPs using confocal microscopy. Liposome pretreatment protected against acrolein-induced decrease in urothelial cell proliferation. LPs also significantly affected the acrolein-induced cytokine (interferon-gamma) release offering protection to the urothelial cells against acrolein damage. We also observed a temperature-dependent urothelial uptake of fluorescent-labeled LPs occurred at 37 °C (but not at 4 °C). Empty LPs alone provide a therapeutic efficacy against acrolein-induced changes in urothelial cell viability and may be a promising local therapy for bladder diseases. Hence, our preliminary evidence provides support for liposome-therapy for urothelial protection and possible repair.

Urothelial papilloma of the bladder: a review of 34 de novo cases.

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Magi-Galluzzi, Cristina; Epstein, Jonathan I

2004-12-01

Urothelial papilloma of the bladder is an uncommon entity when using restrictive diagnostic criteria. We retrospectively studied 34 patients who were diagnosed with urothelial papilloma of the bladder using the criteria of the 1998 WHO/ISUP classification system. Six cases were in-house and the remaining 28 were referred from other institutions as consults to one of the authors. In all cases, the diagnosis of papilloma was the first manifestation of urothelial neoplasia. The mean age of the patients at diagnosis was 57.8 years (range, 23-87 years). The male-to-female ratio was 2.4:1 (24 males and 10 females). The tumor size averaged 3.3 mm (range, 1-20 mm; median, 2 mm). Simple papillary fronds were seen in all cases; in 5 cases the additional finding of secondary budding off of small fronds from larger ones was also seen. In all cases, the fronds had a round morphology; yet in 4 cases elongated fronds were also noted. In 5 cases, dilated lymphatics within the fibrovascular fronds were apparent. One case had foamy histiocytes within the fibrovascular stalks. In all cases, the lining consisted of normal-appearing urothelium without hyperplasia, dysplasia, and/or mitotic figures. Some of the distinctive histologic features seen were changes in the umbrella cells: vacuolization (n = 4), prominence with cytologic atypia (n = 2), eosinophilic syncytial morphology (n = 1), apocrine-like morphology (n = 1), and mucinous metaplasia (n = 1). Follow-up was available in 26 cases with a mean follow-up for those without evidence of progression of 28.9 months (range, 3-127 months). Three patients (8.8%) developed recurrent papilloma 4, 15, and 18 months after the initial diagnosis of papilloma; 1 of these patients also showed progression to noninvasive low-grade urothelial carcinoma at the time of recurrence (15 months). Three patients (8.8%) progressed to higher-grade disease: 2 to noninvasive low grade urothelial carcinoma (11 and 15 months after the original diagnosis) and 1

Calpain3 is expressed in a proteolitically active form in papillomavirus-associated urothelial tumors of the urinary bladder in cattle.

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Sante Roperto

Full Text Available BACKGROUND: Calpain 3 (Capn3, also named p94, is a skeletal muscle tissue-specific protein known to be responsible for limb-girdle muscular dystrophy type 2A (LGMD2A. Recent experimental studies have hypothesized a pro-apoptotic role of Capn3 in some melanoma cell lines. So far the link between calpain3 and tumors comes from in vitro studies. The objective of this study was to describe Capn3 activation in naturally occurring urothelial tumors of the urinary bladder in cattle. METHODS AND FINDINGS: Here we describe, for the first time in veterinary and comparative oncology, the activation of Capn3 in twelve urothelial tumor cells of the urinary bladder of cattle. Capn3 protein was initially identified with nanoscale liquid chromatography coupled with tandem mass spectrometry (nano LC-MS/MS in a co-immunoprecipitation experiment on E2F3, known to be a transcription factor playing a crucial role in bladder carcinogenesis in humans. Capn3 expression was then confirmed by reverse transcription polymerase chain reaction (RT-PCR. Finally, the Ca(2+-dependent proteolytic activity of Capn3 was assayed following ion exchange chromatography. Morphologically, Capn3 expression was documented by immunohistochemical methods. In fact numerous tumor cells showed an intracytoplasmic immunoreactivity, which was more rarely evident also at nuclear level. In urothelial tumors, bovine papillomavirus type 2 (BPV-2 DNA was amplified by PCR and the expression of E5 protein, the major oncogenic protein of BVP-2, was detected by western blotting, immunohistochemistry, and immunofluorescence. E2F3 overexpression and pRb protein downregulation were shown by western blotting. CONCLUSION: The role of capn3 protein in urothelial cancer of the urinary bladder remains to be elucidated: further studies would be required to determine the precise function of this protease in tumor development and progression. However, we suggest that activated Capn3 may be involved in molecular

Identification of Novel Gene Targets and Putative Regulators of Arsenic-Associated DNA Methylation in Human Urothelial Cells and Bladder Cancer

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Rager, Julia E.; Miller, Sloane; Tulenko, Samantha E.; Smeester, Lisa; Ray, Paul D.; Yosim, Andrew; Currier, Jenna M.; Ishida, María C.; González-Horta, Maria del Carmen; Sánchez-Ramírez, Blanca; Ballinas-Casarrubias, Lourdes; Gutiérrez-Torres, Daniela S.; Drobná, Zuzana; Del Razo, Luz M.; García-Vargas, Gonzalo G.; Kim, William Y.; Zhou, Yi-Hui; Wright, Fred A.; Stýblo, Miroslav; Fry, Rebecca C.

2016-01-01

There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to a myriad of adverse health effects, including cancer of the bladder. The present study set out to identify DNA methylation patterns associated with iAs and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic (As)-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total As (tAs) and As species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 As-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the As- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer. PMID:26039340

Proline-rich tyrosine kinase 2 (Pyk2 regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells.

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Marco Genua

Full Text Available The insulin-like growth factor receptor I (IGF-IR plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2 modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.

Electron tomography of fusiform vesicles and their organization in urothelial cells.

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Samo Hudoklin

Full Text Available The formation of fusiform vesicles (FVs is one of the most distinctive features in the urothelium of the urinary bladder. FVs represent compartments for intracellular transport of urothelial plaques, which modulate the surface area of the superficial urothelial (umbrella cells during the distension-contraction cycle. We have analysed the three-dimensional (3D structure of FVs and their organization in umbrella cells of mouse urinary bladders. Compared to chemical fixation, high pressure freezing gave a new insight into the ultrastructure of urothelial cells. Electron tomography on serial sections revealed that mature FVs had a shape of flattened discs, with a diameter of up to 1.2 µm. The lumen between the two opposing asymmetrically thickened membranes was very narrow, ranging from 5 nm to 10 nm. Freeze-fracturing and immunolabelling confirmed that FVs contain two opposing urothelial plaques connected by a hinge region that made an omega shaped curvature. In the central cytoplasm, 4-15 FVs were often organized into stacks. In the subapical cytoplasm, FVs were mainly organized as individual vesicles. Distension-contraction cycles did not affect the shape of mature FVs; however, their orientation changed from parallel in distended to perpendicular in contracted bladder with respect to the apical plasma membrane. In the intermediate cells, shorter and more dilated immature FVs were present. The salient outcome from this research is the first comprehensive, high resolution 3D view of the ultrastructure of FVs and how they are organized differently depending on their location in the cytoplasm of umbrella cells. The shape of mature FVs and their organization into tightly packed stacks makes them a perfect storage compartment, which transports large amounts of urothelial plaques while occupying a small volume of umbrella cell cytoplasm.

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma.

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Alexander, Riley E; Hu, Yingchuan; Kum, Jennifer B; Montironi, Rodolfo; Lopez-Beltran, Antonio; Maclennan, Gregory T; Idrees, Muhammad T; Emerson, Robert E; Ulbright, Thomas M; Grignon, David G; Eble, John N; Cheng, Liang

2012-11-01

Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

Low grade urothelial carcinoma mimicking basal cell hyperplasia and transitional metaplasia in needle prostate biopsy

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Julian Arista-Nasr

2016-04-01

Full Text Available ABSTRACT Purpose The vast majority of urothelial carcinomas infiltrating the bladder are consistent with high-grade tumors that can be easily recognized as malignant in needle prostatic biopsies. In contrast, the histological changes of low-grade urothelial carcinomas in this kind of biopsy have not been studied. Materials and Methods We describe the clinicopathologic features of two patients with low-grade bladder carcinomas infiltrating the prostate. They reported dysuria and hematuria. Both had a slight elevation of the prostate specific antigen and induration of the prostatic lobes. Needle biopsies were performed. At endoscopy bladder tumors were found in both cases. Results Both biopsies showed nests of basophilic cells and cells with perinuclear clearing and slight atypia infiltrating acini and small prostatic ducts. The stroma exhibited extensive desmoplasia and chronic inflammation. The original diagnosis was basal cell hyperplasia and transitional metaplasia. The bladder tumors also showed low-grade urothelial carcinoma. In one case, the neoplasm infiltrated the lamina propria, and in another, the muscle layer. In both, a transurethral resection was performed for obstructive urinary symptoms. The neoplasms were positive for high molecular weight keratin (34BetaE12 and thrombomodulin. No metastases were found in either of the patients, and one of them has survived for five years. Conclusions The diagnosis of low-grade urothelial carcinoma in prostate needle biopsies is difficult and may simulate benign prostate lesions including basal cell hyperplasia and urothelial metaplasia. It is crucial to recognize low-grade urothelial carcinoma in needle biopsies because only an early diagnosis and aggressive treatment can improve the prognosis for these patients.

Increased CYP1A1 expression in human exfoliated urothelial cells of cigarette smokers compared to non-smokers

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Doerrenhaus, Angelika; Roos, Peter H. [Institute for Occupational Physiology at the University Dortmund, Dortmund (Germany); Mueller, Tina [Institute for Occupational Physiology at the University Dortmund, Dortmund (Germany); University Dortmund, Department of Statistics, Mathematical Statistics with Applications in Biometrics, Dortmund (Germany)

2007-01-15

Polycyclic aromatic hydrocarbons, arylamines and nitrosamines, constituents of cigarette smoke, are known inducers of bladder cancer. The biochemical response of the target tissue, the bladder urothelium, following inhalation of cigarette smoke has not been studied so far. We used exfoliated transitional urothelial cells from human urine samples to analyze effects of smoking on induction of the cytochrome P450 enzyme CYP1A1. Samples of 40 subjects, including male and female smokers and non-smokers, were examined. A prerequisite for the immunofluorescence microscopic analysis of the cells was the enrichment of the urothelial cell population. This was achieved by a new method which is based on magnetic cell sorting exploiting specific binding of immobilized Griffonia simplicifolia lectin to the surface of urothelial cells. Immunostaining of the final cell preparation with a monoclonal antibody to CYP1A1 showed that about 6% of the urothelial cells of non-smokers stained positive for CYP1A1. However, this fraction of positive cells was more than 44% of the urothelial cells in samples from cigarette smokers. In spite of the individual variation, the difference was statistically significant. There were no gender-related differences in the portion of CYP1A1 expressing urothelial cells of smokers and non-smokers. In essence, we show for the first time that human urothelial cells respond to cigarette smoking by induction of CYP1A1. The approach opens new fields of mechanistic and biomarker research with respect to the pathogenetic processes of cancer development in the human bladder. (orig.)

Cytopathologic differential diagnosis of low-grade urothelial carcinoma and reactive urothelial proliferation in bladder washings: a logistic regression analysis.

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Cakir, Ebru; Kucuk, Ulku; Pala, Emel Ebru; Sezer, Ozlem; Ekin, Rahmi Gokhan; Cakmak, Ozgur

2017-05-01

Conventional cytomorphologic assessment is the first step to establish an accurate diagnosis in urinary cytology. In cytologic preparations, the separation of low-grade urothelial carcinoma (LGUC) from reactive urothelial proliferation (RUP) can be exceedingly difficult. The bladder washing cytologies of 32 LGUC and 29 RUP were reviewed. The cytologic slides were examined for the presence or absence of the 28 cytologic features. The cytologic criteria showing statistical significance in LGUC were increased numbers of monotonous single (non-umbrella) cells, three-dimensional cellular papillary clusters without fibrovascular cores, irregular bordered clusters, atypical single cells, irregular nuclear overlap, cytoplasmic homogeneity, increased N/C ratio, pleomorphism, nuclear border irregularity, nuclear eccentricity, elongated nuclei, and hyperchromasia (p ˂ 0.05), and the cytologic criteria showing statistical significance in RUP were inflammatory background, mixture of small and large urothelial cells, loose monolayer aggregates, and vacuolated cytoplasm (p ˂ 0.05). When these variables were subjected to a stepwise logistic regression analysis, four features were selected to distinguish LGUC from RUP: increased numbers of monotonous single (non-umbrella) cells, increased nuclear cytoplasmic ratio, hyperchromasia, and presence of small and large urothelial cells (p = 0.0001). By this logistic model of the 32 cases with proven LGUC, the stepwise logistic regression analysis correctly predicted 31 (96.9%) patients with this diagnosis, and of the 29 patients with RUP, the logistic model correctly predicted 26 (89.7%) patients as having this disease. There are several cytologic features to separate LGUC from RUP. Stepwise logistic regression analysis is a valuable tool for determining the most useful cytologic criteria to distinguish these entities. © 2017 APMIS. Published by John Wiley & Sons Ltd.

Mucoepidermoid carcinoma of lung masquerading as urothelial carcinoma of bladder

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Graham, Donna M.; O’Connor, Kate M.; Hinchion, John; Coate, Linda E.; Burke, Louise; Power, Derek G.

2013-01-01

Background Mucoepidermoid carcinoma (MEC) of the lung is a rare subtype of non-small cell lung cancer. There is no consensus regarding optimal management for this disease. Case report We present a case of MEC of the lung in a 75 year-old female with a history of superficial urothelial carcinoma of the bladder. The patient was found to have an asymptomatic lung mass. Initial biopsy suggested metastatic recurrence of urothelial carcinoma and therefore, cisplatin and gemcitabine chemotherapy was administered prior to surgical resection. Pathological analysis of the resected specimen confirmed a diagnosis of stage IIIA MEC with focal high-grade features including transitional cell-like areas. Adjuvant radiotherapy was administered due to a positive microscopic resection margin. No chemotherapy was given due to lack of supporting data. The patient developed widespread metastatic disease 3 months following completion of radiotherapy and died 1 month later. Conclusion This case demonstrates the possibility of dual pathology in cases where metastatic disease is suspected. The use of small tissue samples may complicate diagnosis due to the heterogeneity of malignant tumours. PMID:24936321

Relationship of PCNA, C-erbB2 and CD44s expression with tumor grade and stage in urothelial carcinomas of the bladder

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Yıldırım, Ayhan; Kösem, Mustafa; Sayar, İlyas; Gelincik, İbrahim; Yavuz, Alparslan; Bozkurt, Aliseydi; Erkorkmaz, Ünal; Bayram, İrfan

2014-01-01

In the present study, the intention was to reveal the relationship of histological grade and stage with c-erbB2, CD44s, and PCNA immunoreactivity in bladder urothelial carcinomas (UC). In our study, we evaluated 46 items of transurethral resection material of patients submitted by YYU Faculty of Medicine, Main Department of Pathology, with a mass revealed in their bladder after clinical and radiological studies at our laboratories and who were diagnosed with urothelial carcinomas. PCNA, c-erbB2, and CD44s were applied in an immunohistochemical manner comprised from nine low-malignant potential papillary urothelial neoplasia, 23 low-grade papillary urothelial carcinoma, and 14 high-grade papillary urothelial carcinoma. Immunostaining was scored according to the percentage of positive cells. The immunohistochemical study demonstrated that the c-erbB2 and PCNA staining ratio increased when an increase occurred in stage and grade. The CD44s staining ratio decreased. C-erbB2, PCNA, and CD44s appear to be a useful marker in the assessment of the prognosis and treatment options in urothelial carcinomas. PMID:25035774

Urothelial Carcinoma of the Urinary Bladder in Young Adults — Clinical Experience at Taipei Veterans General Hospital

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Yu-Ching Wen

2005-06-01

Conclusion: Urothelial carcinoma of the urinary bladder in young adults is usually associated with low grade and low stage. Invasive bladder cancer had no worse a survival rate than superficial bladder cancer.

Expression and Role of GPR87 in Urothelial Carcinoma of the Bladder

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Yoshiyuki Kakehi

2013-06-01

Full Text Available The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was assessed in seven human bladder cancer cell lines. A replication-deficient recombinant adenoviral vector expressing shRNA targeting GPR87 (Ad-shGPR87, was constructed. Gene silencing was carried out using Ad-shGPR87. Immunohistochemical analysis was performed for transurethral resection of bladder tumor samples from 71 patients with non-muscle-invasive bladder cancer. We observed GPR87 expression in five of the seven cell lines, and silencing GPR87 gene expression significantly reduced cell viability. GPR87 expression was positive in 38 (54% of 71 tumors. Ki-67 index was associated with positive GPR87 staining status (p < 0.0001. Patients with GPR87-positive tumors had shorter intravesical recurrence-free survival than those with GPR87-negative tumors (p = 0.010. Multivariate analysis revealed that GPR87 staining status was an independent prognostic parameter for intravesical recurrence (p = 0.041. Progression from non-muscle-invasive to muscle-invasive tumor was more frequently observed in patients with GPR87-positive tumors, although this trend did not reach statistical significance (p = 0.056. These results warrant further prospective studies to clarify the role of GPR87 expression in intravesical recurrence and progression in bladder cancer.

Urothelial cancer of bladder in young versus older adults: clinical and pathological characteristics and outcomes.

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Telli, Onur; Sarici, Hasmet; Ozgur, Berat Cem; Doluoglu, Omer Gokhan; Sunay, Mehmet Melih; Bozkurt, Selen; Eroglu, Muzaffer

2014-09-01

Bladder urothelial carcinoma is rare in young adults and occurs more commonly in older individuals. The aim of this study was to compare the clinical behavior, pathologic characteristics, and prognosis of urothelial carcinoma of urinary bladder in young versus older adults. A retrospective review of our records between 2007 and 2013 identified 56 patients (42 males and 14 females) with transitional cell carcinoma of the bladder who were less than 40 years old. Clinical and pathological parameters of patients who were less than 40 years of age were compared with those of a series of patients older than 40 years of age (the control group) during the same period. A survival analysis was performed using the Kaplan-Meier method and log-rank test, and Cox regression was performed to identify clinical parameters that affected the clinical outcomes. The mean age was 29.21 years (range, 5-40 years) for patients less than 40 years old and 61.66 years (range, 41-75) for those older than 40 years. The mean follow-up was 40.26 months (range, 12-65 months) for young patients and 42.57 months (range, 12-72 months) for the older patients. Young bladder cancer patients had smaller-sized tumors (less than 3 cm), less high-grade cancers, higher papillary urothelial neoplasms of low malignant potential, and low-grade tumors than patients older than 40 years. Multivariate logistic regression analysis predicted tumor recurrence in young patients with high-grade tumors [odds ratio (OR), 1.959; 95% confidence interval (CI), 1.235-2.965; p = 0.046] and tumors larger than 3 cm (OR, 1.772; 95% CI, 1.416-1.942; p = 0.032). The 5-year overall survival rate was 100% for young patients and 88.1% for older patients. No difference was observed in the recurrence-free (p = 0.321) and progression-free (p = 0.422) survival rates between the two groups. We concluded that although the clinical stage distribution, natural history, and outcomes of bladder urothelial cancer in young adults are

Co-existence of mucin-producing urothelial-type adenocarcinoma of the prostate and inverted papilloma of the bladder

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Xiao-Nan Mu

2017-06-01

Full Text Available Adenocarcinoma of prostate with mucinous differentiation arising in the male urethra is extremely rare, with only 21 cases reported in the previous literature. A diagnosis of mucin-producing urothelial carcinoma of the prostate is based on the pathology, immunohistochemistry, and clinical examination by excluding the secondary adenocarcinoma of the prostate. We present a case of unexpected mucinous urothelial carcinoma of prostate with co-existing inverted papilloma of bladder in a 57-year-old man. The patient underwent transurethral resection of the prostate (TURP and transurethral resection of a bladder tumour (TUR-Bt, and the pathologic result showed mucinous prostate carcinoma and bladder inverted papilloma. Immunohistological stain was negative for prostate-specific antigen (PSA, prostate-specific acid phosphatase (PSAP, and P63, but positive for cytokeratin 7 (CK 7, CK 20, clone 34E12 and P504S. A complete endoscopic examination was performed to exclude the secondary adenocarcinoma of prostate. This case illustrates the clinical and pathological features of a rare and unexpected mucin-producing urothelial carcinoma of prostate in a bladder neoplasm patient.

Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review.

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Cho, Min Hyun; Kim, Sung Han; Park, Weon Seo; Joung, Jae Young; Seo, Ho Kyung; Chung, Jinsoo; Lee, Kang Hyun

2016-10-20

Sarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2-0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen. We report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule

Plasmacytoid Urothelial Carcinoma of the Urinary Bladder Metastatic to the Duodenum: A Case Report—Diagnostic Relevance of GATA3 Immunohistochemistry

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Hermann Brustmann

2017-01-01

Full Text Available Plasmacytoid urothelial carcinoma (PUC of the urinary bladder is a rare and aggressive subtype of urothelial carcinoma. Its deceptive morphology is characterized by a discohesive growth of cells with plasmacytoid morphology. Since this tumor might be confused with plasmacytoma, lymphoma, or carcinoma variants, appropriate diagnosis in small biopsy samples could be challenging. This study reports the case of a 53-year-old man who presented with frequent nocturnal urgency, without hematuria. A transurethral bladder and a prostate resection specimen displayed infiltration of neoplastic cells in a spray-like discohesive pattern with occasional formation of small irregular nests and cord-like arrangements. The basic morphology of the tumor cells was plasmacytoid, with eccentric nuclei and eosinophilic cytoplasm. Tumor cells grew through the lamina muscularis mucosae, with splintering of the bladder wall musculature and infiltration of prostatic tissue. They displayed strong and diffuse nuclear reactivity for p53 and GATA3. Eight months after surgery, the patient experienced upper abdominal discomfort. A duodenal biopsy showed infiltration of plasmacytoid atypical cells strongly immunoreactive for GATA3, consistent with the previously diagnosed PUC. The patient died eleven months after the primary diagnosis of his PUC of tumor cachexia losing about 50% of his original body weight, furthermore, with ascites and intraperitoneal tumor spread.

Female, Black, and Unmarried Patients Are More Likely to Present With Metastatic Bladder Urothelial Carcinoma.

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Klaassen, Zachary; DiBianco, John M; Jen, Rita P; Evans, Austin J; Reinstatler, Lael; Terris, Martha K; Madi, Rabii

2016-10-01

Although there are well-established risk factors for the diagnosis of bladder cancer, there is no consensus regarding risk factors for presentation of advanced or metastatic disease at diagnosis. The objective of this study was to identify the demographic and clinical factors associated with metastasis at diagnosis in patients with bladder urothelial carcinoma. Patients diagnosed with bladder urothelial carcinoma from 2004 to 2010 were identified in the Surveillance, Epidemiology, and End Results (SEER) database (n = 108,417). The primary outcome was metastatic disease at the time of diagnosis. Demographic and socioeconomic variables were analyzed, and multivariable logistic regression models were performed to generate odds ratios (OR) for factors associated with metastasis at diagnosis. Of patients with bladder cancer, 3018 (2.8%) had metastasis at diagnosis and 105,399 (97.2%) had nonmetastatic disease. Patients with metastatic disease at diagnosis were more frequently female (29.6% vs. 23.6%, P vs. 5.0%, P unmarried (44.1% vs. 32.5%, P vs. male, OR 1.21), black race (vs. white, OR 1.71), unmarried (vs. married, OR 1.46), unemployed (OR 1.02), and foreign-born status (OR 1.01). Female gender, black race, unmarried, unemployed, and foreign-born status are independently associated with metastasis at diagnosis for bladder urothelial carcinoma. All clinicians should be aware of these potential health care disparities in order to involve social services and other support mechanisms in efforts to improve early care. Copyright © 2016 Elsevier Inc. All rights reserved.

Enhanced urothelial expression of human chorionic gonadotropin beta (hCGβ) in bladder pain syndrome/interstitial cystitis (BPS/IC).

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Schwalenberg, Thilo; Stolzenburg, Jens-Uwe; Ho, Thi Phuc; Mallock, Tobias; Hartenstein, Siegurd; Alexander, Henry; Zimmermann, Gerolf; Hohenfellner, Rudolf; Denzinger, Stefan; Burger, Maximilian; Horn, Lars-Christian; Neuhaus, Jochen

2012-06-01

Bladder pain syndrome/interstitial cystitis (BPS/IC) is associated with urothelial lesions. Pathomechanisms of urothelial damage and factors for urothelial restoration are unknown. hCG is a factor for cellular differentiation, angiogenesis and immune competence of the endometrium during pregnancy. Clinical observations demonstrate improvement of BPS/IC symptoms during pregnancy or during infertility treatment with hCG. Our research aims were to examine the expression of hCG and luteinizing hormone receptor (LHR) in the urothelium of BPS/IC patients and compare the levels of hCGβ with healthy controls. Bladder biopsies of BPS/IC (CLSM: n = 10; qPCR: n = 15); Tumour-free control tissue from cystectomies (n = 12). hCGα, hCGβ and LHR expression were examined by confocal laser scanning microscopy (CLSM), and hCGβ expression was quantified. hCGβ5 and hCGβ7 mRNA splice variants were quantified in real-time polymerase chain reaction. We found constitutive expression of hCGα, hCGβ and LHR in healthy controls. HCGβ was significantly upregulated in BPS/IC patients in CLSM. PCR analysis revealed higher levels of hCGβ7 than hCGβ5 in controls and BPS/IC patients. The constitutive expression of hCG and LHR speaks in favour for a functional signalling in urothelial cells without any association with either pregnancy or tumour. We show for the first time that hCGβ is upregulated in BPS/IC urothelium and that hCGβ7 is the dominant splice variant in those cells. Our findings imply a major role of hCG for urothelial integrity and a disturbance of hCG signalling in case of BPS/IC. We conclude that hCG could gain therapeutical relevance in the future.

Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin.

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Buraschi, Simone; Xu, Shi-Qiong; Stefanello, Manuela; Moskalev, Igor; Morcavallo, Alaide; Genua, Marco; Tanimoto, Ryuta; Birbe, Ruth; Peiper, Stephen C; Gomella, Leonard G; Belfiore, Antonino; Black, Peter C; Iozzo, Renato V; Morrione, Andrea

2016-06-28

We have recently demonstrated a critical role for progranulin in bladder cancer. Progranulin contributes, as an autocrine growth factor, to the transformed phenotype by modulating Akt-and MAPK-driven motility, invasion and anchorage-independent growth. Progranulin also induces F-actin remodeling by interacting with the F-actin binding protein drebrin. In addition, progranulin is overexpressed in invasive bladder cancer compared to normal tissue controls, suggesting that progranulin might play a key role in driving the transition to the invasive phenotype of urothelial cancer. However, it is not established whether targeting progranulin could have therapeutic effects on bladder cancer. In this study, we stably depleted urothelial cancer cells of endogenous progranulin by shRNA approaches and determined that progranulin depletion severely inhibited the ability of tumorigenic urothelial cancer cells to migrate, invade and grow in anchorage-independency. We further demonstrate that progranulin expression is critical for tumor growth in vivo, in both xenograft and orthotopic tumor models. Notably, progranulin levels correlated with response to cisplatin treatment and were upregulated in bladder tumors. Our data indicate that progranulin may constitute a novel target for therapeutic intervention in bladder tumors. In addition, progranulin may serve as a novel biomarker for bladder cancer.

Discrimination of bladder cancer cells from normal urothelial cells with high specificity and sensitivity: combined application of atomic force microscopy and modulated Raman spectroscopy.

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Canetta, Elisabetta; Riches, Andrew; Borger, Eva; Herrington, Simon; Dholakia, Kishan; Adya, Ashok K

2014-05-01

Atomic force microscopy (AFM) and modulated Raman spectroscopy (MRS) were used to discriminate between living normal human urothelial cells (SV-HUC-1) and bladder tumour cells (MGH-U1) with high specificity and sensitivity. MGH-U1 cells were 1.5-fold smaller, 1.7-fold thicker and 1.4-fold rougher than normal SV-HUC-1 cells. The adhesion energy was 2.6-fold higher in the MGH-U1 cells compared to normal SV-HUC-1 cells, which possibly indicates that bladder tumour cells are more deformable than normal cells. The elastic modulus of MGH-U1 cells was 12-fold lower than SV-HUC-1 cells, suggesting a higher elasticity of the bladder cancer cell membranes. The biochemical fingerprints of cancer cells displayed a higher DNA and lipid content, probably due to an increase in the nuclear to cytoplasm ratio. Normal cells were characterized by higher protein contents. AFM studies revealed a decrease in the lateral dimensions and an increase in thickness of cancer cells compared to normal cells; these studies authenticate the observations from MRS. Nanostructural, nanomechanical and biochemical profiles of bladder cells provide qualitative and quantitative markers to differentiate between normal and cancerous cells at the single cellular level. AFM and MRS allow discrimination between adhesion energy, elasticity and Raman spectra of SV-HUC-1 and MGH-U1 cells with high specificity (83, 98 and 95%) and sensitivity (97, 93 and 98%). Such single-cell-level studies could have a pivotal impact on the development of AFM-Raman combined methodologies for cancer profiling and screening with translational significance. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Pannexin 1 channels play essential roles in urothelial mechanotransduction and intercellular signaling.

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Hiromitsu Negoro

Full Text Available Urothelial cells respond to bladder distension with ATP release, and ATP signaling within the bladder and from the bladder to the CNS is essential for proper bladder function. In other cell types, pannexin 1 (Panx1 channels provide a pathway for mechanically-induced ATP efflux and for ATP-induced ATP release through interaction with P2X7 receptors (P2X7Rs. We report that Panx1 and P2X7R are functionally expressed in the bladder mucosa and in immortalized human urothelial cells (TRT-HU1, and participate in urothelial ATP release and signaling. ATP release from isolated rat bladders induced by distention was reduced by the Panx1 channel blocker mefloquine (MFQ and was blunted in mice lacking Panx1 or P2X7R expression. Hypoosmotic shock induced YoPro dye uptake was inhibited by MFQ and the P2X7R blocker A438079 in TRT-HU1 cells, and was also blunted in primary urothelial cells derived from mice lacking Panx1 or P2X7R expression. Rinsing-induced mechanical stimulation of TRT-HU1 cells triggered ATP release, which was reduced by MFQ and potentiated in low divalent cation solution (LDPBS, a condition known to enhance P2X7R activation. ATP signaling evaluated as intercellular Ca2+ wave radius was significantly larger in LDPBS, reduced by MFQ and by apyrase (ATP scavenger. These findings indicate that Panx1 participates in urothelial mechanotransduction and signaling by providing a direct pathway for mechanically-induced ATP release and by functionally interacting with P2X7Rs.

uPAR Expression Pattern in Patients with Urothelial Carcinoma of the Bladder

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Dohn, Line Hammer; Pappot, Helle; Iversen, Benedikte Richter

2015-01-01

The objective of the present study was to confirm the expression and localisation pattern of the urokinase-type plasminogen activator receptor (uPAR) focusing on its possible clinical relevance in patients with urothelial neoplasia of the bladder. uPAR is a central molecule in tissue remodelling...... during cancer invasion and metastasis and is an established prognostic marker in various cancer diseases other than bladder cancer. Formalin-fixed and paraffin-embedded tumour-tissue blocks from 186 patients treated with radical cystectomy were analysed. uPAR expression was scored as either negative...... or positive as well as by the actual score. Separate scores were obtained for cancer cells, macrophages and myofibroblasts at the invasive front and in tumour core. We were able to confirm, in an independent patient cohort, the tissue expression and localisation pattern of uPAR as investigated...

The Role of Structural Extracellular Matrix Proteins in Urothelial Bladder Cancer

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Andrea Brunner

2007-01-01

Full Text Available The extracellular matrix (ECM plays a key role in the modulation of cancer cell invasion. In urothelial carcinoma of the bladder (UC the role of ECM proteins has been widely studied. The mechanisms, which are involved in the development of invasion, progression and generalization, are complex, depending on the interaction of ECM proteins with each other as well as with cancer cells. The following review will focus on the pathogenetic role and prognostic value of structural proteins, such as laminins, collagens, fi bronectin (FN, tenascin (Tn-C and thrombospondin 1 (TSP1 in UC. In addition, the role of integrins mediating the interaction of ECM molecules and cancer cells will be addressed, since integrin-mediated FN, Tn-C and TSP1 interactions seem to play an important role during tumor cell invasion and angiogenesis.

Suppression of urinary bladder urothelial carcinoma cell by the ethanol extract of pomegranate fruit through cell cycle arrest and apoptosis.

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Lee, Song-Tay; Lu, Min-Hua; Chien, Lan-Hsiang; Wu, Ting-Feng; Huang, Li-Chien; Liao, Gwo-Ing

2013-12-21

Pomegranate possesses many medicinal properties such as antioxidant, anti-inflammation and antitumor. It has been extensively used as a folk medicine by many cultures. Pomegranate fruit has been shown to have the inhibitory efficacy against prostate cancer and lung cancer in vitro and in vivo. It can be exploited in chemoprevention and chemotherapy of prostate cancer. In this study we examined the anti-cancer efficacy of pomegranate fruit grown in Taiwan against urinary bladder urothelial carcinoma (UBUC) and its mechanism of action. Edible portion of Taiwanese pomegranate was extracted using ethanol and the anti-cancer effectiveness of ethanol extract was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometry and western immunoblotting were exploited to uncover the molecular pathways underlying anti-UBUC activity of Taiwanese pomegranate ethanol extract. This study demonstrated that Taiwanese pomegranate fruit ethanol extract (PEE) could effectively restrict the proliferation of UBUC T24 and J82 cells. Cell cycle analyses indicated that the S phase arrest induced by PEE treatment might be caused by an increase in cyclin A protein level and a decrease in the expression of cyclin-dependent kinase 1. The results of western immunoblotting demonstrated that PEE treatment could not only evoke the activation of pro-caspase-3, -8,-9 but also increase Bax/Bcl-2 ratio in T24 cells. The above observations implicated that PEE administration might trigger the apoptosis in T24 cells through death receptor signaling and mitochondrial damage pathway. Besides we found that PEE exposure to T24 cells could provoke intensive activation of procaspase-12 and enhance the expressions of CHOP and Bip, endoplasmic reticulum (ER) stress marker, suggesting that ER stress might be the cardinal apoptotic mechanism of PEE-induced inhibition of bladder cancer cell. The analytical results of this study help to provide insight into the molecular mechanism

Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

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Lee, Young H. [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Apolo, Andrea B. [Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Agarwal, Piyush K.; Bottaro, Donald P., E-mail: dbottaro@helix.nih.gov [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

2014-11-25

There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

Immunohistochemical Differentiation between Urothelial Papillomas and Papillary Neoplasms of Low Malignant Potential of the Urinary Bladder.

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Alrashidy, Mohammed; Atef, Aliaa; Baky, Tarek Abdel

2016-01-01

Urothelial papilloma and non-invasive papillary carcinoma are common neoplasms of the urinary bladder. Distinguishing papillomas and papillary carcinomas, especially the low grade type, is often debatable on the basis of histological features alone. We investigated immunohistochemical expression of cytokeratin 20 (CK20), p53, and Ki-67 in a group of 20 urothelial papilloma cases and 30 noninvasive papillary neoplasms of low malignant potential (PNLMP) of the urinary bladder. Whole tissue sections were examined. Among the 30 carcinoma cases, 12 (40%) showed strong reactivity for the whole panel, 16 (53%) reacted positively for two markers, and 2 (7%) reacted just to one of them. Ki-67 was considered positive in 27 cases (90%) and p53 in 24 (80%), CK20 showed positive reactivity in 21 cases (70%). Only small percentages of papillomas were positive, and then only weakly. We concluded that the intense positivity of suspicious cells for at least one of these markers would confirm the presence of malignant changes and favours the diagnosis of carcinoma.

Pure primary small cell carcinoma of urinary bladder: A rare diagnostic entity

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Sonia Gon

2013-01-01

Full Text Available Small cell carcinoma of the bladder is a rare, aggressive, poorly differentiated neuroendocrine neoplasm accounting for only 0.3-0.7% of all bladder tumors. Since the tumor is very rare, pathogenesis is uncertain. Small cell carcinomas of the urinary bladder are mixed with classic urothelial carcinomas or adenocarcinomas of the bladder in 68% cases, making pure primary small cell carcinoma even a rarer entity. The unknown etiology and natural history of small cell carcinoma of the urinary bladder represent a challenge both to the pathologist and urologists for its diagnosis and treatment, respectively.

Urokinase-type plasminogen activator receptor (uPAR) expression is associated with T-stage and survival in urothelial carcinoma of the bladder

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Dohn, Line Hammer; Illemann, Martin; Høyer-Hansen, Gunilla

2015-01-01

OBJECTIVES: To evaluate the expression-and localization pattern of the urokinase-type plasminogen activator receptor (uPAR), focusing on its clinical implications in patients with urothelial neoplasia of the bladder treated with radical cystectomy. uPAR is a central molecule in tissue remodeling...... during cancer invasion and metastasis and is an established prognostic marker in cancer. The expression and localization of uPAR and its prognostic significance is only limitedly investigated in urothelial bladder neoplasia. MATERIALS AND METHODS: The expression-and localization pattern of u......PAR was investigated in formalin-fixed paraffin-embedded tumor tissue from 149 patients treated with radical cystectomy between 1988 and 2005. uPAR expression was determined by immunohistochemistry and scored as either negative or positive. Separate values were obtained for cancer cells, macrophages...

Pathogenesis of acute radiation effects in the urinary bladder. Experimental results

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Doerr, W.; Eckhardt, M.; Ehme, A.; Koi, S.

1998-01-01

Purpose: The present review summarizes experimental studies of the pathogenesis of acute radiation-induced changes in urinary bladder function. Material and methods: Transurethral cystometry was used for longitudinal assessment of bladder function in mice. With this technique, radiation-induced changes in storage capacity can be quantified. In histological studies, changes in urothelial cell density and in urothelial protein expression during the acute radiation response were determined. Acetylsalicylic acid (ASA) was used for the treatment of acute functional changes. Results: The histological studies did not reveal any systematic fluctuations in urothelial cell density during the time of the acute radiation response. However, characteristic changes in the expression of proteins associated with urothelial cell function, differentiation and cell contact were observed, which correlated with the functional impairment. By local or systemical application of ASA, a significant restoration of bladder function compared to placebo treatment could be achieved. Conclusion: Acute functional radiation effects in the urinary bladder are not based on urothelial denudation. However, changes in protein expression indicate an impairment of the urothelial barrier function. The results of ASA treatment demonstrate that prostaglandins are involved in the response. Alterations in urothelial or endothelial prostaglandin metabolism may be primarily radiation-induced or secondary because of the impaired urothelial barrier. (orig.) [de

Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity

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Wang Xiaojun; Sun Zheng; Chen Weimin; Eblin, Kylee E.; Gandolfi, Jay A.; Zhang, Donna D.

2007-01-01

Arsenic is widely spread in our living environment and imposes a big challenge on human health worldwide. Arsenic damages biological systems through multiple mechanisms including the generation of reactive oxygen species. The transcription factor Nrf2 regulates the cellular antioxidant response that protects cells from various insults. In this study, the protective role of Nrf2 in arsenic toxicity was investigated in a human bladder urothelial cell line, UROtsa. Using a UROtsa cell line stably infected with Nrf2-siRNA, we clearly demonstrate that compromised Nrf2 expression sensitized the cells to As(III)- and MMA(III)-induced toxicity. On the other hand, the activation of the Nrf2 pathway by tert-butylhydroquinone (tBHQ) and sulforaphane (SF), the known Nrf2-inducers, rendered UROtsa cells more resistant to As(III) and MMA(III). Furthermore, the wild-type mouse embryo fibroblast (WT-MEF) cells were protected from As(III)- and MMA(III)-induced toxicity following Nrf2 activation by tBHQ or SF, whereas neither tBHQ nor SF conferred protection in the Nrf2 -/- MEF cells, demonstrating that tBHQ- or SF-mediated protection against As(III)- and MMA(III)-induced toxicity depends on Nrf2 activation. These results, obtained by both loss of function and gain of function analyses, clearly demonstrate the protective role of Nrf2 in arsenic-induced toxicity. The current work lays the groundwork for using Nrf2 activators for therapeutic and dietary interventions against adverse effects of arsenic

A novel bioreactor to simulate urinary bladder mechanical properties and compliance for bladder functional tissue engineering.

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Wei, Xin; Li, Dao-bing; Xu, Feng; Wang, Yan; Zhu, Yu-chun; Li, Hong; Wang, Kun-jie

2011-02-01

Bioreactors are pivotal tools for generating mechanical stimulation in functional tissue engineering study. This study aimed to create a bioreactor that can simulate urinary bladder mechanical properties, and to investigate the effects of a mechanically stimulated culture on urothelial cells and bladder smooth muscle cells. We designed a bioreactor to simulate the mechanical properties of bladder. A pressure-record system was used to evaluate the mechanical properties of the bioreactor by measuring the pressure in culture chambers. To test the biocompatibility of the bioreactor, viabilities of urothelial cells and smooth muscle cells cultured in the bioreactor under static and mechanically changed conditions were measured after 7-day culture. To evaluate the effect of mechanical stimulations on the vital cells, urethral cells and smooth muscle cells were cultured in the simulated mechanical conditions. After that, the viability and the distribution pattern of the cells were observed and compared with cells cultured in non-mechanical stimulated condition. The bioreactor system successfully generated waveforms similar to the intended programmed model while maintaining a cell-seeded elastic membrane between the chambers. There were no differences between viabilities of urothelial cells ((91.90 ± 1.22)% vs. (93.14 ± 1.78)%, P > 0.05) and bladder smooth muscle cells ((93.41 ± 1.49)% vs. (92.61 ± 1.34)%, P > 0.05). The viability of cells and tissue structure observation after cultured in simulated condition showed that mechanical stimulation was the only factor affected cells in the bioreactor and improved the arrangement of cells on silastic membrane. This bioreactor can effectively simulate the physiological and mechanical properties of the bladder. Mechanical stimulation is the only factor that affected the viability of cells cultured in the bioreactor. The bioreactor can change the growth behavior of urothelial cells and bladder smooth muscle cells, resulting in

Resolution of hypercalcemia of malignancy following radical cystectomy in a patient with paraneoplastic syndrome associated with urothelial carcinoma of the bladder

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Alfredo Harb-De La Rosa

2015-01-01

Full Text Available Hypercalcemia of malignancy is a common finding associated with different types of cancers; however, its association with urothelial carcinoma of the bladder is rare. We report a case of a 69-year-old male with nonmetastatic urothelial carcinoma of the bladder who developed hypercalcemia that failed to respond to medical management, but resolved completely after undergoing resection of the tumor through radical cystectomy.

Voided urine versus bladder washing cytology for detection of urothelial carcinoma: which is better?

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Keller, Anna Krarup; Jensen, Jørgen Bjerggaard

2017-08-01

Cytology is recommended as part of the follow-up of high-grade non-muscle-invasive bladder cancer (NMIBC). However, currently there are no solid guideline recommendations regarding the use of voided urine versus bladder washing for cytology as part of the diagnosis or follow-up of NMIBC. The aim of this study was to investigate whether the cytological outcome was equal regarding the two techniques. The authors reviewed all outpatient flexible cystoscopies carried out in their department in 2013. Patient records in the registry of pathology were examined and those with simultaneous urine and bladder washing cytology were included. Previous urothelial disease and positive histology within 3 months after the cystoscopy were registered. A total of 1458 patients had both voided urine and bladder washing cytology and were included in the study, of whom 643 (44%) had a history of urothelial disease. An equal outcome of urine and bladder washing cytology was found in 1447 patients (99.2%). For the remaining 11 patients, only four patients underwent further examinations based on cytology findings in addition to what had already been planned after cystoscopy. Of the included patients, 100 (6.9%) had a positive histological outcome within 3 months. In most patients, no relevant difference between voided urine and bladder washing cytology was observed. Therefore, if cytology is indicated, it is recommended to use the test that is most readily available locally. The additional gain in using both urine and bladder wash is minimal, and can therefore be discarded.

Bladder Cancer—Patient Version

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The most common type of bladder cancer is transitional cell carcinoma, also called urothelial carcinoma. Smoking is a major risk factor for bladder cancer. Bladder cancer is often diagnosed at an early stage. Start here to find information on bladder cancer treatment, screening, research, and statistics.

Expression status and prognostic significance of mammalian target of rapamycin pathway members in urothelial carcinoma of urinary bladder after cystectomy.

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Schultz, Luciana; Albadine, Roula; Hicks, Jessica; Jadallah, Sana; DeMarzo, Angelo M; Chen, Ying-Bei; Nielsen, Matthew E; Neilsen, Matthew E; Gonzalgo, Mark L; Sidransky, David; Schoenberg, Mark; Netto, George J

2010-12-01

Bladder urothelial carcinoma has high rates of mortality and morbidity. Identifying novel molecular prognostic factors and targets of therapy is crucial. Mammalian target of rapamycin (mTOR) pathway plays a pivotal role in establishing cell shape, migration, and proliferation. Tissue microarrays were constructed from 132 cystectomies (1994-2002). Immunohistochemistry was performed for Pten, c-myc, p27, phosphorylated (phos)Akt, phosS6, and 4E-BP1. Markers were evaluated for pattern, percentage, and intensity of staining. Mean length of follow-up was 62.6 months (range, 1-182 months). Disease progression, overall survival (OS), and disease-specific survival (DSS) rates were 42%, 60%, and 68%, respectively. Pten showed loss of expression in 35% of bladder urothelial carcinoma. All markers showed lower expression in invasive bladder urothelial carcinoma compared with benign urothelium with the exception of 4E-BP1. Pten, p27, phosAkt, phosS6, and 4E-BP1 expression correlated with pathologic stage (pathological stage; P<.03). Pten, 4E-BP1, and phosAkt expression correlated with divergent aggressive histology and invasion. phosS6 expression inversely predicted OS (P=.01), DSS (P=.001), and progression (P=.05). c-myc expression inversely predicted progression (P=.01). In a multivariate analysis model that included TNM stage grouping, divergent aggressive histology, concomitant carcinoma in situ, phosS6, and c-myc expression, phosS6 was an independent predictor of DSS (P=.03; hazard ratio [HR], -0.19), whereas c-myc was an independent predictor of progression (P=.02; HR, -0.38). In a second model substituting organ-confined disease and lymph node status for TNM stage grouping, phosS6 and c-myc remained independent predictors of DSS (P=.03; HR, -0.21) and progression (P=.03; HR, -0.34), respectively. We found an overall down-regulation of mTOR pathway in bladder urothelial carcinoma. phosS6 independently predicted DSS, and c-myc independently predicted progression

Urothelial cells in smears from cervix uteri

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Palaoro, Luis Alberto; Guerra, Fernando; Angeleri, Anabela; Palamas, Marta; Melba, Sardi-Segovia; Rocher, Adriana Esther

2012-01-01

Objectives: To establish the cytological criteria to identify the urothelial cells in cervical smears in order to avoid mistakes in the cytological diagnosis. Materials and Methods: Cervical smears from 34 post menopausal women with vesicovaginal fistulas, advanced bladder prolapse and genital erosive lichen planes (vulvar kraurosis) (Group 1) and transitional cell metaplasia of the cervix (TCM, Group 2) were stained with Papanicolaou technique. The cervical samples were taken during the routine annual examination for prevention of the uterine cancer. Results: The smears of cervix from Group 1 showed urothelial cells from the three layers of the transitional epithelium. The umbrella cells are the bigger ones with relatively large nuclei. Frequently, they are multinucleated with single or multiple nucleoli and a typical “frothy” cytoplasm (cytoplasmic vacuoles). The cells of the Group 2 showed nuclei with oval to spindled shapes, some tapered ends, less cytoplasm than squamous metaplastic cells, powdery chromatin, small nucleoli and nuclear grooves. Conclusions: The umbrella cells may be mistaken for dysplastic cells originating in low grade squamous intraepithelial lesions lesions (LSILs) due to their nuclear and cytoplasm sizes. Therefore, it is important to know the possibility of their appearance in the cervical smears, especially in post menopausal patients in order to avoid a false diagnosis of an intraepithelial lesion. It is unlikely that deeper cells of urothelium would be confused with high grade squamous intraepithelial lesion (HSIL) cells. However, their presence might be a reason of mistake in the diagnosis. TCM is an under-recognized metaplastic phenomenon of the cervix and vagina, which is a mimicker of high-grade squamous intraepithelial lesion. The differential characteristic between umbrella cells, cells from TCM and the deeper urothelial cells, and LSIL and HSIL are detailed in the present paper. PMID:22438615

Langerhans cell histiocytosis of the urinary bladder in a patient with bladder cancer previously treated with intravesical Bacillus Calmette-Guérin therapy.

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Numakura, Satoe; Morikawa, Teppei; Ushiku, Tetsuo; Toyoshima, Toyoaki; Fukayama, Masashi

2014-02-01

We report an extremely rare case of Langerhans cell histiocytosis (LCH) of the urinary bladder. A 68-year-old man presented with gross hematuria. Cystoscopy showed multiple papillary tumors in the urinary bladder, and transurethral resection was performed. Pathological diagnosis was high-grade papillary urothelial carcinoma with lamina propria invasion. The patient received six treatments with intravesical Bacillus Calmette-Guérin (BCG) therapy. Seven months after surgery, follow-up cystoscopy showed three elevated lesions in the urinary bladder, two of which were identified histologically as recurrent urothelial carcinoma. Microscopic examination of the lesion at the anterior wall revealed diffuse infiltration of medium to large histiocytoid cells in the lamina propria, many of which had distorted nuclei and nuclear grooves. Dense eosinophilic infiltration was also observed. Immunohistochemically, the histiocytoid cells were diffusely positive for S-100 and CD1a, but negative for cytokeratin AE1/AE3 and melanosome-associated antigen recognized by HMB-45. Based on the histological and immunohistochemical features, we diagnosed the lesion as LCH of the urinary bladder. There was no evidence of recurrence of either bladder cancer or LCH after an 18-month follow-up. To avoid misdiagnosis, urologists and pathologists should be aware that LCH may develop in the urinary bladder after intravesical BCG therapy for bladder cancer. Copyright © 2013 Elsevier GmbH. All rights reserved.

Clinicopathological spectrum of urothelial carcinoma of the urinary bladder - a study of 541 cases at afip pakistan

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Ahmed, R.; Hashmi, S.N.; Muhammad, I.

2015-01-01

Objective: To analyze the clinicopathological spectrum of urothelial carcinoma of urinary bladder. Study Design: Descriptive case series. Place and Duration of Study: Armed Forces Institute of Pathology (AFIP), from 1st January 2012 to 31st October 2013. Patients and methods: All cases of urothelial carcinoma were retrieved from AFIP tumour registry. Age, gender, histological type, grade and variant of tumour was noted. The data was analyzed by using computer software program SPSS version 19. Descriptive statistics and frequencies were calculated for age, gender, histological type, grade and variants. Results: A total of 541 cases of urothelial carcinoma were included in the study. The age at presentation ranged from 22 to 94 years with median age of 63.56 ± 12 years. A number (61%) of the cases were from 6th to 8th decade of life. The gender distribution showed 92.8% of patients (n=502) were males and 7.2 % (n=39) were females with male to female ratio of 12.9: 1. The most common histological type was papillary urothelial carcinoma; present in 493 cases (91.1%) followed by nonpapillary urothelial carcinoma; 48 cases (8.9%). Among papillary urothelial carcinomas, 302 cases (61.3%) were high grade and 191 cases (38.7%) were low grade. Among nonpapillary urothelial carcinomas, all were high grade and variant histology was observed in all cases. The variants included squamoid differentiation which was present in 27 cases (56.3%), nested variant in 8 cases (16.7%). The sarcomatoid, undifferentiated and clear cell variants in 3 cases (6.3%) each, micropapillary variant in 2 cases (4.2%), lymphoepithelial-like and plasmacytoid variant in 1 case (2.1%) each. Conclusion: Urothelial carcinoma is more common in males. Most of the tumours are papillary urothelial carcinomas. Most of them are high grade and pure urothelial carcinomas. A number of histologic variants are also recognized. Among them, squamoid differentiation is the most common variant histology. (author)

Bladder cancer and schistosomiasis

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Zaghloul, M.S.

2012-01-01

Schistosoma-associated bladder cancer was believed, for several decades, to be a completely unique entity of disease, different from urothelial cancer. This was probably due to its distinct clinico pathologic and demographic features that varied from those of urothelial entity. The carcinogenesis is an extremely complex process resulting from the accumulation of many genetic and epigenetic changes leading to alterations in the cell proliferation regulation process. In bladder cancer, many of these carcinogenic cascades were not fully documented or somewhat conflicting. In spite of the efforts performed, much is still needed to explore the presence or absence of the carcinogenic difference with a different etiology. The control of schistosomiasis in certain countries and the subsequent decrease in the intensity of infestation showed changing of features approaching that of urothelial tumors. However the schistosoma-associated bladder cancer presented in more advanced stages than schistosoma-non associated urothelial cancer. More recently, data are gathered that, upon applying the same treatment protocol and management care, stage by stage comparison of the treatment end-results were found to be similar in bladder cancer patients with a different etiology. All treatment options; including radical cystectomy with or without adjuvant or neoadjuvant chemo- or radiotherapy or tri modality bladder preserving treatment seem to lead to similar end-results regardless of etiologic factor(s) implicated in bladder cancer development.

Urothelial carcinoma of urinary bladder with exclusive heterologous component of epithelioid rhabdomyosarcoma at metastatic site.

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Agarwal, Poojan; Pasricha, Sunil; Gupta, Gurudutt; Sharma, Anila; Mehta, Anurag

2018-01-01

Urothelial carcinoma of urinary bladder with divergent differentiation into rhabdomyosarcoma (RMS) is an extremely uncommon aggressive phenomenon. We present a case of a 74-year-old male with bladder carcinoma which metastasized to the abdominal wall as epithelioid RMS. To the best knowledge of our literature searches, an oligometastasis of exclusive heterologous component has not been described before. The clinical, radiological, and immunohistochemistry profile of the patient supported the monoclonal nature of the tumor.

Gemcitabine: Selective cytotoxicity, induction of inflammation and effects on urothelial function

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Farr, Stefanie E; Chess-Williams, Russ; McDermott, Catherine M, E-mail: camcderm@bond.edu.au

2017-02-01

Intravesical gemcitabine has recently been introduced for the treatment of superficial bladder cancer and has a favourable efficacy and toxicity profile in comparison to mitomycin c (MMC), the most commonly used chemotherapeutic agent. The aim of this study was to assess the cytotoxic potency of gemcitabine in comparison to MMC in urothelial cell lines derived from non-malignant (UROtsa) and malignant (RT4 and T24) tissues to assess selectivity. Cells were treated with gemcitabine or mitomycin C at concentrations up to the clinical doses for 1 or 2 h respectively (clinical duration). Treatment combined with hyperthermia was also examined. Cell viability, ROS formation, urothelial function (ATP, acetylcholine and PGE2 release) and secretion of inflammatory cytokines were assessed. Gemcitabine displayed a high cytotoxic selectivity for the two malignant cell lines (RT4, T24) compared to the non-malignant urothelial cells (UROtsa, proliferative and non-proliferative). In contrast, the cytotoxic effects of MMC were non-selective with equivalent potency in each of the cell lines. The cytotoxic effect of gemcitabine in the malignant cell lines was associated with an elevation in free radical formation and was significantly decreased in the presence of an equilibrative nucleoside transporter inhibitor. Transient changes in urothelial ATP and PGE{sub 2} release were observed, with significant increase in release of interleukin-6, interleukin-8 and interleukin-1β from urothelial cells treated with gemcitabine. The selectivity of gemcitabine for malignant urothelial cells may account for the less frequent adverse urological effects with comparison to other commonly used chemotherapeutic agents. - Highlights: • Intravesical gemcitabine has recently been introduced to treat bladder cancer. • Gemcitabine is selectively toxic for malignant urothelial cells. • Urothelial ATP, PGE{sub 2} and inflammatory cytokines were altered by gemcitabine. • Selectivity of gemcitabine

Chronic arsenic exposure increases TGFalpha concentration in bladder urothelial cells of Mexican populations environmentally exposed to inorganic arsenic

International Nuclear Information System (INIS)

Valenzuela, Olga L.; Germolec, Dori R.; Borja-Aburto, Victor H.; Contreras-Ruiz, Jose; Garcia-Vargas, Gonzalo G.; Razo, Luz M. del

2007-01-01

Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-α) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAs III , MAs V , DMAs III , DMAs V ). This study examines the relationship between TGF-α concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-α in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-α concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-α levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-α concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p < 0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-α than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p = 0.003). These results suggest that TGF-α in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas

CEA-producing urothelial cell carcinoma with metastasis presenting as a rectal adenocarcinoma

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Ming-Hsin Yang

2012-11-01

Full Text Available This is a case study of a 61-year-old male who presented with difficult defecation for 1 month. A circumferential submucosal rectal tumor was noted on a digital rectal examination and colonoscopy. Laboratory examination revealed high serum levels of carcinoembryonic antigen (CEA; 43.75 ng/mL and carbohydrate antigen 19-9 (CA19-9; 11,790 U/mL. In addition, tumor biopsies revealed a poorly differentiated adenocarcinoma of the rectum with intact mucosa. The patient had history of advanced stage-T2 urothelial cell carcinoma of bladder, which had been downstaged to T0 by neoadjuvant chemotherapy followed by radical cystectomy 1 year prior. After investigating the initial bladder tumor specimens, a small portion of the tumor with high CEA expression comparable to the submucosal rectal tumor was found. The size of the tumor was reduced and the levels of the tumor markers decreased after administering FOLFIRI chemotherapy targeted at the adenocarcinoma. Although neoadjuvant chemotherapy may have a selective pressure to eliminate most urothelial cell carcinoma, physicians should be aware that it can lead to rectal metastasis via CEA-producing components.

Urothelial carcinoma associated 1 is a hypoxia-inducible factor-1α-targeted long noncoding RNA that enhances hypoxic bladder cancer cell proliferation, migration, and invasion.

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Xue, Mei; Li, Xu; Li, Zhengkun; Chen, Wei

2014-07-01

Urothelial carcinoma associated 1 (UCA1) has been identified as an oncogenic long noncoding RNA (lncRNA) that is involved in bladder cancer progression and acts as a diagnostic biomarker for bladder carcinoma. Here, we studied the expression and function of lncRNA-UCA1 in the hypoxic microenvironment of bladder cancer. The expression and transcriptional activity of lncRNA-UCA1 were measured by quantitative real-time polymerase chain reaction and luciferase assays. Cell proliferation and apoptosis were evaluated by MTT assays and flow cytometry. Cell migration and invasion were detected by wound healing, migration, and invasion assays. The binding of hypoxia-inducible factor-1α (HIF-1α) to hypoxia response elements (HREs) in the lncRNA-UCA1 promoter was confirmed by electrophoretic mobility shift assay and chromatin immunoprecipitation. HRE mutations were generated by using a site-directed mutagenesis kit, and HIF-1α knockdown was mediated by small interfering RNA. The effect of HIF-1α inhibition by YC-1 on lncRNA-UCA1 expression was also examined. LncRNA-UCA1 was upregulated by hypoxia in bladder cancer cells. Under hypoxic conditions, lncRNA-UCA1 upregulation increased cell proliferation, migration, and invasion and inhibited apoptosis. The underlying mechanism of hypoxia-upregulated lncRNA-UCA1 expression was that HIF-1α specifically bound to HREs in the lncRNA-UCA1 promoter. Furthermore, HIF-1α knockdown or inhibition could prevent lncRNA-UCA1 upregulation under hypoxia. These findings revealed the mechanism of lncRNA-UCA1 upregulation in hypoxic bladder cancer cells and suggested that effective blocking of lncRNA-UCA1 expression in the hypoxic microenvironment of bladder cancer could be a novel therapeutic strategy.

Expression of OCT4A: The First Step to the Next Stage of Urothelial Bladder Cancer Progression

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Wojciech Jóźwicki

2014-09-01

Full Text Available OCT4 (octamer-binding transcription factor is a transcription factor responsible for maintaining the pluripotent properties of embryonic stem cells. In this paper, we present the results of studies to investigate the role of the OCT4 splicing variant in urothelial bladder cancer and the relationship between the OCT4 phenotype and the morphological parameters of tumor malignancy. Ninety patients who received a cystectomy for bladder cancer were enrolled. The expression of OCT4 protein was analyzed by immunohistochemistry. The ratio of OCT4-positive cells was the lowest in pT1 (pathological assessment (p—tumor extent confined to mucosa (T1 tumors and the highest in pTis (non-papillary tumor extent confined to urothelium and pT2 (tumor extent including muscularis propria tumors. Information about the percentage of OCT4A-positive tumor cells could facilitate choosing the treatment mode in borderline pTis–pT1 (crossing the border of the basement membrane; the first stage of progression and pT1–pT2 (crossing the border of the muscularis propria; the second stage of progression cases: a higher percentage of OCT4A-positive cells should support more radical therapy. A significantly higher percentage of cases with moderate OCT4 intensity was found in metastasizing (the third stage of progression cases with >2 positive lymph nodes. The percentage of OCT4-positive cells was significantly higher for cancers with a high grade, higher non-classic differentiation number and greater aggressiveness of invasion. The differentiation, maturation and aggressiveness of tumor invasion appear to depend on the expression of the OCT4 phenotype in cancer cells, similar to the successive stages of malignancy progression in urothelial cancer.

Unusual manifestations of secondary urothelial carcinoma

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Chaohui Lisa Zhao

2016-03-01

Full Text Available High-grade papillary urothelial carcinoma regularly invades the bladder wall, adjacent prostate, seminal vesicles, ureters, vagina, rectum, retroperitoneum, and regional lymph nodes. In advanced stages, it may disseminate to the liver, lungs, and bone marrow. On rare occasions, unusual metastatic foci like skin have been reported. The incidence of urothelial carcinoma has increased with associated rise in variants of urothelial carcinoma and unusual metastatic foci. It is imperative that urologists and pathologists are aware of the unusual variants and unusual metastatic locations to expedite the diagnostic process. Hereby we report an unusual case of secondary involvement of spinal nerve by conventional urothelial carcinoma. Also a second case of rhabdoid variant of urothelial carcinoma showing synchronous involvement of bladder and subcutaneous tissue of upper extremity is presented.

FGFR3 and P53 characterize alternative genetic pathways in the pathogenesis of urothelial cell carcinoma

NARCIS (Netherlands)

B.W. van Rhijn (Bas); Th.H. van der Kwast (Theo); A.N. Vis (André); W.J. Kirkels (Wim); E.R. Boeve; A.C. Jobsis; E.C. Zwarthoff (Ellen)

2004-01-01

textabstractFibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53

Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma

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Ning X

2017-03-01

Full Text Available Xin Ning, Yaoliang Deng Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, People’s Republic of China Background: Genomic profiling can be used to identify the predictive effect of genomic subsets for determining prognosis in bladder urothelial carcinoma (BUC after radical cystectomy. This study aimed to investigate potential gene and pathway markers associated with prognosis in BUC.Methods: A microarray dataset of BUC was obtained from The Cancer Genome Atlas database. Differentially expressed genes (DEGs were identified by DESeq of the R platform. Kaplan–Meier analysis was applied for prognostic markers. Key pathways and genes were identified using bioinformatics tools, such as gene set enrichment analysis, gene ontology, the Kyoto Encyclopedia of Genes and Genomes, gene multiple association network integration algorithm (GeneMANIA, Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection.Results: A comparative gene set enrichment analysis of tumor and adjacent normal tissues suggested BUC tumorigenesis resulted mainly from enrichment of cell cycle and DNA damage and repair-related biological processes and pathways, including TP53 and mitotic recombination. Two hundred and fifty-six genes were identified as potential prognosis-related DEGs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the potential prognosis-related DEGs were enriched in angiogenesis, including the cyclic adenosine monophosphate biosynthetic process, cyclic guanosine monophosphate-protein kinase G, mitogen-activated protein kinase, Rap1, and phosphoinositide-3-kinase-AKT signaling pathway. Nine hub genes, TAGLN, ACTA2, MYH11, CALD1, MYLK, GEM, PRELP, TPM2, and OGN, were identified from the intersection of protein–protein interaction and GeneMANIA networks. Module analysis of protein–protein interaction and GeneMANIA networks mainly showed

Macronutrient intake and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition

NARCIS (Netherlands)

Allen, N.E.; Appleby, P.N.; Key, T.J.; Bueno-De-Mesquita, H.B.; Ros, M.M.; Kiemeney, L.A.L.M.; Tjonneland, A.; Roswall, N.; Overvad, K.; Weikert, S.; Boeing, H.; Chang-Claude, J.; Teucher, B.; Panico, S.; Sacerdote, C.; Tumino, R.; Palli, D.; Sieri, S.; Peeters, P.; Quiros, J.R.; Jakszyn, P.; Molina-Montes, E.; Chirlaque, M.D.; Ardanaz, E.; Dorronsoro, M.; Khaw, K.T.; Wareham, N.; Ljungberg, B; Hallmans, G.; Ehrnstrom, R.; Ericson, U.; Gram, I.T.; Parr, C.L.; Trichopoulou, A.; Karapetyan, T.; Dilis, V.; Clavel-Chapelon, F.; Boutron-Ruault, M.C.; Fagherrazzi, G.; Romieu, I.; Gunter, M.J.; Riboli, E.

2013-01-01

Previous studies have suggested that dietary factors may be important in the development of bladder cancer. We examined macronutrient intake in relation to risk of urothelial cell carcinoma among 469,339 men and women in the European Prospective Investigation into Cancer and Nutrition. Associations

Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer

Science.gov (United States)

Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation i...

Imaging of urinary bladder tumors

International Nuclear Information System (INIS)

Hadjidekov, G.

2015-01-01

Full text: Primary bladder neoplasms account for 2%-6% of all tumors, with urinary bladder cancer ranked as the fourth most common cancer in males. Transitional cell carcinoma (TCC) is the most common subtype of urothelial tumour accounting for approximately 90% of all urothelial cancers. It is typically observed in men aged 50-70 years with history of smoking or occupational exposure to carcinogens. Most urothelial neoplasms are low-grade papillary tumors, with high incidence of recurrence, requires rigorous follow-up but have a relatively good prognosis. Other bladder neoplasm include squamous cell carcinoma accounts for 2%-15% mainly according to geographic location; adenocarcinoma - less than 2% /both occurring in the context of chronic bladder infection and irritation/; mesenchymal tumors in 5%, with the most common examples being rhabdomyosarcoma in children and leiomyosarcoma in adults. More rare mesenchymal tumors include paraganglioma, lymphoma, leiomyoma and solitary fibrous tumor which have no specific typical imaging findings to be differentiated. Multidetector computed tomography urography is an efficient tool for diagnosis and follow-up in patients with transitional cell carcinoma and it can be considered the primary radiologic method for detection, staging and assessment of the entire urothelium regarding the multicentric nature of TCC. MRI is rapidly expanding modality of choice especially in locally staging the tumor and in controversies. Accurate TNM staging is primordial in choosing treatment and prognosis for patients with bladder carcinoma. Correct interpretation and classification of the tumour is helpful for the urologists to determine further management in these cases. The learning objectives of the presentation are: to illustrate the spectrum of CT and MRI findings and to assess their clinical value in patients with transitional cell carcinoma and some other bladder neoplasm; to discuss the TNM staging based on the imaging findings; to be

Positive fibroblast growth factor receptor 3 immunoreactivity is associated with low-grade non-invasive urothelial bladder cancer

NARCIS (Netherlands)

C. Poyet (Cédric); T. Hermanns (Thomas); Q. Zhong (Qing); E. Drescher (Eva); D. Eberli (Daniel); M. Burger (Maximilian); F. Hofstaedter (Ferdinand); A. Hartmann (Arndt); R. Stöhr (Robert); E.C. Zwarthoff (Ellen); T. Sulser (Tullio); P.J. Wild (Peter J.)

2015-01-01

textabstractIn addition to conventional clinicopathological parameters, molecular markers are also required in order to predict the course of disease in patients with urothelial bladder cancer (BC). Little is known about fibroblast growth factor receptor 3 (FGFR3) immunoreactivity and the clinical

Impact of urothelial carcinoma with divergent differentiation on tumor stage

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S Chalise

2016-03-01

Full Text Available Background: Urinary bladder cancer is classified as urothelial or non-urothelial. Ninenty percent of bladder cancer are urothelial and has propensity for divergent differentiation. Squamous differentiation is associated with unfavourable prognostic features. The aim of this study is to determine the significance of urothelial carcinoma with divergent differentiation in relation to tumor stage and lymphovascular as well as perineural invasion in radical cystectomy and partial cystectomy specimen.Materials and methods: This prospective study was done among 51 patients who underwent radical cystectomy or partial cystectomy at Bhaktapur Cancer Hospital from 1st August 2013 to 31st December 2015. Received specimen was grossed following standard protocol and histopathological evaluation was done in relation to tumor type, depth of invasion, Lymphovascular and perineural invasion.Results: Pure urothelial carcinoma comprises 47.1% of cases. Among the divergent differentiation, urothelial carcinoma with squamous differentiation was the commonest one (39.2% followed by glandular differentiation (5.9%, sarcomatoid differentiation (3.9%, clear cell variant (2.0% and squamous along with sarcomatoid variant (2.0%. Statistical significant correlation was found between urothelial carcinoma with divergent differentiation and tumor stage (p<0.012. Statistically significant correlation was also found between urothelial carcinoma with divergent differentiation and lymphovascular invasion (p=0.012 as well as perineural invasion (p=0.037.Conclusion:  Most common divergent differentiation was squamous differentiation. Urothelial carcinoma with divergent differentiation was associated with higher stage and lymphovascular as well as perineural invasion. So it is mandatory to search for the divergent differentiation in urothelial carcinoma as this may be associated with unfavourable prognosis.

Cystitis: From Urothelial Cell Biology to Clinical Applications

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Gilho Lee

2014-01-01

Full Text Available Cystitis is a urinary bladder disease with many causes and symptoms. The severity of cystitis ranges from mild lower abdominal discomfort to life-threatening haemorrhagic cystitis. The course of disease is often chronic or recurrent. Although cystitis represents huge economical and medical burden throughout the world and in many cases treatments are ineffective, the mechanisms of its origin and development as well as measures for effective treatment are still poorly understood. However, many studies have demonstrated that urothelial dysfunction plays a crucial role. In the present review we first discuss fundamental issues of urothelial cell biology, which is the core for comprehension of cystitis. Then we focus on many forms of cystitis, its current treatments, and advances in its research. Additionally we review haemorrhagic cystitis with one of the leading causative agents being chemotherapeutic drug cyclophosphamide and summarise its management strategies. At the end we describe an excellent and widely used animal model of cyclophosphamide induced cystitis, which gives researches the opportunity to get a better insight into the mechanisms involved and possibility to develop new therapy approaches.

Expression of RFC/SLC19A1 is associated with tumor type in bladder cancer patients.

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Alyaa M Abdel-Haleem

Full Text Available Urinary bladder cancer (UBC ranks ninth in worldwide cancer. In Egypt, the pattern of bladder cancer is unique in that both the transitional and squamous cell types prevail. Despite much research on the topic, it is still difficult to predict tumor progression, optimal therapy and clinical outcome. The reduced folate carrier (RFC/SLC19A1 is the major transport system for folates in mammalian cells and tissues. RFC is also the primary means of cellular uptake for antifolate cancer chemotherapeutic drugs, however, membrane transport of antifolates by RFC is considered as limiting to antitumor activity. The purpose of this study was to compare the mRNA expression level of RFC/SLC19A1 in urothelial and non-urothelial variants of bladder carcinomas. Quantification of RFC mRNA in the mucosa of 41 untreated bladder cancer patients was performed using RT-qPCR. RFC mRNA steady-state levels were ∼9-fold higher (N = 39; P<0.0001 in bladder tumor specimens relative to normal bladder mRNA. RFC upregulation was strongly correlated with tumor type (urothelial vs. non-urothelial; p<0.05 where median RFC mRNA expression was significantly (p<0.05 higher in the urothelial (∼14-fold compared to the non-urothelial (∼4-fold variant. This may account for the variation in response to antifolate-containing regimens used in the treatment of either type. RFC mRNA levels were not associated with tumor grade (I, II and III or stage (muscle-invasive vs. non-muscle invasive implying that RFC cannot be used for prognostic purposes in bladder carcinomas and its increased expression is an early event in human bladder tumors pathogenesis. Further, RFC can be considered as a potential marker for predicting response to antifolate chemotherapy in urothelial carcinomas.

A case of brain and leptomeningeal metastases from urothelial carcinoma of the bladder.

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Erhamamcı, S; Reyhan, M; Altinkaya, N

2014-01-01

Brain metastases are unusual from urethelial carcinoma of bladder and particularly the occurrence of leptomeningeal metastases is extremely rare, with few cases described in the literature. We present a case of a 45-year-old man with a rare brain metastases as the first metastatic manifestation secondary to urethelial carcinoma of bladder followed by leptomeningeal metastases without any other organ involvement. Eleven months after the diagnosis of high-grade urethelial carcinoma of bladder (T2N0M0), the patient was detected having brain metastases by MRI. FDG PET/CT images for the metastatic evaluation showed no abnormal FDG uptake elsewhere in the body except the brain. Histopathology examination from brain lesion demonstrated the cerebral lesion to be a metastatic urothelial carcinoma. Two months later, the patient was diagnosed to have leptomeningeal metastases by MRI. Our patient's condition gradually worsened, and he died 3 months after the diagnosis of leptomeningeal metastases. Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.

Androgen Receptor Signaling in Bladder Cancer

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Li, Peng; Chen, Jinbo; Miyamoto, Hiroshi

2017-01-01

Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer. PMID:28241422

Androgen Receptor Signaling in Bladder Cancer

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Peng Li

2017-02-01

Full Text Available Emerging preclinical findings have indicated that steroid hormone receptor signaling plays an important role in bladder cancer outgrowth. In particular, androgen-mediated androgen receptor signals have been shown to correlate with the promotion of tumor development and progression, which may clearly explain some sex-specific differences in bladder cancer. This review summarizes and discusses the available data, suggesting the involvement of androgens and/or the androgen receptor pathways in urothelial carcinogenesis as well as tumor growth. While the precise mechanisms of the functions of the androgen receptor in urothelial cells remain far from being fully understood, current evidence may offer chemopreventive or therapeutic options, using androgen deprivation therapy, in patients with bladder cancer.

Long non-coding RNA urothelial carcinoma-associated 1 as a tumor biomarker for the diagnosis of urinary bladder cancer.

Science.gov (United States)

Wang, Zichun; Wang, Xiaoxiong; Zhang, Daming; Yu, Yongchun; Cai, Licheng; Zhang, Cheng

2017-06-01

To investigate the diagnostic value of urothelial carcinoma-associated 1 as a urine biomarker in urinary bladder cancer patients by performing a comprehensive meta-analysis. A comprehensive literature search was conducted by the databases PubMed, Embase, Cochrane Library, China Knowledge Resource Integrated, and Web of Science. The quality of eligible studies was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was used to pool the sensitivity, specificity, likelihood ratio, and diagnostic odds ratio. Receiver operating characteristic curves and hierarchical summary receiver operating characteristic models were employed to check the overall test performance in this meta-analysis. Seven publications involving 678 patients and 563 controls were included in this meta-analysis. The pooled sensitivity was 0.84 (95% confidence interval: 0.80-0.88), specificity was 0.87 (95% confidence interval: 0.75-0.94), positive likelihood ratio was 6.5 (95% confidence interval: 3.10-13.62), negative likelihood ratio was 0.18 (95% confidence interval: 0.13-0.25), and diagnostic odds ratio was 36 (95% confidence interval: 13-99). The area under the summary receiver operating characteristic curve was 0.89 (95% confidence interval: 0.86-0.91). Our results indicated that urothelial carcinoma-associated 1 was a potential diagnostic biomarker with good specificity and sensitivity in urinary bladder cancer. Further prospective studies with larger cohorts are necessary to evaluate the diagnostic accuracy of urothelial carcinoma-associated 1 for urinary bladder cancer.

Tumor-Associated Macrophages Provide Significant Prognostic Information in Urothelial Bladder Cancer.

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Minna M Boström

Full Text Available Inflammation is an important feature of carcinogenesis. Tumor-associated macrophages (TAMs can be associated with either poor or improved prognosis, depending on their properties and polarization. Current knowledge of the prognostic significance of TAMs in bladder cancer is limited and was investigated in this study. We analyzed 184 urothelial bladder cancer patients undergoing transurethral resection of a bladder tumor or radical cystectomy. CD68 (pan-macrophage marker, MAC387 (polarized towards type 1 macrophages, and CLEVER-1/Stabilin-1 (type 2 macrophages and lymphatic/blood vessels were detected immunohistochemically. The median follow-up time was 6.0 years. High macrophage counts associated with a higher pT category and grade. Among patients undergoing transurethral resection, all studied markers apart from CLEVER-1/Stabilin-1 were associated with increased risk of progression and poorer disease-specific and overall survival in univariate analyses. High levels of two macrophage markers (CD68/MAC387+/+ or CD68/CLEVER-1+/+ groups had an independent prognostic role after transurethral resection in multivariate analyses. In the cystectomy cohort, MAC387, alone and in combination with CD68, was associated with poorer survival in univariate analyses, but none of the markers were independent predictors of outcome in multivariate analyses. In conclusion, this study demonstrates that macrophage phenotypes provide significant independent prognostic information, particularly in bladder cancers undergoing transurethral resection.

Status of Her2 over expression in muscle invasive urothelial bladder carcinoma: Report of 21 cases

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Nesrine Mejri

2014-01-01

Four patients died from disease, one of them had Her2 3+ score. Conclusion: Her2 overexpression can be observed in muscle invasive urothelial bladder carcinoma in an important number of patients. Evaluation criteria must be standardized, especially with heterogeneous cases. Metastases tests can also readdress the expression of Her2, which gives the patient a supplementary therapeutic tool.

Cytotoxic and toxicogenomic effects of silibinin in bladder cancer

Indian Academy of Sciences (India)

Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness forpreventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activityof silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial ...

A novel role for drebrin in regulating progranulin bioactivity in bladder cancer.

Science.gov (United States)

Xu, Shi-Qiong; Buraschi, Simone; Morcavallo, Alaide; Genua, Marco; Shirao, Tomoaki; Peiper, Stephen C; Gomella, Leonard G; Birbe, Ruth; Belfiore, Antonino; Iozzo, Renato V; Morrione, Andrea

2015-05-10

We recently established a critical role for the growth factor progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer.

Orally administered nicotine induces urothelial hyperplasia in rats and mice

International Nuclear Information System (INIS)

Dodmane, Puttappa R.; Arnold, Lora L.; Pennington, Karen L.; Cohen, Samuel M.

2014-01-01

Highlights: • Rats and mice orally administered with nicotine tartrate for total of 4 weeks. • No treatment-related death or whole body toxicity observed in any of the groups. • Urothelium showed simple hyperplasia in treated rats and mice. • No significant change in BrdU labeling index or SEM classification of urothelium. - Abstract: Tobacco smoking is a major risk factor for multiple human cancers including urinary bladder carcinoma. Tobacco smoke is a complex mixture containing chemicals that are known carcinogens in humans and/or animals. Aromatic amines a major class of DNA-reactive carcinogens in cigarette smoke, are not present at sufficiently high levels to fully explain the incidence of bladder cancer in cigarette smokers. Other agents in tobacco smoke could be excreted in urine and enhance the carcinogenic process by increasing urothelial cell proliferation. Nicotine is one such major component, as it has been shown to induce cell proliferation in multiple cell types in vitro. However, in vivo evidence specifically for the urothelium is lacking. We previously showed that cigarette smoke induces increased urothelial cell proliferation in mice. In the present study, urothelial proliferative and cytotoxic effects were examined after nicotine treatment in mice and rats. Nicotine hydrogen tartrate was administered in drinking water to rats (52 ppm nicotine) and mice (514 ppm nicotine) for 4 weeks and urothelial changes were evaluated. Histopathologically, 7/10 rats and 4/10 mice showed simple hyperplasia following nicotine treatment compared to none in the controls. Rats had an increased mean BrdU labeling index compared to controls, although it was not statistically significantly elevated in either species. Scanning electron microscopic visualization of the urothelium did not reveal significant cytotoxicity. These findings suggest that oral nicotine administration induced urothelial hyperplasia (increased cell proliferation), possibly due to a

Loss of prostasin (PRSS8) in human bladder transitional cell carcinoma cell lines is associated with epithelial-mesenchymal transition (EMT)

International Nuclear Information System (INIS)

Chen, Li-Mei; Verity, Nicole J; Chai, Karl X

2009-01-01

The glycosylphosphatidylinositol (GPI)-anchored epithelial extracellular membrane serine protease prostasin (PRSS8) is expressed abundantly in normal epithelia and essential for terminal epithelial differentiation, but down-regulated in human prostate, breast, and gastric cancers and invasive cancer cell lines. Prostasin is involved in the extracellular proteolytic modulation of the epidermal growth factor receptor (EGFR) and is an invasion suppressor. The aim of this study was to evaluate prostasin expression states in the transitional cell carcinomas (TCC) of the human bladder and in human TCC cell lines. Normal human bladder tissues and TCC on a bladder cancer tissue microarray (TMA) were evaluated for prostasin expression by means of immunohistochemistry. A panel of 16 urothelial and TCC cell lines were evaluated for prostasin and E-cadherin expression by western blot and quantitative PCR, and for prostasin gene promoter region CpG methylation by methylation-specific PCR (MSP). Prostasin is expressed in the normal human urothelium and in a normal human urothelial cell line, but is significantly down-regulated in high-grade TCC and lost in 9 (of 15) TCC cell lines. Loss of prostasin expression in the TCC cell lines correlated with loss of or reduced E-cadherin expression, loss of epithelial morphology, and promoter DNA hypermethylation. Prostasin expression could be reactivated by demethylation or inhibition of histone deacetylase. Re-expression of prostasin or a serine protease-inactive variant resulted in transcriptional up-regulation of E-cadherin. Loss of prostasin expression in bladder transitional cell carcinomas is associated with epithelial-mesenchymal transition (EMT), and may have functional implications in tumor invasion and resistance to chemotherapy

Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron

International Nuclear Information System (INIS)

Ihlaseh-Catalano, Shadia M.; Bailey, Kathryn A.; Cardoso, Ana Paula F.; Ren, Hongzu; Fry, Rebecca C.; Camargo, João Lauro V.de; Wolf, Douglas C.

2014-01-01

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that at high dietary levels (2500 ppm) induces rat urinary bladder hyperplasia after 20 weeks of exposure and neoplasia after 2 years. The effects on the urothelium after short-term exposure have not been described. The present 7-day study evaluated the dose-dependency of urothelial alterations in the urinary bladder using light microscopy, scanning electron microscopy, and genome-wide transcriptional profiling. Male Wistar rats were fed 0, 125, 500, 2500 ppm diuron for 7 days. The urinary bladder and isolated urothelial cells of these animals were processed for microscopic examination and gene expression profiling, respectively. No significant treatment-related morphologic effects were observed. The number of differentially expressed genes (DEGs) in the exposed groups increased with diuron levels. Diuron-altered genes involved in cell-to-cell interactions and tissue organization were identified in all treatment groups. After 7 days of diuron exposure, transcriptional responses were observed in the urothelium in the absence of clear morphologic changes. These morphological findings are different from those observed in a previous study in which 20 weeks of diuron exposure was associated with simple hyperplasia secondary to the persistent cytotoxicity and necrosis associated with continuous cellular regeneration. Comparison of the gene expression profiles of rats exposed to the 2500 ppm carcinogenic diuron dose for 7 days versus 20 weeks revealed few similarities between these two time points at the gene or pathway level. Taken together, these data provide insight into the dose- and temporal-dependent morphological and transcriptional changes associated with diuron exposure that may lead to the development of tumors in the rat urinary bladder

Abnormal Sensory Protein Expression and Urothelial Dysfunction in Ketamine-Related Cystitis in Humans

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Yao Chou Tsai

2016-09-01

Full Text Available Purpose The aim of this study was to analyze patterns of sensory protein expression and urothelial dysfunction in ketamine-related cystitis (KC in humans. Methods Biopsies of bladder mucosa were performed in 29 KC patients during cystoscopy. Then specimens were analyzed for tryptase, zonula occludens-1 (ZO-1, E-cadherin, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL with immunofluorescence staining and quantification. In addition, 10 healthy control bladder specimens were analyzed and compared with the KC specimens. Another 16 whole bladder specimens obtained from partial cystectomy were also analyzed for the muscarinic receptors M2 and M3, endothelial nitric oxide synthase (eNOS, inducible nitric oxide synthase (iNOS, β-3 adrenergic receptors (β3-ARs, and the P2X3 receptor by western blotting. In addition, 3 normal control bladder specimens were analyzed and compared with the KC specimens. Results The KC bladder mucosa revealed significantly less expression of ZO-1 and E-cadherin, and greater expression of TUNEL and tryptase activity than the control samples. The expression of M3 and β3-AR in the KC specimens was significantly greater than in the controls. The expression of iNOS, eNOS, M2, and P2X3 was not significantly different between the KC and control specimens. Conclusions The bladder tissue of KC patients revealed significant urothelial dysfunction, which was associated with mast-cell mediated inflammation, increased urothelial cell apoptosis, and increased expression of the M3 and β3-AR.

Evaluation of silk biomaterials in combination with extracellular matrix coatings for bladder tissue engineering with primary and pluripotent cells.

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Franck, Debra; Gil, Eun Seok; Adam, Rosalyn M; Kaplan, David L; Chung, Yeun Goo; Estrada, Carlos R; Mauney, Joshua R

2013-01-01

Silk-based biomaterials in combination with extracellular matrix (ECM) coatings were assessed as templates for cell-seeded bladder tissue engineering approaches. Two structurally diverse groups of silk scaffolds were produced by a gel spinning process and consisted of either smooth, compact multi-laminates (Group 1) or rough, porous lamellar-like sheets (Group 2). Scaffolds alone or coated with collagen types I or IV or fibronectin were assessed independently for their ability to support attachment, proliferation, and differentiation of primary cell lines including human bladder smooth muscle cells (SMC) and urothelial cells as well as pluripotent cell populations, such as murine embryonic stem cells (ESC) and induced pluripotent stem (iPS) cells. AlamarBlue evaluations revealed that fibronectin-coated Group 2 scaffolds promoted the highest degree of primary SMC and urothelial cell attachment in comparison to uncoated Group 2 controls and all Group 1 scaffold variants. Real time RT-PCR and immunohistochemical (IHC) analyses demonstrated that both fibronectin-coated silk groups were permissive for SMC contractile differentiation as determined by significant upregulation of α-actin and SM22α mRNA and protein expression levels following TGFβ1 stimulation. Prominent expression of epithelial differentiation markers, cytokeratins, was observed in urothelial cells cultured on both control and fibronectin-coated groups following IHC analysis. Evaluation of silk matrices for ESC and iPS cell attachment by alamarBlue showed that fibronectin-coated Group 2 scaffolds promoted the highest levels in comparison to all other scaffold formulations. In addition, real time RT-PCR and IHC analyses showed that fibronectin-coated Group 2 scaffolds facilitated ESC and iPS cell differentiation toward both urothelial and smooth muscle lineages in response to all trans retinoic acid as assessed by induction of uroplakin and contractile gene and protein expression. These results

Clinical outcome of primary small cell carcinoma of the urinary bladder

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Hou CP

2013-08-01

Full Text Available Chen-Pang Hou,1,2 Yu-Hsiang Lin,1,2 Chien-Lun Chen,1,2 Phei-Lang Chang,1,2 Ke-Hung Tsui1,2 1Department of Urology, Chang Gung Memorial Hospital-Linko, Taiwan, Republic of China; 2College of Medicine, Chang Gung University, Taiwan, Republic of China Purpose: Primary small cell carcinoma of the urinary bladder is a rare malignant disease. It accounts for less than 1% of all urinary bladder carcinomas. The purpose of this study is to review the clinical features, the treatment modalities, and the overall survival of these patients. We also compare the clinical outcomes between patients of bladder small cell carcinoma (SCC and bladder urothelial carcinoma (UC. Materials and methods: We reviewed the charts of patients with bladder tumors from January 1995 to December 2012 in the Chang Gung Memorial Hospital. A total of 2421 malignant bladder tumor patients were reviewed and there were 18 patients who were diagnosed with primary bladder SCC. The patients' characteristics, including age, gender, smoking history, presented symptoms, tumor size, locations, clinical stages, treatment modalities, pathology appearance, recurrence conditions, and survival conditions were all recorded. We also compared the clinical outcomes and the overall survival rates between patients with bladder SCC and those with UC. Results: Bladder SCC accounted for about 0.74% of all bladder malignancies in our institution. The mean age at diagnosis was 70.67 years, and the male-to-female ratio was 2.6:1. Thirteen patients had a history of cigarette smoking. All patients presented with symptoms of gross hematuria, and three of them had bladder tamponade requiring blood clot evacuation by cystoscopy. Only one patient had T1 disease, ten patients had stage III disease, and seven patients had lymph node or distant metastasis (stage IV disease. The mean tumor size was 4.29 cm in diameter. For the majority (61.11% of patients, SCC coexisted with UC components. The average survival time

Commentary on "tissue-specific mutagenesis by N-butyl-N-(4-hydroxybutyl) nitrosamine as the basis for urothelial cell carcinogenesis." He Z, Kosinska W, Zhao ZL, Wu XR, Guttenplan JB, Department of Basic Science, New York University Dental College, NY, USA.: Mutat Res 2012;742(1-2):92-5 [Epub 2011 Dec 4].

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Scherr, Douglas S

2014-02-01

Bladder cancer is one of the few cancers that have been linked to carcinogens in the environment and tobacco smoke. Of the carcinogens tested in mouse chemical carcinogenesis models, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) is one that reproducibly causes high-grade, invasive cancers in the urinary bladder, but not in any other tissues. However, the basis for such a high-level tissue-specificity has not been explored. Using mutagenesis in lacI (Big Blue™) mice, we show here that BBN is a potent mutagen and it causes high-level of mutagenesis specifically in the epithelial cells (urothelial) of the urinary bladder. After a 2-6-week treatment of 0.05% BBN in the drinking water, mutagenesis in urothelial cells of male and female mice was about two orders of magnitude greater than the spontaneous mutation background. In contrast, mutagenesis in smooth muscle cells of the urinary bladder was about five times lower than in urothelial tissue. No appreciable increase in mutagenesis was observed in kidney, ureter, liver or forestomach. In lacI (Big Blue™) rats, BBN mutagenesis was also elevated in urothelial cells, albeit not nearly as profoundly as in mice. This provides a potential explanation as to why rats are less prone than mice to the formation of aggressive form of bladder cancer induced by BBN. Our results suggest that the propensity to BBN-triggered mutagenesis of urothelial cells underlies its heightened susceptibility to this carcinogen and that mutagenesis induced by BBN represents a novel model for initiation of bladder carcinogenesis. Copyright © 2014 Elsevier Inc. All rights reserved.

Metabolism of 4-nitrobiphenyl (NBP) by cultured rat urothelial cells

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Swaminathan, S.; Lang, D.B.; Reznikoff, C.A.

1986-01-01

The potential of rat urothelial cells to metabolize NBP was evaluated by incubating 4.3 x 10 7 viable cells with 20 μM [ 3 H]NBP in a serum free medium for 48 hours. The culture medium was examined for metabolites of NBP by extraction with ethyl acetate and subsequent chromatographic analysis. High pressure liquid chromatography of the solvent extract using a Whatman ODS-3, C-18 column in 70% methanol-water at a flow rate of 1 ml/min revealed two major peaks at retention times of approximately 8 and 13 min. Thin layer chromatography showed two regions of radioactivity at Rf values of 0.35 and 0.83, the latter corresponding with NBP. Based on the chromatographic data the metabolite with the retention time of 8.0 min in HPLC and an Rf of 0.35 in TLC has been tentatively identified as 4-acetylaminobiphenyl. Analysis of binding to proteins and nucleic acids following exposure to [ 3 H]NBP revealed a significant amount (0.03% of initially applied radioactivity) in the protein fractions. Control samples of NBP incubated in medium, without the urothelial cells revealed only the parent compound. These data suggest that rat bladder cells possess the metabolic capability to reduce NBP and to generate reactive metabolites that bind to cellular macromolecules

Urothelial cancers following radiation therapy for cervical cancer

International Nuclear Information System (INIS)

Nakata, Seiji; Hasumi, Masaru; Sato, Jin; Mayuzumi, Takuji; Kumasaka, Fuminari; Shimizu, Toshihiro.

1996-01-01

Some reports have indicated that bladder cancer is induced by radiation therapy for cervical cancer. We encountered 6 cases of urothelial cancer (5 cases of bladder cancer and 1 case of ureter cancer) following radiation therapy for cervical cancer. Age at the time of diagnosis of cervical cancer ranged from 38 to 66 years, and the average was 51.2±11.0 (S.D.) years old. Age at the time of diagnosis of urothelial cancer ranged from 53 to 83 years, and the average was 67.5±10.3 years old. The interval between the diagnosis of cervical cancer and urothelial cancer ranged from 3 to 25 years, averaging 16.3 years. It is impossible to evaluate the risk of development of urothelial cancer after radiation therapy based on our data. However, it is important to make an effort to diagnose urothelial cancer at an early stage by educating patients (e.g., advising regular urine tests) after the follow-up period to cervical cancer. (author)

Human epidermal growth factor receptor 2/neu overexpression in urothelial carcinoma of the bladder and its prognostic significance: Is it worth hype?

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Santosh Kumar

2015-01-01

Full Text Available Aims: In urothelial tumors of the urinary bladder, human epidermal growth factor receptor 2 (HER-2/neu expression has been reported over 10 years, but there is no clear correlation between prognosis and recurrence rate. The present study evaluates prognostic implication of HER-2/neu expression. Subjects and Methods: In this study, 100 formalin-fixed paraffin-embedded specimens of primary transitional cell carcinoma of the bladder were processed. HER-2/neu monoclonal antibody immunohistochemistry staining procedure used for the study. Results: A total of 70 (70% patients were positive for overexpression of HER-2/neu. HER-2/neu was positive in patients with 42 (70% superficial tumor, 28 (70% muscle invasive tumor, 41 (75.9% high-grade tumor, 29 (63% low grade tumor, 31 (68.9% recurrent tumor, and 6 (66.6% had positive lymph nodes. Conclusions: Human epidermal growth factor receptor 2/neu over expression was not correlated with the tumor stage, lymphnode metastasis or recurrence of the disease. HER-2/neu overexpression was statistically insignificantly correlated with the differentiation grade (P < 0.161 as compared to previous studies. Future studies on HER-2 expression with chemo-sensitivity and efficacy of HER-2-targeted therapies in urothelial carcinomas is needed.

Loss of prostasin (PRSS8 in human bladder transitional cell carcinoma cell lines is associated with epithelial-mesenchymal transition (EMT

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Chai Karl X

2009-10-01

Full Text Available Abstract Background The glycosylphosphatidylinositol (GPI-anchored epithelial extracellular membrane serine protease prostasin (PRSS8 is expressed abundantly in normal epithelia and essential for terminal epithelial differentiation, but down-regulated in human prostate, breast, and gastric cancers and invasive cancer cell lines. Prostasin is involved in the extracellular proteolytic modulation of the epidermal growth factor receptor (EGFR and is an invasion suppressor. The aim of this study was to evaluate prostasin expression states in the transitional cell carcinomas (TCC of the human bladder and in human TCC cell lines. Methods Normal human bladder tissues and TCC on a bladder cancer tissue microarray (TMA were evaluated for prostasin expression by means of immunohistochemistry. A panel of 16 urothelial and TCC cell lines were evaluated for prostasin and E-cadherin expression by western blot and quantitative PCR, and for prostasin gene promoter region CpG methylation by methylation-specific PCR (MSP. Results Prostasin is expressed in the normal human urothelium and in a normal human urothelial cell line, but is significantly down-regulated in high-grade TCC and lost in 9 (of 15 TCC cell lines. Loss of prostasin expression in the TCC cell lines correlated with loss of or reduced E-cadherin expression, loss of epithelial morphology, and promoter DNA hypermethylation. Prostasin expression could be reactivated by demethylation or inhibition of histone deacetylase. Re-expression of prostasin or a serine protease-inactive variant resulted in transcriptional up-regulation of E-cadherin. Conclusion Loss of prostasin expression in bladder transitional cell carcinomas is associated with epithelial-mesenchymal transition (EMT, and may have functional implications in tumor invasion and resistance to chemotherapy.

Dose and temporal effects on gene expression profiles of urothelial cells from rats exposed to diuron.

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Ihlaseh-Catalano, Shadia M; Bailey, Kathryn A; Cardoso, Ana Paula F; Ren, Hongzu; Fry, Rebecca C; de Camargo, João Lauro V; Wolf, Douglas C

2014-11-05

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that at high dietary levels (2500 ppm) induces rat urinary bladder hyperplasia after 20 weeks of exposure and neoplasia after 2 years. The effects on the urothelium after short-term exposure have not been described. The present 7-day study evaluated the dose-dependency of urothelial alterations in the urinary bladder using light microscopy, scanning electron microscopy, and genome-wide transcriptional profiling. Male Wistar rats were fed 0, 125, 500, 2500 ppm diuron for 7 days. The urinary bladder and isolated urothelial cells of these animals were processed for microscopic examination and gene expression profiling, respectively. No significant treatment-related morphologic effects were observed. The number of differentially expressed genes (DEGs) in the exposed groups increased with diuron levels. Diuron-altered genes involved in cell-to-cell interactions and tissue organization were identified in all treatment groups. After 7 days of diuron exposure, transcriptional responses were observed in the urothelium in the absence of clear morphologic changes. These morphological findings are different from those observed in a previous study in which 20 weeks of diuron exposure was associated with simple hyperplasia secondary to the persistent cytotoxicity and necrosis associated with continuous cellular regeneration. Comparison of the gene expression profiles of rats exposed to the 2500 ppm carcinogenic diuron dose for 7 days versus 20 weeks revealed few similarities between these two time points at the gene or pathway level. Taken together, these data provide insight into the dose- and temporal-dependent morphological and transcriptional changes associated with diuron exposure that may lead to the development of tumors in the rat urinary bladder. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Small cell carcinoma of the urinary bladder diverticulum: A case report and review of the literature

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Wu Xu Dong

2013-01-01

Full Text Available Small cell carcinoma of the urinary bladder is very rare. Small cell carcinoma of the urinary bladder is a mass with swiftly aggressive and metastatic, and with a poor prognosis. Due to its scarcity, no forward-looking researches assessing the most effective treatment have been issued in the medical literature. It can happen either in connection with urothelial (transitional cell carcinoma or in a pure form. Its treatment should include surgery, chemotherapy and radiotherapy. In this article,we report a case occurring in a mixed form in the urinary bladder diverticulum and we concisely review the published literature with respect to the clinical manifestation, pathology,differential diagnosis, treatment and prognosis.

Hydrostatic pressure enhances mitomycin C induced apoptosis in urothelial carcinoma cells.

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Chen, Shao-Kuan; Chung, Chih-Ang; Cheng, Yu-Che; Huang, Chi-Jung; Ruaan, Ruoh-Chyu; Chen, Wen-Yih; Li, Chuan; Tsao, Chia-Wen; Hu, Wei-Wen; Chien, Chih-Cheng

2014-01-01

Urothelial carcinoma (UC) of the bladder is the second most common cancer of the genitourinary system. Clinical UC treatment usually involves transurethral resection of the bladder tumor followed by adjuvant intravesical immunotherapy or chemotherapy to prevent recurrence. Intravesical chemotherapy induces fewer side effects than immunotherapy but is less effective at preventing tumor recurrence. Improvement to intravesical chemotherapy is, therefore, needed. Cellular effects of mitomycin C (MMC) and hydrostatic pressure on UC BFTC905 cells were assessed. The viability of the UC cells was determined using cellular proliferation assay. Changes in apoptotic function were evaluated by caspase 3/7 activities, expression of FasL, and loss of mitochondrial membrane potential. Reduced cell viability was associated with increasing hydrostatic pressure. Caspase 3/7 activities were increased following treatment of the UC cells with MMC or hydrostatic pressure. In combination with 10 kPa hydrostatic pressure, MMC treatment induced increasing FasL expression. The mitochondria of UC cells displayed increasingly impaired membrane potentials following a combined treatment with 10 μg/ml MMC and 10 kPa hydrostatic pressure. Both MMC and hydrostatic pressure can induce apoptosis in UC cells through an extrinsic pathway. Hydrostatic pressure specifically increases MMC-induced apoptosis and might minimize the side effects of the chemotherapy by reducing the concentration of the chemical agent. This study provides a new and alternative approach for treatment of patients with UC following transurethral resection of the bladder tumor. Copyright © 2014 Elsevier Inc. All rights reserved.

The potential effect of age on the natural behavior of bladder cancer: Does urothelial cell carcinoma progress differently in various age groups?

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Gunlusoy, Bulent; Ceylan, Yasin; Degirmenci, Tansu; Aydogdu, Ozgu; Bozkurt, Ibrahim Halil; Yonguc, Tarik; Sen, Volkan; Kozacioglu, Zafer

2016-05-01

We aimed to evaluate the potential effect of age on the natural behavior of bladder cancer and to compare these findings between different age groups. The clinical and pathologic data of 239 patients treated at our institution between 1994 and 2014 were analyzed. The patients were classified into three groups according to age: ≤ 40 years (Group 1), 41-59 years (Group 2), and ≥ 60 years (Group 3). The following data were collected: characteristics of the patients, initial pathological findings after transurethral resection, tumor stage and grade, tumor size and multiplicity, and disease recurrence and progression. The mean age of the patients at initial diagnosis was 34.2±5.5 years, 53±5.1 years, and 71.1±7 years in Groups 1, 2, and 3, respectively. There were 207 (86.6%) patients with nonmuscle-invasive urothelial bladder cancer and 32 (13.4%) patients with muscle-invasive disease. Tumor recurrence was significantly lower in Group 1 than in Group 2 (p=0.001) and Group 3 (p=0.001). Although the time to tumor recurrence was significantly different between the three groups (p=0.001), no significant difference was noted in the time to progression (p=0.349). Patients with urothelial cancer younger than 40 years tend to have single and small tumors. The tumor recurrence rate is lower in the younger age group, but tumor progression is similar in older and younger patients. Therefore, the findings indicate that clinicians should be careful when assessing the invasiveness of urothelial tumors in younger patients and start treatment as soon as possible. Copyright © 2016. Published by Elsevier Taiwan.

Rhabdomyosarcoma of the urinary bladder in adults: predilection for alveolar morphology with anaplasia and significant morphologic overlap with small cell carcinoma.

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Paner, Gladell P; McKenney, Jesse K; Epstein, Jonathan I; Amin, Mahul B

2008-07-01

Rhabdomyosarcoma (RMS) represents the most common malignant soft tissue tumor in children and adolescents with the urinary bladder representing a frequent site. Most of these urinary bladder tumors are embryonal RMS, predominantly the botryoid subtype. RMSs of the urinary bladder in adults are distinctively rare and the subject of only case reports. We report the clinicopathologic features of 5 bladder neoplasms with rhabdomyosarcomatous differentiation in adults and emphasize the differential diagnosis in the adult setting. The patients, 4 men and 1 woman, ranged in age from 23 to 85 years (mean 65.4 y). Gross hematuria was the most common initial symptom, although 2 patients had metastatic disease at presentation. Four cases were pure primary RMSs of the bladder and 1 case was a sarcomatoid urothelial carcinoma with RMS representing the extensive heterologous component. All 5 cases demonstrated a diffuse growth pattern (ie, non-nested), of which 4 cases had nuclear anaplasia (Wilms criteria without the atypical mitotic figure requirement); only 1 case (the sarcomatoid carcinoma) showed obvious rhabdomyoblastic differentiation (ie, strap cells). Three cases were of the alveolar subtype (1 admixed with embryonal histology) and 2 were RMS, not further classified. Microscopically, all tumors had a primitive undifferentiated morphology with cells containing scant cytoplasm, varying round to fusiform nuclei with even chromatin distribution, and frequent mitoses. The degree of morphologic overlap with small cell carcinoma of the bladder, a relatively more common round cell tumor in adults, was striking. The epithelial component of the sarcomatoid carcinoma was high-grade invasive urothelial carcinoma with glandular differentiation. No other case had previous history of bladder cancer or concurrent carcinoma in situ or invasive urothelial carcinoma. All tumors showed immunohistochemical expression for desmin, myogenin, and/or MyoD1. Synaptophysin was performed in 4 cases

The Changing Treatment Landscape for Metastatic Urothelial Carcinoma.

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Flaig, Thomas W

2018-05-01

Urothelial carcinoma is the predominant histologic type of bladder cancer. After 30 years of minimal progress in the treatment of advanced-stage disease, recent advances in the genomic characterization of urothelial cancer and breakthroughs in bladder cancer therapeutics have rejuvenated the field. Nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab are among the exciting recent novel therapeutic advances gaining approvals by the FDA for treatment of advanced-stage urothelial carcinoma. Yet the challenge for clinicians is to determine the optimal choice of agents as first-line or second-line therapy and which offers the best chance for overall survival for the individual patient in this rapidly changing field. Copyright © 2018 by the National Comprehensive Cancer Network.

Expression of Vitamin D Receptor (VDR Positively Correlates with Survival of Urothelial Bladder Cancer Patients

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Wojciech Jóźwicki

2015-10-01

Full Text Available Vitamin D3 shows tumoristatic and anticancer effects by acting through the vitamin D receptor (VDR, while hydroxylation of 25-hydroxyvitamin D3 at position 1α by CYP27B1 is an essential step in its activation. The expression of both the VDR and CYP27B1 has been found in many normal and cancer tissues, but there is a lack of information about its expression in human bladder cancers. The aim of the present research was to examine whether the expression of the VDR and CYP27B1 in bladder cancer was related to the prognostic markers and disease outcome. We analyzed VDR and CYP27B1 in samples of tumor and normal tissues obtained from 71 urinary bladder cancer patients. The highest VDR immunostaining was found in normal epithelium and was significantly lower in bladder cancer cells (p < 0.001 with Mann–Whitney U test. VDR expression was lowest in more advanced (pT2b–pT4 (p = 0.005 with Mann–Whitney U test and metastasizing cancers (p < 0.05 and p = 0.004 with Mann–Whitney U test for nuclear and cytoplasmic VDR immunostaining, respectively. The lack of cytoplasmic and nuclear VDR was also related to shorter overall survival (for cytoplasmic VDR immunolocalization 13.3 vs. 55.3 months of survival, HR = 1.92, p = 0.04 and for nuclear VDR immunostaining 13.5 vs. 55.3 months of survival, HR = 2.47, p = 0.002 with Mantel-Cox test. In cases with the lack of high cytoplasmic VDR staining the non-classic differentiations (NDs was observed in higher percentage of tumor area. CYP27B1 expression was lower in cancer cells than in normal epithelial cells (p = 0.03 with Mann–Whitney U test, but its expression did not correlate with tumor stage (pT, metastasizing, grade, mitotic activity or overall survival. In conclusion, expression of the VDR and CYP27B1 are deregulated in urothelial bladder cancers. Although our results showing a relationship between the decreased VDR expression and prognostic markers and survival time indicate potential usefulness of

Knockdown of long non-coding RNA Taurine Up-Regulated 1 inhibited doxorubicin resistance of bladder urothelial carcinoma via Wnt/β-catenin pathway.

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Xie, Dalong; Zhang, Hui; Hu, Xuanhao; Shang, Chao

2017-10-24

In genitourinary system, bladder cancer (BC) is the most common and lethal malignant tumor, which most common type is bladder urothelial carcinoma (BUC). Long non-coding RNA (lncRNA) Taurine Up-Regulated 1 (TUG1) gene is high-expressed in several malignant tumors, including BC. In this study, over-expression of TUG1 was found in BUC tissues and cell line resistant to doxorubicin (Dox). Knockdown of TUG1 inhibited the Dox resistance and promoted the cytotoxicity induced by Dox in T24/Dox cells. TUG1 knockdown also depressed the Wnt/β-catenin pathway, and the activation the Wnt/β-catenin pathway partly reversed the inhibitory effects of TUG1 knockdown on Dox resistance in T24/Dox cells. In conclusion, up-regulation of lncRNA TUG1 was related with the poor response of BUC patients to Dox chemotherapy, knockdown of TUG1 inhibited the Dox resistance of BUC cells via Wnt/β-catenin pathway. These findings might assist in the discovery of novel potential diagnostic and therapeutic target for BUC, thereby improve the effects of clinical treatment in patients.

Functional TRP and ASIC-like channels in cultured urothelial cells from the rat.

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Kullmann, F Aura; Shah, M A; Birder, L A; de Groat, W C

2009-04-01

Transient receptor potential (TRP) and acid-sensing ion channels (ASIC) are molecular detectors of chemical, mechanical, thermal, and nociceptive stimuli in sensory neurons. They have been identified in the urothelium, a tissue considered part of bladder sensory pathways, where they might play a role in bladder function. This study investigated functional properties of TRP and ASIC channels in cultured urothelial cells from the rat using patch-clamp and fura 2 Ca(2+) imaging techniques. The TRPV4 agonist 4alpha-phorbol-12,13 didecanoate (4alpha-PDD; 1-5 microM) and the TRPA1/TRPM8 agonist icilin (50-100 microM) elicited transient currents in a high percentage of cells (>70%). 4alpha-PDD responses were suppressed by the TRPV4 antagonist HC-010961 (10 microM). The TRPV1 agonist capsaicin (1-100 microM) and the TRPA1/TRPM8 agonist menthol (5-200 microM) elicited transient currents in a moderate percentage of cells ( approximately 25%). All of these agonists increased intracellular calcium concentration ([Ca(2+)](i)). Most cells responded to more than one TRP agonist (e.g., capsaicin and 4alpha-PDD), indicating coexpression of different TRP channels. In the presence of the TRPV1 antagonist capsazepine (10 microM), changes in pH induced by HCl elicited ionic currents (pH 5.5) and increased [Ca(2+)](i) (pH 6.5) in approximately 50% of cells. Changes in pH using acetic acid (pH 5.5) elicited biphasic-like currents. Responses induced by acid were sensitive to amiloride (10 microM). In summary, urothelial cells express multiple TRP and ASIC channels, whose activation elicits ionic currents and Ca(2+) influx. These "neuron-like" properties might be involved in transmitter release, such as ATP, that can act on afferent nerves or smooth muscle to modulate their responses to different stimuli.

Impact of lymphovascular invasion on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection

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Sha N

2015-11-01

Full Text Available Nan Sha,* Linguo Xie,* Tao Chen,* Chen Xing, Xiaoteng Liu, Yu Zhang, Zhonghua Shen, Hao Xu, Zhouliang Wu, Hailong Hu, Changli Wu Department of Urology, Tianjin Key Laboratory of Urology, Tianjin Institute of Urology, Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China *These authors contributed equally to this work Objective: To evaluate the clinical significance of lymphovascular invasion (LVI on recurrence and progression rates in patients with pT1 urothelial carcinoma of bladder after transurethral resection.Methods: This retrospective study was performed with 155 patients with newly diagnosed pT1 urothelial carcinoma of bladder who were treated with transurethral resection of bladder tumor at our institution from January 2006 to January 2010. The presence or absence of LVI was examined by pathologists. Chi-square test was performed to identify the correlations between LVI and other clinical and pathological features. Kaplan–Meier method was used to estimate the recurrence-free survival (RFS and progression-free survival curves and difference was determined by the log-rank test. Univariate and multivariate analyses were performed to determine the predictive factors through a Cox proportional hazards analysis model.Results: LVI was detected in a total of 34 patients (21.9%. While LVI was associated with high-grade tumors (P<0.001 and intravesical therapy (P=0.009. Correlations with age (P=0.227, sex (P=0.376, tumor size (P=0.969, tumor multiplicity (P=0.196, carcinoma in situ (P=0.321, and smoking (P=0.438 were not statistically significant. There was a statistically significant tendency toward higher recurrence rate and shorter RFS time in LVI-positive patients. However, no statistically significant differences were observed in progression rate between the two groups. Moreover, multivariate Cox proportional hazards analysis revealed that LVI, tumor size, and smoking were independent prognostic predictors of

BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines

NARCIS (Netherlands)

Bevers, R. F.; de Boer, E. C.; Kurth, K. H.; Schamhart, D. H.

1998-01-01

Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction

A STUDY OF P53 EXPRESSION IN UROTHELIAL NEOPLASMS OF URINARY BLADDER

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G. Sathish Kumar

2017-07-01

Full Text Available BACKGROUND Urothelial Cell Carcinoma (UCC of urinary bladder is the seventh commonest cancer wordwide.1 At initial diagnosis, 30% of UCC display solid and invasive growth patterns and are locally advanced or metastatic at the time of diagnosis. 70% of tumours are noninvasive papillary UCC confined to the epithelium and subepithelial connective tissue,2 which can be managed by endoscopic resection. A significant number of post-resected cases, progress for recurrence of tumour and infiltration to muscle layers. Invasive bladder cancer has high morbidity and uniform mortality when it is metastatic. There are no effective tools to predict aggressiveness of tumour, so that these cases can be managed more successfully. Mutated Tp53/p53 is the genetic abnormality most frequently associated with UCC and related to cell transformation, malignancy and high recurrence rates.2 MATERIALS AND METHODS This is a descriptive study conducted in the departments of urology and pathology and during the period of March 2014 to February 2015. All consecutive cystoscopic biopsies, Trans urethral resection of bladder tumour (TURBT and radical cystectomy specimens histopathologically diagnosed as UCC were included in the study. p53 expression was assessed by immunohistochemistry. Positive and negative controls were used. Bivariate analysis was done using Chi-square test in all cases. RESULTS A total of 80 cases were analysed. Significant association of p53 expression was found in higher grades of tumour. Also, noted relation of p53 mutation with tumour size, multifocality, multiplicity, muscle invasion and tumour stage, which were statistically not significant. CONCLUSION Bladder tumour grade shows significant association to p53 expression. Papillary neoplasm of low malignant potential (PUNLMP tumours are negative for p53, and in the present study, there was significant difference in p53 over expression low-grade papillary UCC compared with PUNLMP. 90% of low

Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway.

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Tian, Binqiang; Zhao, Yingmei; Liang, Tao; Ye, Xuxiao; Li, Zuowei; Yan, Dongliang; Fu, Qiang; Li, Yonghui

2017-08-01

We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

Vulvar Metastasis from Bladder Cancer

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Fouad Aoun

2015-01-01

Full Text Available Vulvar metastasis of urothelial carcinoma of the bladder is a very rare entity; few cases are reported in the English literature. In this paper, we describe the clinical and pathological characteristics, evolution, and treatment of a patient with vulvar metastasis of urothelial carcinoma of the bladder followed by a brief review of the reported cases in the literature.

Lipid Cell and Micropapillary Variants of Urothelial Carcinoma of the Ureter

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Yu Miyama

2015-11-01

Full Text Available We report on a case of urothelial carcinoma (UC with lipid cell and micropapillary variants in the ureter. A 64-year-old man presented with gross hematuria. Urinary cytology revealed the presence of atypical urothelial cells. Computed tomography and drip infusion/retrograde pyelography identified a mass-occupying lesion in the left mid-ureter, as well as left hydronephrosis. A clinical diagnosis of left ureteral cancer was given and the patient underwent left nephroureterectomy. Microscopically, the major component of the tumor was a conventional high-grade UC. In the invasive region, however, lipid cell and micropapillary variants of UC were also observed. Upon immunohistochemical analysis, all of the components were diffusely positive for cytokeratin 7 and p53. Intense membranous expression of human epidermal growth factor receptor 2 (HER2 was also observed in both the lipid cell and micropapillary variants of UC, whereas weak and incomplete staining was observed in most regions of the conventional UC. The pathological stage was pT3 N2. Multiple times, the patient experienced recurrence of the UC in the urinary bladder and urethra. Although the patient underwent total cystectomy and urethrectomy, 52 months following the initial surgery, signs of local recurrence developed, as well as multiple lymph node and bone metastases. The patient died 75 months following the initial surgery. To the best of our knowledge, this is the first reported case of a lipid cell variant of ureteral UC. The overexpression of HER2 may be associated with both the lipid cell and micropapillary variants of UC.

Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression.

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Beckham, Carla J; Olsen, Jayme; Yin, Peng-Nien; Wu, Chia-Hao; Ting, Huei-Ju; Hagen, Fred K; Scosyrev, Emelian; Messing, Edward M; Lee, Yi-Fen

2014-08-01

High grade bladder cancer is an extremely aggressive malignancy associated with high rates of morbidity and mortality. Understanding how exosomes may affect bladder cancer progression could reveal novel therapeutic targets. Exosomes derived from human bladder cancer cell lines and the urine of patients with high grade bladder cancer were assessed for the ability to promote cancer progression in standard assays. Exosomes purified from the high grade bladder cancer cell line TCC-SUP and the nonmalignant urothelial cell line SV-HUC were submitted for mass spectrometry analysis. EDIL-3 was identified and selected for further analysis. Western blot was done to determine EDIL-3 levels in urinary exosomes from patients with high grade bladder cancer. shRNA gene knockdown and recombinant EDIL-3 were applied to study EDIL-3 function. Exosomes isolated from high grade bladder cancer cells and the urine of patients with high grade bladder cancer promoted angiogenesis and migration of bladder cancer cells and endothelial cells. We silenced EDIL-3 expression and found that shEDIL-3 exosomes did not facilitate angiogenesis, and urothelial and endothelial cell migration. Moreover, exosomes purified from the urine of patients with high grade bladder cancer contained significantly higher EDIL-3 levels than exosomes from the urine of healthy controls. EDIL-3 activated epidermal growth factor receptor signaling while blockade of epidermal growth factor receptor signaling abrogated this EDIL-3 induced bladder cell migration. Exosomes derived from the urine of patients with bladder cancer contains bioactive molecules such as EDIL-3. Identifying these components and their associated oncogenic pathways could lead to novel therapeutic targets and treatment strategies. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

uPAR Expression Pattern in Patients with Urothelial Carcinoma of the Bladder--Possible Clinical Implications.

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Line Hammer Dohn

Full Text Available The objective of the present study was to confirm the expression and localisation pattern of the urokinase-type plasminogen activator receptor (uPAR focusing on its possible clinical relevance in patients with urothelial neoplasia of the bladder. uPAR is a central molecule in tissue remodelling during cancer invasion and metastasis and is an established prognostic marker in various cancer diseases other than bladder cancer. Formalin-fixed and paraffin-embedded tumour-tissue blocks from 186 patients treated with radical cystectomy were analysed. uPAR expression was scored as either negative or positive as well as by the actual score. Separate scores were obtained for cancer cells, macrophages and myofibroblasts at the invasive front and in tumour core. We were able to confirm, in an independent patient cohort, the tissue expression and localisation pattern of uPAR as investigated by Immunohistochemistry as well as a significant association between uPAR positivity and increasing tumour stage and tumour grade. This demonstrates the robustness of our previous and current findings. In addition the association between uPAR positive myofibroblasts and poor survival was reproduced. The highest hazard ratios for survival were seen for uPAR positive myofibroblasts both at the invasive front and in tumour core. Evaluating uPAR expression by the actual score showed a significant association between uPAR positive myofibroblasts in tumour core and an increased risk of cancer specific mortality. Our investigations have generated new and valuable biological information about the cell types being involved in tumour invasion and progression through the plasminogen activation system.

Histological grading of papillary urothelial carcinoma of the bladder: prognostic value of the 1998 WHO/ISUP classification system and comparison with conventional grading systems

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Oosterhuis, J. W. A.; Schapers, R. F. M.; Janssen-Heijnen, M. L. G.; Pauwels, R. P. E.; Newling, D. W.; ten Kate, F.

2002-01-01

AIM: To test the prognostic value of the 1998 WHO/ISUP (World Health Organisation/International Society of Urologic Pathology) consensus classification system in Ta papillary urothelial neoplasms of the bladder. METHODS: The histological slides of 322 patients with a primary Ta tumour were

Effects of Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] on the urinary bladder of male Wistar rats

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Nascimento, Merielen Garcia; Cotrim Sartor de Oliveira, Maria Luiza; Lima, Adriano Silva; Camargo, Joao Lauro Viana de

2006-01-01

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide widely used on agricultural crops such as soy, cotton and sugar cane. In a previous long-term study this herbicide exerted carcinogenic activity on the urinary bladder mucosa of male Wistar rats. In general, the genotoxic and mutagenic potentials of Diuron are considered to be negative. The present study aimed to evaluate the mode of action of Diuron on the urinary bladder mucosa of male Wistar rats. Six-week old male Wistar rats were fed pelleted Nuvilab diet mixed with Diuron at 125, 500 and 2500 ppm. As a positive control, 8.3% sodium saccharin (NaS) was fed in the diet. Preceding the sacrifice of the animals at the 20th week, urinary pH was measured and the genotoxic potential of Diuron was evaluated by the comet assay. Histological urothelial lesions in the urinary bladder and in the renal pelvis mucosa, cell proliferation/apoptosis evaluations, and scanning electron microscopy (SEM) of the urinary bladder mucosa were also performed. No DNA changes were found in urothelial or peripheral blood cells, and urinary pH was comparable to controls in all Diuron groups. In the urinary bladder urothelium, the incidence of simple hyperplasia (SH) by light microscopy was significantly increased (7/10; p < 0.005) in the 2500 ppm Diuron group but not at the lower doses. By SEM, three of five animals treated with 2500 ppm Diuron showed urothelial cell necrosis and hyperplasia. In the renal pelvis, the incidence of SH was significantly increased in the Diuron 500 and 2500 ppm and in the NaS 8.3% groups. Cell proliferation was significantly increased in the Diuron 2500 ppm (p < 0.05) and NaS 8.3% (p < 0.05) groups. The results indicate that a high dietary concentration of Diuron is associated with urothelial necrosis and continuous regenerative cell proliferation that leads to urothelial hyperplasia

Intravenous chemotherapy combined with intravesical chemotherapy to treat T1G3 bladder urothelial carcinoma after transurethral resection of bladder tumor: results of a retrospective study

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Zhang Y

2016-01-01

Full Text Available Yu Zhang,1,* Linguo Xie,1,* Tao Chen,1,* Wanqin Xie,2 Zhouliang Wu,1 Hao Xu,1 Chen Xing,1 Nan Sha,1 Zhonghua Shen,1 Yunkai Qie,1 Xiaoteng Liu,1 Hailong Hu,1 Changli Wu1 1Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, 2Key Laboratory of Genetics and Birth Health of Hunan Province, The Family Planning Research Institute of Hunan Province, Changsha, People’s Republic of China *These authors contributed equally to this work Objective: The management of stage 1 and grade 3 (T1G3 bladder cancer continues to be controversial. Although the transurethral resection of bladder tumor (TURBT followed by intravesical chemotherapy is a conservative strategy for treatment of T1G3 bladder cancer, a relatively high risk of tumor recurrence and progression remains regarding the therapy. This study aimed to compare the efficacy of intravenous chemotherapy combined with intravesical chemotherapy versus intravesical chemotherapy alone for T1G3 bladder cancer after TURBT surgery. Methods: We retrospectively reviewed the cases of 457 patients who were newly diagnosed with T1G3 bladder urothelial carcinoma between January 2009 and March 2014. After TURBT, 281 patients received intravesical chemotherapy alone, whereas 176 patients underwent intravesical chemotherapy in combination with intravenous chemotherapy. Tumor recurrence and progression were monitored periodically by urine cytology and cystoscopy in follow-up. Recurrence-free survival and progression-free survival of the two chemotherapy strategies following TURBT were analyzed. Univariable and multivariable Cox hazards analyses were performed to predict the prognostic factors for tumor recurrence and progression. Results: The tumor recurrence rate was 36.7% for patients who received intravesical chemotherapy alone after TURBT, compared with 19.9% for patients who received intravenous chemotherapy combined with intravesical chemotherapy after

Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

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Kitamura, Hiroshi, E-mail: hkitamu@sapmed.ac.jp; Tsukamoto, Taiji [Department of Urology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8543 (Japan)

2011-07-29

Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8{sup +} T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.

Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

International Nuclear Information System (INIS)

Kitamura, Hiroshi; Tsukamoto, Taiji

2011-01-01

Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8 + T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules

Peristomal pagetoid spread of urothelial carcinoma of the ureter

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Fumio Ito

2013-09-01

Full Text Available Patients with ostomy including urinary stoma often develop peristomal complications, especially skin damage. The patient in this case was a 69-year old female with a history of urothelial carcinoma of the bladder and left ureter who underwent transurethral resection of a bladder tumor, nephroureterectomy and cystectomy combined with ureterocutaneostomy. Later, she had recurrence of urothelial carcinoma in the remaining ureter that spread to the peristomal epidermis, with a skin appearance resembling Paget’s disease. We report this case based on its clinical significance since we believe it is the first description of this condition in the literature.

Advanced small cell carcinoma of the bladder: clinical characteristics, treatment patterns and outcomes in 960 patients and comparison with urothelial carcinoma

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Geynisman, Daniel M.; Handorf, Elizabeth; Wong, Yu-Ning; Doyle, Jamie; Plimack, Elizabeth R.; Horwitz, Eric M.; Canter, Daniel J.; Uzzo, Robert G.; Kutikov, Alexander; Smaldone, Marc C.

2015-01-01

To describe the clinical characteristics, treatment patterns and outcomes in advanced small cell bladder cancer (aSCBC) patients and compare to those with urothelial carcinoma (UC). Individuals in the National Cancer Data Base with a diagnosis of either nodal (TxN+M0) or distant metastatic (TxNxM1) disease were identified from 1998 to 2010. We assessed the relationships between stage, treatment modalities and survival in the aSCBC cohort and compared these to UC patients. In the 960 patient aSCBC cohort (62% M1), 50% received palliative therapy alone, 68% in M1 versus 21% in M0 groups (P < 0.0001). Single modality local therapy (15%) and surgical (21%) or radiation-based (14%) multimodal therapy (MMT) were used in the other 50%. Cystectomy-based MMT was utilized in 45% of N+M0 versus 6.4% of NxM1 patients (P < 0.0001). Median overall survival (OS) for aSCBC patients was 8.6 months; 13.0 months in N+M0 versus 5.3 months in NxM1 patients (P < 0.0001). Survival was similar between TxN1M0 and TxN2-3M0 patients (14.8 months vs. 12.1 months, P = 0.15). Urothelial carcinoma patients (n = 27,796, 45% M1) lived longer compared to aSCBC patients in the N+M0 group (17.3 months vs. 13.0 months, P = 0.0007). There were not clinically significant differences in OS between UC and aSCBC patients in the M1 group. Advanced SCBC is a rare disease with a poor survival and palliative therapy is common, especially in M1 patients. In comparison to UC, the outcomes for aSCBC patients are worse in those with lymph node only involvement but similar in those with distant disease

Toll-like receptor 6 and connective tissue growth factor are significantly upregulated in mitomycin-C-treated urothelial carcinoma cells under hydrostatic pressure stimulation.

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Chen, Shao-Kuan; Chung, Chih-Ang; Cheng, Yu-Che; Huang, Chi-Jung; Chen, Wen-Yih; Ruaan, Ruoh-Chyu; Li, Chuan; Tsao, Chia-Wen; Hu, Wei-Wen; Chien, Chih-Cheng

2014-06-01

Urothelial carcinoma (UC) is the most common histologic subtype of bladder cancer. The administration of mitomycin C (MMC) into the bladder after transurethral resection of the bladder tumor (TURBT) is a common treatment strategy for preventing recurrence after surgery. We previously applied hydrostatic pressure combined with MMC in UC cells and found that hydrostatic pressure synergistically enhanced MMC-induced UC cell apoptosis through the Fas/FasL pathways. To understand the alteration of gene expressions in UC cells caused by hydrostatic pressure and MMC, oligonucleotide microarray was used to explore all the differentially expressed genes. After bioinformatics analysis and gene annotation, Toll-like receptor 6 (TLR6) and connective tissue growth factor (CTGF) showed significant upregulation among altered genes, and their gene and protein expressions with each treatment of UC cells were validated by quantitative real-time PCR and immunoblotting. Under treatment with MMC and hydrostatic pressure, UC cells showed increasing apoptosis using extrinsic pathways through upregulation of TLR6 and CTGF.

Diuron metabolites and urothelial cytotoxicity: In vivo, in vitro and molecular approaches

International Nuclear Information System (INIS)

Da Rocha, Mitscheli S.; Arnold, Lora L.; Dodmane, Puttappa R.; Pennington, Karen L.; Qiu, Fang; De Camargo, João Lauro V.; Cohen, Samuel M.

2013-01-01

Diuron is carcinogenic to the rat urinary bladder at high dietary levels. The proposed mode of action (MOA) for diuron is urothelial cytotoxicity and necrosis followed by regenerative urothelial hyperplasia. Diuron-induced urothelial cytotoxicity is not due to urinary solids. Diuron is extensively metabolized, and in rats, N-(3,4-dichlorophenyl)urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl urea (2-OH-DCPU) were the predominant urinary metabolites; lesser metabolites included N-(3,4-dichlorophenyl)-3-methylurea (DCPMU) and trace levels of 3,4-dichloroaniline (DCA). In humans, DCPMU and DCPU have been found in the urine after a case of product abuse. To aid in elucidating the MOA of diuron and to evaluate the metabolites that are responsible for the diuron toxicity in the bladder epithelium, we investigated the urinary concentrations of metabolites in male Wistar rats treated with 2500 ppm of diuron, the urothelial cytotoxicity in vitro of the metabolites and their gene expression profiles. DCPU was found in rat urine at concentrations substantially greater than the in vitro IC50 and induced more gene expression alterations than the other metabolites tested. 2-OH-DCPU was present in urine at a concentration approximately half of the in vitro IC50, whereas DCPMU and DCA were present in urine at concentrations well below the IC50. For the diuron-induced MOA for the rat bladder, we suggest that DCPU is the primary metabolite responsible for the urothelial cytotoxicity with some contribution also by 2-OH-DCPU. This study supports a MOA for diuron-induced bladder effects in rats consisting of metabolism to DCPU (and 2-OH-DCPU to a lesser extent), concentration and excretion in urine, urothelial cytotoxicity, and regenerative proliferation

Diuron metabolites and urothelial cytotoxicity: in vivo, in vitro and molecular approaches.

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Da Rocha, Mitscheli S; Arnold, Lora L; Dodmane, Puttappa R; Pennington, Karen L; Qiu, Fang; De Camargo, João Lauro V; Cohen, Samuel M

2013-12-15

Diuron is carcinogenic to the rat urinary bladder at high dietary levels. The proposed mode of action (MOA) for diuron is urothelial cytotoxicity and necrosis followed by regenerative urothelial hyperplasia. Diuron-induced urothelial cytotoxicity is not due to urinary solids. Diuron is extensively metabolized, and in rats, N-(3,4-dichlorophenyl)urea (DCPU) and 4,5-dichloro-2-hydroxyphenyl urea (2-OH-DCPU) were the predominant urinary metabolites; lesser metabolites included N-(3,4-dichlorophenyl)-3-methylurea (DCPMU) and trace levels of 3,4-dichloroaniline (DCA). In humans, DCPMU and DCPU have been found in the urine after a case of product abuse. To aid in elucidating the MOA of diuron and to evaluate the metabolites that are responsible for the diuron toxicity in the bladder epithelium, we investigated the urinary concentrations of metabolites in male Wistar rats treated with 2500ppm of diuron, the urothelial cytotoxicity in vitro of the metabolites and their gene expression profiles. DCPU was found in rat urine at concentrations substantially greater than the in vitro IC50 and induced more gene expression alterations than the other metabolites tested. 2-OH-DCPU was present in urine at a concentration approximately half of the in vitro IC50, whereas DCPMU and DCA were present in urine at concentrations well below the IC50. For the diuron-induced MOA for the rat bladder, we suggest that DCPU is the primary metabolite responsible for the urothelial cytotoxicity with some contribution also by 2-OH-DCPU. This study supports a MOA for diuron-induced bladder effects in rats consisting of metabolism to DCPU (and 2-OH-DCPU to a lesser extent), concentration and excretion in urine, urothelial cytotoxicity, and regenerative proliferation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pure Lymphoepithelioma-Like Carcinoma Originating from the Urinary Bladder

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Takashi Nagai

2016-03-01

Full Text Available Lymphoepithelioma-like carcinoma of the urinary bladder (LELCB is a rare variant of infiltrating urothelial carcinoma. We report a case of LELCB in a 43-year-old man. Ultrasonography and cystoscopy revealed two bladder tumors, one on the left side of the trigone and the other on the right side of the trigone. Transurethral resection of the bladder tumors was performed and pathological analysis revealed undifferentiated carcinoma. We therefore performed radical cystectomy and urinary diversion. Immunohistochemically the tumor cells were positive for cytokeratin, but negative for Epstein-Barr virus-encoded small RNA in situ hybridization as found for previous cases of LELCB. The final pathological diagnosis was a lymphoepithelioma-like variant of urothelial carcinoma with perivesical soft tissue invasion. For adjuvant systemic chemotherapy, three courses of cisplatin were administered. The patient subsequently became free of cancer 72 months postoperatively. Based on the literature, pure or predominant LELCB types show favorable prognoses due to their sensitivity to chemotherapy or radiotherapy. An analysis of the apparent diffusion coefficient (ADC values of bladder tumors examined in our institution revealed that the ADC value measured for this LELCB was relatively low compared to conventional urothelial carcinomas. This suggests that measuring the ADC value of a lymphoepithelioma-like carcinoma prior to operation may be helpful in predicting LELCB.

Prognostic significance of epidermal growth factor receptor (EGFR) over expression in urothelial carcinoma of urinary bladder.

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Hashmi, Atif Ali; Hussain, Zubaida Fida; Irfan, Muhammad; Khan, Erum Yousuf; Faridi, Naveen; Naqvi, Hanna; Khan, Amir; Edhi, Muhammad Muzzammil

2018-06-07

Epidermal growth factor receptor (EGFR) has been shown to have abnormal expression in many human cancers and is considered as a marker of poor prognosis. Frequency of over expression in bladder cancer has not been studied in our population; therefore we aimed to evaluate the frequency and prognostic significance of EGFR immunohistochemical expression in locoregional population. We performed EGFR immunohistochemistry on 126 cases of bladder cancer and association of EGFR expression with tumor grade, lamina propria invasion, deep muscle invasion and recurrence of disease was evaluated. High EGFR expression was noted in 26.2% (33 cases), 15.1% (19 cases) and 58.7% (74 cases) revealed low and no EGFR expression respectively. Significant association of EGFR expression was noted with tumor grade, lamina propria invasion, deep muscle invasion and recurrence status while no significant association was seen with age, gender and overall survival. Kaplan- Meier curves revealed significant association of EGFR expression with recurrence while no significant association was seen with overall survival. Significant association of EGFR overexpression with tumor grade, muscularis propria invasion and recurrence signifies its prognostic value; therefore EGFR can be used as a prognostic biomarker in Urothelial bladder carcinoma.

Molecular subtype classification of urothelial carcinoma in Lynch syndrome.

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Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias; Jönsson, Mats; Sjödahl, Gottfrid; Nilbert, Mef; Liedberg, Fredrik

2018-05-23

Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed and compared with sporadic bladder cancer. The 41 Lynch syndrome-associated UC developed at a mean age of 61 years with 59% women. mRNA expression profiling and immunostaining classified the majority of the Lynch syndrome-associated UC as Urothelial-like tumors with only 20% being Genomically Unstable, Basal/SCC-like or other subtypes. The subtypes were associated with stage, grade, and microsatellite instability. Comparison to larger data sets revealed that Lynch syndrome-associated UC share molecular similarities with sporadic UC. In conclusion, transcriptomic and immunohistochemical profiling identifies a predominance of the Urothelial-like molecular subtype in Lynch syndrome and reveals that the molecular subtypes of sporadic bladder cancer are relevant also within this hereditary, mismatch-repair defective subset. This article is protected by copyright. All rights reserved. Molecular Oncology (2018) © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Identification of "tumor-associated" nucleolar antigens in human urothelial cancer.

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Yu, D; Pietro, T; Jurco, S; Scardino, P T

1987-09-01

Nucleoli isolated from HeLa S3 cells were used to produce rabbit antisera capable of binding nucleoli of transitional cell carcinomas (TCCa) of the bladder. Cross-reactivity of the rabbit antiserum with normal nucleoli was reduced by absorption with fetal calf serum, normal human serum, and human placental nucleoli. This antinucleolar antiserum exhibited strong reactivity in immunoperoxidase assays performed on specimens of human bladder cancer. In frozen tissue sections of 24 patients with TCCa and eight individuals without tumor, nucleolar staining was observed in all malignant specimens, but was not observed in seven of the normal specimens. Cytologic examination of bladder washing specimens from 47 normal individuals showed absence of nucleolar staining in 43 (91%) of 47 normal specimens while 12 (86%) of 14 specimens from patients with TCCa were positive. These results suggest that there are antigens associated with the nucleoli of HeLa cells and transitional cell carcinomas which are generally absent (or in low concentration) in normal human urothelial cells, and that antisera to these antigens may be useful in the cytologic diagnosis of human transitional cell carcinoma.

Detonation nanodiamonds are promising nontoxic delivery system for urothelial cells.

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Zupančič, Daša; Kreft, Mateja Erdani; Grdadolnik, Maja; Mitev, Dimitar; Iglič, Aleš; Veranič, Peter

2018-01-01

Detonation nanodiamonds (DNDs) are carbon-based nanomaterials that are among the most promising nanoparticles available for biomedical applications so far. This is due to their biocompatibility, which could be contributed to their inert core and conformable surface nature. However, DNDs cytotoxicity for urothelial cells and the routes of their internalization remains an open question in the aspect of nanodiamond surface. We therefore analyzed four types of DNDs for cytotoxicity and internalization with normal urothelial cells and two types of cancer urothelial cell lines in vitro. Viability of any of the cell types we used was not compromised with any of four DNDs we evaluated after 24-, 48- and 72-h incubation in three different concentrations of DNDs. Transmission electron microscopy revealed that all four types of DNDs were endocytosed into all three types of urothelial cells tested here. We observed DNDs in endosomes, as well as in multivesicular bodies and multilamellar bodies. These results propose using of DNDs as a delivery system for urological applications in human nanomedicine.

TRPV2 mediates adrenomedullin stimulation of prostate and urothelial cancer cell adhesion, migration and invasion.

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Agathe Oulidi

Full Text Available Adrenomedullin (AM is a 52-amino acid peptide initially isolated from human pheochromocytoma. AM is expressed in a variety of malignant tissues and cancer cell lines and was shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, AM is a survival factor for certain cancer cells. Some data suggest that AM might be involved in the progression cancer metastasis via angiogenesis and cell migration and invasion control. The Transient Receptor Potential channel TRPV2 is known to promote in prostate cancer cell migration and invasive phenotype and is correlated with the stage and grade of bladder cancer. In this work we show that AM induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to plasma membrane and the subsequent increase in resting calcium level.

Olaparib in Treating Patients With Metastatic or Advanced Urothelial Cancer With DNA-Repair Defects

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2018-06-14

Abnormal DNA Repair; ATM Gene Mutation; ATR Gene Mutation; BAP1 Gene Mutation; BARD1 Gene Mutation; BLM Gene Mutation; BRCA1 Gene Mutation; BRCA2 Gene Mutation; BRIP1 Gene Mutation; CHEK1 Gene Mutation; CHEK2 Gene Mutation; FANCC Gene Mutation; FANCD2 Gene Mutation; FANCE Gene Mutation; FANCF Gene Mutation; MEN1 Gene Mutation; Metastatic Urothelial Carcinoma; MLH1 Gene Mutation; MSH2 Gene Mutation; MSH6 Gene Mutation; MUTYH Gene Mutation; NPM1 Gene Mutation; PALB2 Gene Mutation; PMS2 Gene Mutation; POLD1 Gene Mutation; POLE Gene Mutation; PRKDC Gene Mutation; RAD50 Gene Mutation; RAD51 Gene Mutation; SMARCB1 Gene Mutation; Stage III Bladder Urothelial Carcinoma AJCC v6 and v7; Stage IV Bladder Urothelial Carcinoma AJCC v7; STK11 Gene Mutation; Urothelial Carcinoma

Asthma status is associated with decreased risk of aggressive urothelial bladder cancer.

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Rava, Marta; Czachorowski, Maciej J; Silverman, Debra; Márquez, Mirari; Kishore, Sirish; Tardón, Adonina; Serra, Consol; García-Closas, Montse; Garcia-Closas, Reina; Carrato, Alfredo; Rothman, Nathaniel; Real, Francisco X; Kogevinas, Manolis; Malats, Núria

2018-02-01

Previous studies suggested an association between atopic conditions and specific cancers. The results on the association with urothelial bladder cancer (UBC) are scarce and inconsistent. To evaluate the association between asthma and risk of UBC, we considered 936 cases and 1,022 controls from the Spanish Bladder Cancer/EPICURO Study (86% males, mean age 65.4 years), a multicenter and hospital-based case-control study conducted during 1998-2001. Participants were asked whether they had asthma and detailed information about occupational exposures, smoking habits, dietary factors, medical conditions and history of medication was collected through face-to-face questionnaires performed by trained interviewers. Since asthma and UBC might share risk factors, association between patients' characteristics and asthma was studied in UBC controls. Association between UBC and asthma was assessed using logistic regression unadjusted and adjusted for potential confounders. The complex interrelationships, direct and mediating effect of asthma on UBC, were appraised using counterfactual mediation models. Asthma was associated with a reduced risk of UBC (odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.37, 0.79) after adjusting for a wide range of confounders. No mediating effect was identified. The reduced risk associated with asthma was restricted to patients with high-risk non-muscle invasive (OR = 0.25, 95%CI 0.10, 0.62) and muscle invasive UBC (OR = 0.32, 95%CI 0.15, 0.69). Our results support that asthma is associated with a decreased risk of UBC, especially among aggressive tumors. Further work on the relationship between asthma and other atopic conditions and cancer risk should shed light on the relationship between immune response mechanisms and bladder carcinogenesis. © 2017 UICC.

Expression of AR, 5αR1 and 5αR2 in bladder urothelial carcinoma and relationship to clinicopathological factors.

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Hata, Shuko; Ise, Kazue; Azmahani, Abdullah; Konosu-Fukaya, Sachiko; McNamara, Keely May; Fujishima, Fumiyoshi; Shimada, Keiji; Mitsuzuka, Koji; Arai, Yoichi; Sasano, Hironobu; Nakamura, Yasuhiro

2017-12-01

Bladder urothelial carcinoma is increasing in incidence with age and its prognosis could become worse when accompanied with metastasis. Effective treatment of these advanced patients is required and it becomes important to understand its underlying biology of this neoplasm, especially with regard to its biological pathways. A potential proposed pathway is androgen receptor (AR)-mediated intracellular signaling but the details have remained relatively unexplored. The expression of AR, 5α-reductase type1 (5αR1) and 5α-reductase type2 (5αR2) were examined in the bladder cancer cell line T24 and surgical pathology specimens. We also evaluated the status of androgen related cell proliferation and migration using the potent, non-aromatizable androgen agonist 5α-dihydrotestosterone (DHT). DHT treatment significantly increased AR mRNA expression level, but not those of 5αR1 and 5αR2 in T24 cells. DHT also suppressed cellular migration with weaker and opposite effects on cell proliferation. A significant inverse correlation was detected between pT stage and AR, 5αR1 and 5αR2 immunoreactivity. Inverse correlations detected between tumor grade and AR/androgen metabolizing enzyme also suggested that the loss of AR and androgen-producing enzymes could be associated with tumor progression. Effects of DHT on cells also suggest that androgens may regulate cellular behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

Preoperative lymph-node staging of invasive urothelial bladder cancer with 18F-fluorodeoxyglucose positron emission tomography/computed axial tomography and magnetic resonance imaging

DEFF Research Database (Denmark)

Jensen, Thor Knak; Holt, Per; Gerke, Oke

2011-01-01

OBJECTIVE: The treatment and prognosis of bladder cancer are based on the depth of primary tumour invasion and the presence of metastases. A highly accurate preoperative tumour, node, metastasis (TNM) staging is critical to proper patient management and treatment. This study retrospectively...... investigated the value of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed axial tomography (¹⁸F-FDG PET/CT) and magnetic resonance imaging (MRI) for preoperative N staging of bladder cancer. Material and methods. From June 2006 to January 2008, 48 consecutive patients diagnosed with bladder......) for MRI and ¹⁸F-FDG PET/CT, respectively. The differences in specificity and negative predictive values were not statistically significant. Conclusions. No significant statistical difference between ¹⁸F-FDG PET/CT and MRI for preoperative N staging of urothelial bladder cancer was found in the study...

Urinary bladder carcinoma with divergent differentiation featuring small cell carcinoma, sarcomatoid carcinoma, and liposarcomatous component.

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Yasui, Mariko; Morikawa, Teppei; Nakagawa, Tohru; Miyakawa, Jimpei; Maeda, Daichi; Homma, Yukio; Fukayama, Masashi

2016-09-01

Both small cell carcinoma and sarcomatoid carcinoma of the urinary bladder are highly aggressive tumors, and a concurrence of these tumors is extremely rare. We report a case of urinary bladder cancer with small cell carcinoma as a predominant component, accompanied by sarcomatoid carcinoma and conventional urothelial carcinoma (UC). Although the small cell carcinoma component had resolved on receiving chemoradiotherapy, rapid growth of the residual tumor led to a fatal outcome. A 47-year-old man presented with occasional bladder irritation and had a 2-year history of asymptomatic hematuria. Cystoscopy revealed a huge mass in the urinary bladder, and transurethral resection was performed. Microscopically, small cell carcinoma was detected as the major tumor component. Spindle-shaped sarcomatoid cells were also observed that were intermingled with small cell carcinoma and conventional UC. In addition, a sheet-like growth of the lipoblast-like neoplastic cells was observed focally. Initially, by providing chemoradiotherapy, we achieved a marked tumor regression; however, the tumor rapidly regrew after the completion of chemoradiotherapy, and the patient underwent radical cystectomy. Only conventional UC and sarcomatoid carcinoma were identified in the cystectomy specimen. The patient died of the disease 4 months after cystectomy. Urinary bladder cancer may include a combination of multiple aggressive histologies as in the present case. Because the variation in the tumor components may affect the efficacy of therapy, a correct diagnosis of every tumor component is necessary. Copyright © 2016 Elsevier GmbH. All rights reserved.

Correlation between Urothelial Differentiation and Sensory Proteins P2X3, P2X5, TRPV1, and TRPV4 in Normal Urothelium and Papillary Carcinoma of Human Bladder

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Igor Sterle

2014-01-01

Full Text Available Terminal differentiation of urothelium is a prerequisite for blood-urine barrier formation and enables normal sensory function of the urinary bladder. In this study, urothelial differentiation of normal human urothelium and of low and high grade papillary urothelial carcinomas was correlated with the expression and localization of purinergic receptors (P2X3, and P2X5 and transient receptor potential vanilloid channels (TRPV1, and TRPV4. Western blotting and immunofluorescence of uroplakins together with scanning electron microscopy of urothelial apical surface demonstrated terminal differentiation of normal urothelium, partial differentiation of low grade carcinoma, and poor differentiation of high grade carcinoma. P2X3 was expressed in normal urothelium as well as in low grade carcinoma and in both cases immunolabeling was stronger in the superficial cells. P2X3 expression decreased in high grade carcinoma. P2X5 expression was detected in normal urothelium and in high grade carcinoma, while in low grade carcinoma its expression was diminished. The expression of TRPV1 decreased in low grade and even more in high grade carcinoma when compared with normal urothelium, while TRPV4 expression was unchanged in all samples. Our results suggest that sensory proteins P2X3 and TRPV1 are in correlation with urothelial differentiation, while P2X5 and TRPV4 have unique expression patterns.

p53-stabilizing Agent CP-31398 Prevents Growth and Invasion of Urothelial Cancer of the Bladder in Transgenic UPII-SV40T Mice

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Venkateshwar Madka

2013-08-01

Full Text Available The high prevalence of bladder cancer and its recurrence make it an important target for chemoprevention. About half of invasive urothelial tumors have mutations in p53. We determined the chemopreventive efficacy of a p53-stabilizing agent, CP-31398, in a transgenic UPII-SV40T mouse model of bladder transitional cell carcinoma (TCC that strongly resembles human TCC. After genotyping, six-week-old UPII-SV40T mice (n = 30/group were fed control (AIN-76A or experimental diets containing 150 or 300 ppm of CP-31398 for 34 weeks. Progression of bladder cancer growth was monitored by magnetic resonance imaging. At 40 weeks of age, all mice were killed; urinary bladders were collected to determine weights, tumor incidence, and histopathology. There was a significant increase in bladder weights of transgenic versus wild-type mice (male: 140.2 mg vs 27.3 mg, P < .0001; female: 34.2 mg vs 14.8 mg, P < .0001. A significant decrease in the bladder tumor weights (by 68.6–80.2%, P < .0001 in males and by 36.9–55.3%, P < .0001 in females was observed in CP-31398-treated mice. Invasive papillary TCC incidence was 100% in transgenic mice fed control diet. Both male and female mice exposed to CP-31398 showed inhibition of invasive TCC. CP-31398 (300 ppm completely blocked invasion in female mice. Molecular analysis of the bladder tumors showed an increase in apoptosis markers (p53, p21, Bax, and Annexin V with a decrease in vascular endothelial growth factor in transgenic mice fed CP-31398. These results suggest that p53-modulating agents can serve as potential chemopreventive agents for bladder TCC.

Unusual presentation of high-grade neuroendocrine carcinoma of the Urinary bladder with small-cell and large-cell features

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Vitor Fiorin de Vasconcellos

2013-10-01

Full Text Available High-grade neuroendocrine carcinoma of the urinary bladder comprehends small-cell and large-cell variants. It is a rare and aggressive neoplasm, mostly diagnosed in advanced stages. It is more frequently encountered among Caucasian men in the sixth decade of life. Urinary symptoms are the most common clinical presentation. Diagnosis is generally not troublesome once the lesions are easily detectable by imaging exams and cystoscopy. This neoplasia is associated with tobacco smoking, and is frequently associated with other carcinomatous components such as urothelial carcinoma, adenocarcinoma, and sarcomatoid carcinoma. The authors report a case of an apparently healthy female patient who presented cervical lymph node enlargement not accompanied by systemic symptoms. The supraclavicular lymph node biopsy revealed metastatic small cell carcinoma. The computed tomography scan showed a bladder wall nodular thickening, enlarged lymph nodes along the iliac, periaortic, mediastinal, cervical and supraclavicular chains, as well as an insufflating lytic bone lesion in the right iliac wing. The positron emission tomography-fluorodeoxyglucose (PET-FDG added to these findings, the presence of a paraesophageal lymph node, lymphadenomegaly in the gluteal region and a vertebral lytic lesion in T10. Resected specimen of the bladder tumor revealed a high-grade neuroendocrine carcinoma with small-cell and large-cell features.

Dose-response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats.

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Cardoso, Ana Paula Ferragut; Ihlaseh Catalano, Shadia Muhammad; da Rocha, Mitscheli Sanches; Nascimento E Pontes, Merielen Garcia; de Camargo, João Lauro Viana; de Oliveira, Maria Luiza Cotrim Sartor

2013-10-04

Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a herbicide that induced urothelial tumors in the urinary bladder of Wistar rats fed 2500ppm during a long-term study. The currently suggested non-genotoxic mode of action (MOA) of diuron encompasses in succession urothelial necrosis induced by direct cytotoxicity, regenerative cell proliferation and sustained urothelial hyperplasia that increases the likelihood of neoplasia development. This study evaluated the dose-response profile of urothelial histological and ultrastructural lesions induced by diuron. Sixty male Wistar rats were fed ad libitum diuron mixed in the diet at 0, 60, 125, 500, 1250, or 2500ppm for 20 weeks. The incidences of urothelial simple hyperplasia and the cell proliferation index were significantly increased in the diuron-fed 1250 and 2500ppm groups. By scanning electron microscopy, the incidences and severity of lesions were significantly increased in the 500 and 1250ppm groups. The incidences of urothelial hyperplasia in the kidney pelvis were significantly increased in the 500, 1250 and 2500ppm groups. The present study documents the dose-response influence of diuron on the rat urothelium, with a no observed effect level (NOEL) at 125ppm; 1250ppm was as effective as 2500ppm at inducing urothelial lesions. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Dose–response of diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] in the urothelial mucosa of Wistar rats

International Nuclear Information System (INIS)

Ferragut Cardoso, Ana Paula; Ihlaseh Catalano, Shadia Muhammad; Sanches da Rocha, Mitscheli; Nascimento e Pontes, Merielen Garcia; Viana de Camargo, João Lauro; Cotrim Sartor de Oliveira, Maria Luiza

2013-01-01

Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a herbicide that induced urothelial tumors in the urinary bladder of Wistar rats fed 2500 ppm during a long-term study. The currently suggested non-genotoxic mode of action (MOA) of diuron encompasses in succession urothelial necrosis induced by direct cytotoxicity, regenerative cell proliferation and sustained urothelial hyperplasia that increases the likelihood of neoplasia development. This study evaluated the dose–response profile of urothelial histological and ultrastructural lesions induced by diuron. Sixty male Wistar rats were fed ad libitum diuron mixed in the diet at 0, 60, 125, 500, 1250, or 2500 ppm for 20 weeks. The incidences of urothelial simple hyperplasia and the cell proliferation index were significantly increased in the diuron-fed 1250 and 2500 ppm groups. By scanning electron microscopy, the incidences and severity of lesions were significantly increased in the 500 and 1250 ppm groups. The incidences of urothelial hyperplasia in the kidney pelvis were significantly increased in the 500, 1250 and 2500 ppm groups. The present study documents the dose–response influence of diuron on the rat urothelium, with a no observed effect level (NOEL) at 125 ppm; 1250 ppm was as effective as 2500 ppm at inducing urothelial lesions

Pathogenic and Diagnostic Potential of BLCA-1 and BLCA-4 Nuclear Proteins in Urothelial Cell Carcinoma of Human Bladder

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Matteo Santoni

2012-01-01

Full Text Available Transitional cell carcinoma (TCC of the bladder is one of the most common malignancies of genitourinary tract. Patients with bladder cancer need a life-long surveillance, directly due to the relatively high recurrence rate of this tumor. The use of cystoscopy represents the gold standard for the followup of previously treated patients. Nevertheless, several factors, including cost and invasiveness, render cystoscopy not ideal for routine controls. Advances in the identification of specific alterations in the nuclear structure of bladder cancer cells have opened novel diagnostic landscapes. The members of nuclear matrix protein family BLCA-1 and BLCA-4, are currently under evaluation as bladder cancer urinary markers. They are involved in tumour cell proliferation, survival, and angiogenesis. In this paper, we illustrate the role of BLCA-1 and BLCA-4 in bladder carcinogenesis and their potential exploitation as biomarkers in this cancer.

High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

International Nuclear Information System (INIS)

Egerod, Frederikke Lihme; Bartels, Annette; Fristrup, Niels; Borre, Michael; Ørntoft, Torben F; Oleksiewicz, Martin B; Brünner, Nils; Dyrskjøt, Lars

2009-01-01

Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression. Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer. The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies. The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer

Three-dimensional organoid culture reveals involvement of Wnt/β-catenin pathway in proliferation of bladder cancer cells.

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Yoshida, Takahiro; Sopko, Nikolai A; Kates, Max; Liu, Xiaopu; Joice, Gregory; McConkey, David J; Bivalacqua, Trinity J

2018-02-16

There has been increasing awareness of the importance of three-dimensional culture of cancer cells. Tumor cells growing as multicellular spheroids in three-dimensional culture, alternatively called organoids, are widely believed to more closely mimic solid tumors in situ . Previous studies concluded that the Wnt/β-catenin pathway is required for regeneration of the normal urothelium after injury and that β-catenin is upregulated in human bladder cancers, but no clear evidence has been advanced to support the idea that the Wnt/β-catenin pathway is directly involved in deregulated proliferation and the other malignant characteristics of bladder cancer cells. Here we report that the Wnt/β-catenin pathway activator, CHIR99021, promoted proliferation of established human bladder cancer cell lines when they were grown in organoid culture but not when they were grown in conventional adherent cultures. CHIR99021 activated Wnt/β-catenin pathway in bladder cancer cell lines in organoid culture. CHIR99021 also stimulated proliferation and the Wnt/b-catenin pathway in primary human bladder cancer organoids. RNAi-mediated knockdown of β-catenin blocked growth of organoids. The effects of CHIR99021 were associated with decreased expression of the urothelial terminal differentiation marker, cytokeratin 20. Our data suggest that the Wnt/β-catenin pathway is required for the proliferation of bladder cancer cells in three-dimensional organoid culture and provide a concrete example of why organoid culture is important for cancer research.

Molecular Diagnosis in Bladder Cancer

NARCIS (Netherlands)

T.C.M. Zuiverloon (Tahlita)

2013-01-01

textabstractEpidemiologyBladder cancer (BC) is the most prevalent type of urothelial cancer and is associated with thehighest costs of all cancer types due to intensive patient surveillance. Because bladder tumorsfrequently recur, patients need to be monitored extensively [1-4]. Incidence increases

Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression.

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Tuygun, Can; Kankaya, Duygu; Imamoglu, Abdurrahim; Sertcelik, Ayse; Zengin, Kursad; Oktay, Murat; Sertcelik, Nurettin

2011-01-01

To investigate the expression of sex-specific hormone receptors in normal bladder urothelium and urothelial carcinomas (UCs) of the bladder, and to analyze clinicopathological features and survival outcomes according to receptor expression. We evaluated the clinical data and tumor specimens of 139 patients with bladder cancer (BC). In addition, 72 samples of normal urothelium were included. Immunohistochemistry was performed using streptavidin-biotin peroxidase method, a monoclonal androgen receptor (AR), and an estrogen receptor-β (ERβ) antibody on paraffin-embedded tissue sections. Expression levels of each receptor were assessed by evaluating 500 tumor cells for each case and the percentage of positively-stained nuclei was recorded. None of the 58 male control cases showed any AR and ERβ expression. Five (35, 71%) of the 14 female control cases expressed ERβ. Of the 139 patients with UCs, 71 (51, 07%) expressed AR (62 male vs. 9 female; P = 0.413) and 44 (31, 65%) (39 male vs. 5 female; P = 0.402) showed ERβ expression (P receptors alone cannot be responsible for gender differences in BC rates because they were expressed in similar rates in both sexes. Copyright © 2011 Elsevier Inc. All rights reserved.

Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.

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Daniel T Johnson

Full Text Available Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl nitrosamine (BBN. We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Paraganglioma of the urinary bladder: a clinicopathologic spectrum of a series of 14 cases emphasizing diagnostic dilemmas.

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Menon, Santosh; Goyal, Pankaj; Suryawanshi, Pallavi; Tongaonkar, Hemant; Joshi, Amit; Bakshi, Ganesh; Desai, Sangeeta

2014-01-01

Paraganglioma (PG) of the urinary bladder is a rare neuroendocrine neoplasm, accounting for bladder tumours. Distinction from urothelial carcinoma is imperative as management and prognosis vary markedly. In this report, we describe our experience with the histopathology of paragangliomas of the urinary bladder with emphasis on the histologic features that have led to their being misdiagnosed as conventional urothelial cancer and, most importantly, those that will help pathologists recognize this rare tumor of the bladder. All cases of PG of urinary bladder diagnosed at our institute from 2002-2012 were retrieved and diagnosis confirmed in accordance with WHO classification. Clinical and treatment details were obtained from hospital medical records. Fourteen cases of PG of urinary bladder including 5 consult cases were analysed. These included 11 transurethral resections ± partial cystectomies, 2 partial cystectomies and 1 radical cystectomy. Two out of the 5 consult cases had been submitted with a diagnosis of urothelial carcinoma and 1 with that of a rhabdomyosarcoma. Age ranged from 15-84 years (median, 43 years) with a male to female ratio of 1:2.5. Presenting symptoms were haematuria, dysuria and flank pain; only 1 case had antecedent hypertension. Histologically, typical 'zellballen' (72%), diffuse (21%) and ribbon-like (7%) growth patterns amidst a richly vascularised stroma were seen. Muscularis propria invasion and necrosis was present in 72% and 21%, respectively. Substantial cautery artifacts led to misdiagnosis in the 3 erroneous cases. Tumour cells were positive for chromogranin, synaptophysin; sustentacular cells were S-100 positive. Follow up was available in 6 patients; median follow-up was 29 months (8-120 months). One patient developed distant metastasis in cervical lymph node 10 years after diagnosis; remaining were alive without evidence of disease. Paraganglioma of the urinary bladder is a rare tumor and may be misdiagnosed as urothelial cancer

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy

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Li, Lu; Douville, Christopher; Wang, Yuxuan; Cohen, Joshua David; Taheri, Diana; Silliman, Natalie; Schaefer, Joy; Ptak, Janine; Dobbyn, Lisa; Papoli, Maria; Kinde, Isaac; Afsari, Bahman; Tregnago, Aline C; Bezerra, Stephania M; VandenBussche, Christopher; Fujita, Kazutoshi; Ertoy, Dilek; Cunha, Isabela W; Yu, Lijia; Bivalacqua, Trinity J; Grollman, Arthur P; Diaz, Luis A; Karchin, Rachel; Danilova, Ludmila; Huang, Chao-Yuan; Shun, Chia-Tung; Turesky, Robert J; Yun, Byeong Hwa; Rosenquist, Thomas A; Pu, Yeong-Shiau; Hruban, Ralph H; Tomasetti, Cristian; Papadopoulos, Nickolas; Kinzler, Ken W

2018-01-01

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer. PMID:29557778

Luminal DMSO: Effects on Detrusor and Urothelial/Lamina Propria Function

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Katrina J. Smith

2014-01-01

Full Text Available DMSO is used as a treatment for interstitial cystitis and this study examined the effects of luminal DMSO treatment on bladder function and histology. Porcine bladder was incubated without (controls or with DMSO (50% applied to the luminal surface and the release of ATP, acetylcholine, and LDH assessed during incubation and in tissues strips after DMSO incubation. Luminally applied DMSO caused ATP, Ach, and LDH release from the urothelial surface during treatment, with loss of urothelial layers also evident histologically. In strips of urothelium/lamina propria from DMSO pretreated bladders the release of both ATP and Ach was depressed, while contractile responses to carbachol were enhanced. Detrusor muscle contractile responses to carbachol were not affected by DMSO pretreatment, but neurogenic responses to electrical field stimulation were enhanced. The presence of an intact urothelium/lamina propria inhibited detrusor contraction to carbachol by 53% and this inhibition was significantly reduced in DMSO pretreated tissues. Detection of LDH in the treatment medium suggests that DMSO permeabilised urothelial membranes causing leakage of cytosolic contents including ATP and Ach rather than enhancing release of these mediators. The increase in contractile response and high levels of ATP are consistent with initial flare up in IC/PBS symptoms after DMSO treatment.

Clinical usefulness of CEA, CA19-9, and CYFRA 21-1 as tumor markers for urothelial bladder carcinoma.

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Washino, Satoshi; Hirai, Masaru; Matsuzaki, Atsushi; Kobayashi, Yutaka

2011-01-01

To evaluate the usefulness of measuring serum CEA, CA19-9, and CYFRA 21-1 levels for the diagnosis and monitoring of bladder cancer. Serum levels of CEA, CA19-9, and CYFRA 21-1 were measured in 85 patients with bladder cancer. The absolute level of each marker and the positive rate were compared with the clinical stage and histological grade of the tumor. Changes of the markers were assessed in patients with or without disease progression, and the correlations between survival and positivity/negativity of these markers were also evaluated. A higher serum level of CYFRA 21-1 was significantly correlated with higher tumor stage (p CEA and CA19-9 levels did not differ significantly among each stage and grade. The CYFRA 21-1 level increased significantly along with disease progression (from 7.33 ± 13.3 to 55.9 ± 127 ng/ml, p marker of advanced- and high-grade urothelial carcinoma of the bladder. It is useful for monitoring this disease and for predicting the prognosis. In contrast, the clinical usefulness of CEA and CA19-9 as tumor markers was not demonstrated. Copyright © 2011 S. Karger AG, Basel.

[Construction of a capsular tissue-engineered ureteral stent seeded with autologous urothelial cells].

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Tan, Haisong; Fu, Weijun; Li, Jianqiang; Wang, Zhongxin; Li, Gang; Ma, Xin; Dong, Jun; Gao, Jiangping; Wang, Xiaoxiong; Zhang, Xu

2013-01-01

To investigate the feasibility of constructing a capsular poly L-lactic acid (PLLA) ureteral stent seeded with autologous urothelial cells using tissue engineering methods. The capsular ureteral stent was constructed by subcutaneously embedding PLLA ureteral stent in the back of beagles for 3 weeks to induce the formation of connective tissue on the surfaces. After decellularization of the stent, the expanded autologous urothelial cells were seeded on the stent. The surface structure and cell adhesion of the stent were observed using HE staining, scanning electron microscope (SEM) and immunocytochemical staining. MTT assay was used to evaluate urothelial cell proliferation on the capsular PLLA ureteral stent and on circumferential small intestinal submucosa graft. HE staining and VIII factor immunohistochemistry revealed numerous capillaries in the connective tissue encapsulating the stent without obvious local inflammatory response. The results of SEM and immunocytochemical staining showed that the capsule contained rich collagenic fibers forming three-dimensional structures, and the seeded autologous urothelial cells could adhere and well aligned on the surface. MTT assay showed normal growth of the cells on the stent as compared with the cells grown on circumferential small intestinal submucosa graft. The capsular PLLA ureteral stent allows adhesion and proliferation of autologous urothelial cells and shows a potential in applications of constructing tissue-engineered ureter.

Flavagline analog FL3 induces cell cycle arrest in urothelial carcinoma cell of the bladder by inhibiting the Akt/PHB interaction to activate the GADD45α pathway.

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Yuan, Gangjun; Chen, Xin; Liu, Zhuowei; Wei, Wensu; Shu, Qinghai; Abou-Hamdan, Hussein; Jiang, Lijuan; Li, Xiangdong; Chen, Rixin; Désaubry, Laurent; Zhou, Fangjian; Xie, Dan

2018-02-07

Prohibitin 1 (PHB) is a potential target for the treatment of urothelial carcinoma of the bladder (UCB). FL3 is a newly synthesized agent that inhibits cancer cell proliferation by targeting the PHB protein; however, the effect of FL3 in UCB cells remains unexplored. FL3 was identified to be a potent inhibitor of UCB cell viability using CCK-8 (cell counting kit-8) assay. Then a series of in vitro and in vivo experiments were conducted to further demonstrate the inhibitory effect of FL3 on UCB cell proliferation and to determine the underlying mechanisms. FL3 inhibited UCB cell proliferation and growth both in vitro and in vivo. By targeting the PHB protein, FL3 inhibited the interaction of Akt and PHB as well as Akt-mediated PHB phosphorylation, which consequently decreases the localization of PHB in the mitochondria. In addition, FL3 treatment resulted in cell cycle arrest in the G2/M phase, and this inhibitory effect of FL3 could be mimicked by knockdown of PHB. Through the microarray analysis of mRNA expression after FL3 treatment and knockdown of PHB, we found that the mRNA expression of the growth arrest and DNA damage-inducible alpha (GADD45α) gene were significantly upregulated. When knocked down the expression of GADD45α, the inhibitory effect of FL3 on cell cycle was rescued, suggesting that FL3-induced cell cycle inhibition is GADD45α dependent. Our data provide that FL3 inhibits the interaction of Akt and PHB, which in turn activates the GADD45α-dependent cell cycle inhibition in the G2/M phase.

Metabolic syndrome and the risk of urothelial carcinoma of the bladder: a case-control study

International Nuclear Information System (INIS)

Montella, Maurizio; Di Maso, Matteo; Crispo, Anna; Grimaldi, Maria; Bosetti, Cristina; Turati, Federica; Giudice, Aldo; Libra, Massimo; Serraino, Diego; La Vecchia, Carlo; Tambaro, Rosa; Cavalcanti, Ernesta; Ciliberto, Gennaro; Polesel, Jerry

2015-01-01

The Metabolic syndrome (MetS) is an emerging condition worldwide, consistently associated with an increased risk of several cancers. Some information exists on urothelial carcinoma of the bladder (UCB) and MetS. This study aims at further evaluating the association between the MetS and UCB. Between 2003 and 2014 in Italy, we conducted a hospital-based case-control study, enrolling 690 incident UCB patients and 665 cancer-free matched patients. The MetS was defined as the presence of at least three of the four selected indicators: abdominal obesity, hypercholesterolemia, hypertension, and diabetes. Odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) for MetS and its components were estimated through multiple logistic regression models, adjusting for potential confounders. Patients with MetS were at a 2-fold higher risk of UCB (95 % CI:1.38–3.19), compared to those without the MetS. In particular, ORs for bladder cancer were 2.20 (95 % CI:1.42–3.38) for diabetes, 0.88 (95 % CI: 0.66-1.17) for hypertension, 1.16 (95 % CI: 0.80-1.67) for hypercholesterolemia, and 1.63 (95 % CI:1.22–2.19) for abdominal obesity. No heterogeneity in risks emerged across strata of sex, age, education, geographical area, and smoking habits. Overall, 8.1 % (95 % CI: 3.9-12.4 %) of UCB cases were attributable to the MetS. This study supports a positive association between the MetS and bladder cancer risk

All-trans retinoic acid directs urothelial specification of murine embryonic stem cells via GATA4/6 signaling mechanisms.

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Joshua R Mauney

2010-07-01

Full Text Available The urinary bladder and associated tract are lined by the urothelium, a transitional epithelium that acts as a specialized permeability barrier that protects the underlying tissue from urine via expression of a highly specific group of proteins known as the uroplakins (UP. To date, our understanding of the developmental processes responsible for urothelial differentiation has been hampered due to the lack of suitable models. In this study, we describe a novel in vitro cell culture system for derivation of urothelial cells from murine embryonic stem cells (ESCs following cultivation on collagen matrices in the presence all trans retinoic acid (RA. Upon stimulation with micromolar concentrations of RA, ESCs significantly downregulated the pluripotency factor OCT-4 but markedly upregulated UP1A, UP1B, UP2, UP3A, and UP3B mRNA levels in comparison to naïve ESCs and spontaneously differentiating controls. Pan-UP protein expression was associated with both p63- and cytokeratin 20-positive cells in discrete aggregating populations of ESCs following 9 and 14 days of RA stimulation. Analysis of endodermal transcription factors such as GATA4 and GATA6 revealed significant upregulation and nuclear enrichment in RA-treated UP2-GFP+ populations. GATA4-/- and GATA6-/- transgenic ESC lines revealed substantial attenuation of RA-mediated UP expression in comparison to wild type controls. In addition, EMSA analysis revealed that RA treatment induced formation of transcriptional complexes containing GATA4/6 on both UP1B and UP2 promoter fragments containing putative GATA factor binding sites. Collectively, these data suggest that RA mediates ESC specification toward a urothelial lineage via GATA4/6-dependent processes.

Taurine modulates neutrophil function but potentiates uropathogenic E. coli infection in the murine bladder.

LENUS (Irish Health Repository)

Condron, Claire

2010-08-01

Eradication of a urinary tract infection (UTI) appears to be related to a number of innate host defence mechanisms and their interactions with invading bacteria. Recurrent UTIs (rUTIs) pose a difficult problem in that these bacteria use both host and bacterial factors to evade elimination. Neutrophil bactericidal function is depressed, both systemically and in urine, in patients with a history of recurrent UTI. Taurine is a semi-essential amino acid and is successful in preserving neutrophil bactericidal function in urine. Taurine may preserve neutrophil function at the urothelium and thus aid UTI resolution. Adult female (6 weeks old) C57Bl\\/6 mice were randomised into three groups: a saline gavage only control group, a saline gavage + E. coli group, and a taurine gavage + E. coli group [21 g\\/70 kg taurine in 0.9% normal saline (N\\/S) for 5 days]. Whilst taurine gavage pre-treatment resulted in increased serum neutrophils respiratory burst activity, at the urothelial-endothelial interface it caused higher colony forming units in the urine and a higher incidence of E. coli invasion in the bladder wall with no evidence of increased bladder wall neutrophils infiltration on MPO assay of histological assessment. Histologically there was also evidence of reduced bladder inflammation and urothelial cell apoptosis. In conclusion, taurine effectively increases neutrophils activity but given its anti-inflammatory properties, at the expense of decreased urothelial-endothelial activation thus preventing clearance of active E. coli infection in the bladder. Despite the negative results, this study demonstrates the importance of modulating interactions at the urothelial interface.

Systemic Immunotherapy of Non–Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor

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Vandeveer, Amanda J.; Fallon, Jonathan K.; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W.

2016-01-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non–muscle invasive, nonmetastatic human urothelial carcinoma. While the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non–muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1 and avelumab administration induced significant (P<0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non–muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. PMID:26921031

The nested variant of bladder transitional cell carcinoma: Review of 12 cases and review of the literature.

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Carrion-Ballardo, C J; Gala-Solana, L; Portillo-Martin, J A; Azueta-Etxebarria, A; Truan-Cacho, D; Campos-Juanatey, F

2015-01-01

The nested variant of bladder transitional cell carcinoma is extremely rare and has a different biological behavior to other bladder tumors. The aim of this study is to analize if their behavior is as aggressive as has been described in the literature. Review of 12 diagnosed cases with nested variant of bladder transitional cell carcinoma and analysis of demographic characteristics, clinical presentation, tumor characteristics, treatment options, analysis of recurrence and cancer-specific survival between January 1997 and December 2010 in our hospital. 50% of the cases had a pathologic stage ≥T2, with grade of differentiation G2 (50%) or G3 (50%). After the pathological result of the TUR (transurethral resection) Bladder, 5 cases underwent radical cystoprostatectomy, 3 a second TUR bladder and 4 cases with treatment chemotherapy and/or radiotherapy (RT). Five out of 12 cases (41.7%) died due to bladder cancer and 3 died (25%) of other causes (urinary sepsis, respiratory failure, renal failure). With a median follow up of 40 months, the overall survival was 50% and cancer-specific survival of 65.6%. The nested variant of bladder transitional cell carcinoma is a disease with an advanced-stage presentation, with high recurrence and mortality rates despite the use of different treatments. So far there is not a clinical practice guideline for this variety of urothelial tumor. Copyright © 2014 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

Performance of Urinary Markers for Detection of Upper Tract Urothelial Carcinoma: Is Upper Tract Urine More Accurate than Urine from the Bladder?

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Simone Bier

2018-01-01

Full Text Available Objectives. To assess the performance of urine markers determined in urine samples from the bladder compared to samples collected from the upper urinary tract (UUT for diagnosis of UUT urothelial carcinoma (UC. Patients and Methods. The study comprised 758 urine samples either collected from the bladder (n=373 or UUT (n=385. All patients underwent urethrocystoscopy and UUT imaging or ureterorenoscopy. Cytology, fluorescence in situ hybridization (FISH, immunocytology (uCyt+, and nuclear matrix protein 22 (NMP22 were performed. Results. UUT UC was diagnosed in 59 patients (19.1% (UUT urine and 27 patients (7.2% (bladder-derived urine. For UUT-derived samples, sensitivities for cytology, FISH, NMP22, and uCyt+ were 74.6, 79.0, 100.0, and 100.0, while specificities were 66.6, 50.7, 5.9, and 66.7%, respectively. In bladder-derived samples, sensitivities were 59.3, 52.9, 62.5, and 50.0% whereas specificities were 82.9, 85.0, 31.3, and 69.8%. In UUT-derived samples, concomitant bladder cancer led to increased false-positive rates of cytology and FISH. Conclusions. Urine markers determined in urine collected from the UUT exhibit better sensitivity but lower specificity compared to markers determined in bladder-derived urine. Concomitant or recent diagnosis of UC of the bladder can further influence markers determined in UUT urine.

Human Epidermal Growth Factor Receptor 2 Overexpression in Micropapillary and Other Variants of Urothelial Carcinoma.

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Behzatoğlu, Kemal; Yörükoğlu, Kutsal; Demir, Hale; Bal, Nebil

2016-06-21

Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification has been shown in urothelial bladder cancer. This could be helpful when using targeted anti-HER2 therapy on these tumors. To evaluate HER2 immunohistochemical expression in conventional urothelial carcinoma (UC), in situ UC, and UC variants primarily in micropapillary urothelial carcinoma (MPUC). The study evaluated 60 MPUC cases; 25 invasive, 20 low-grade noninvasive, and 10 high-grade noninvasive UC cases; 8 in situ UC cases; and 69 UC variant cases. The immunohistochemistry staining was scored according to recommendations of the American Society of Clinical Oncology/College of American Pathologists 2013 HER2 test guideline established for breast cancer and only 3+ staining was considered HER2 overexpression. HER2 overexpression was determined by 3+ staining. 34 of 60 MPUC cases (56%) showed HER2 overexpression (3+ staining). We observed 3+ staining HER2 overexpression in nine of 25 conventional invasive UC cases (36%), four of eight in situ UC cases (50%), and three of six lipid cell variant cases (50%). 3+ staining HER2 overexpression was not seen in eight glandular, six small cell, and five sarcomatoid variant cases. HER2 overexpression was negative in the 20 low-grade noninvasive UC cases but positive in two of the 10 high-grade noninvasive UC cases (20%). We observed HER2 overexpression most commonly in MPUC cases. We also found HER2 overexpression in conventional invasive and in situ UC cases. Pure in situ UC and conventional invasive UC, especially MPUC, could be candidate tumors for treatment with anti-HER2 antibody (trastuzumab therapy). Targeted therapy has a limited place in treatment of bladder cancer. In this study, human epidermal growth factor receptor 2 (HER2) overexpression in bladder carcinomas was evaluated in a large number of cases. Anti-HER2 therapy could be used in bladder cancers, as in breast and gastric cancers. Copyright © 2016 European

Transcriptional profile of diuron-induced toxicity on the urinary bladder of male Wistar rats to inform mode of action.

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Ihlaseh, Shadia M; Bailey, Kathryn A; Hester, Susan D; Jones, Carlton; Ren, Hongzu; Cardoso, Ana Paula F; Oliveira, Maria Luiza C S; Wolf, Douglas C; de Camargo, João Lauro V

2011-08-01

Diuron (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is a substituted urea herbicide that induces rat urinary bladder urothelial tumors at high dietary levels (2500 ppm). The specific mode of action and molecular alterations triggered by diuron, however, have not been clarified. The present study evaluated the dose-dependent effects of mucosal alterations and transcriptional changes in the urinary bladder of rats exposed to diuron. Six-week-old male Wistar rats were treated with 0, 60, 125, 1250, and 2500 ppm of diuron in the diet for 20 weeks. Histologic examination showed urothelial hyperplasia present in rats treated with either 1250 or 2500 ppm of diuron but not 60 or 125 ppm. Comprehensive gene expression analyses of urothelial cell RNA were conducted using Affymetrix microarrays. The numbers of differentially expressed transcripts between each treatment group and control increased with diuron dose. Based on similar histology and gene expression responses, the treatment groups were regrouped into a high-dose (1250 and 2500 ppm) and low-dose group (60 and 125 ppm). These data suggest that persistent exposure to high dietary concentrations of diuron induces oxidative stress, increases cellular metabolism, and enhances cell death that is associated with sustained urothelial hyperplasia.

Systemic Immunotherapy for Urothelial Cancer: Current Trends and Future Directions

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Shilpa Gupta

2017-01-01

Full Text Available Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC. Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1 inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for firstline platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.

Confocal Laser Endomicroscopy for the Diagnosis of Urothelial Carcinoma in the Bladder and the Upper Urinary Tract: Protocols for Two Prospective Explorative Studies.

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Liem, Esmee Iml; Freund, Jan Erik; Baard, Joyce; de Bruin, D Martijn; Laguna Pes, M Pilar; Savci-Heijink, C Dilara; van Leeuwen, Ton G; de Reijke, Theo M; de la Rosette, Jean Jmch

2018-02-07

Visual confirmation of a suspicious lesion in the urinary tract is a major corner stone in diagnosing urothelial carcinoma. However, during cystoscopy (for bladder tumors) and ureterorenoscopy (for tumors of the upper urinary tract) no real-time histopathologic information can be obtained. Confocal laser endomicroscopy (CLE) is an optical imaging technique that allows for in vivo high-resolution imaging and may allow real-time tumor grading of urothelial lesions. The primary objective of both studies is to develop descriptive criteria for in vivo CLE images of urothelial carcinoma (low-grade, high-grade, carcinoma in situ) and normal urothelium by comparing CLE images with corresponding histopathology. In these two prospective clinical trials, CLE imaging will be performed of suspicious lesions and normal tissue in the urinary tract during surgery, prior to resection or biopsy. In the bladder study, CLE will be performed in 60 patients using the Cystoflex UHD-R probe. In the upper urinary tract study, CLE will be performed in 25 patients during ureterorenoscopy, who will undergo radical treatment (nephroureterectomy or segmental ureter resection) thereafter. All CLE images will be analyzed frame by frame by three independent, blinded observers. Histopathology and CLE-based diagnosis of the lesions will be evaluated. Both studies comply with the IDEAL stage 2b recommendations. Presently, recruitment of patients is ongoing in both studies. Results and outcomes are expected in 2018. For development of CLE-based diagnosis of urothelial carcinoma in the bladder and the upper urinary tract, a structured conduct of research is required. This study will provide more insight in tissue-specific CLE criteria for real-time tumor grading of urothelial carcinoma. Confocal Laser Endomicroscopy: ClinicalTrials.gov NCT03013894; https://clinicaltrials.gov /ct2/show/NCT03013894?term=NCT03013894&rank=1 (Archived by WebCite at http://www.webcitation.org/6wiPZ378I); and Dutch Central

Relevance of prostate cancer in patients with synchronous invasive bladder urothelial carcinoma: a monocentric retrospective analysis

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Lucio Dell’Atti

2015-03-01

Full Text Available Objectives: We retrospectively reviewed data of patients with incidental prostate cancer (PCa who underwent radical cystoprostatectomy (RCP for invasive bladder cancer and we analyzed their features with regard to incidence, pathologic characteristics, clinical significance, and implications for management. Material and Methods: Clinical data and pathological features of 64 patients who underwent standard RCP for bladder cancer were included in this study. Besides the urothelial carcinoma of the urinary bladder, the location and tumor volume of the PCa, prostate apex involvement, Gleason score, pathological staging and surgical margins were evaluated. Clinically significant PCa was defined as a tumor with a Gleason 4 or 5 pattern, stage ≥ pT3, lymph node involvement, positive surgical margin or multifocality of three or more lesions. Postoperative follow-up was scheduled every 3 months in the first year, every 6 months in the second and third year, annually thereafter. Results: 11 out of 64 patients (17.2% who underwent RCP had incidentally diagnosed PCa. 3 cases (27.3% were diagnosed as significant PCa, while 8 cases (72.7% were clinically insignificant. The positive surgical margin of PCa was detected in 1 patient with significant disease. The prostate apex involvement was present in 1 patient of the significant PCa group. Median follow-up period was 47.8 ± 29.2 (range 4-79. During the follow-up, biochemical recurrence occurred in 1 patient (9%. Concernig the cancer specific survival there was no statistical significance (P = 0.326 between the clinically significant and clinical insignificant cancer group. Conclusions: In line with published studies, incidental PCa does not impact on the prognosis of bladder cancer of patients undergoing RCP.

A Phase II Safety and Efficacy Study of the Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor Pazopanib in Patients With Metastatic Urothelial Cancer

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Pili, Roberto; Qin, Rui; Flynn, P.J.; Picus, Joel; Millward, Michael; Ho, Wing Ming; Pitot, Henry; Tan, Winston; Miles, Kiersten M.; Erlichman, Charles; Vaishampayan, Ulka

2013-01-01

Vascular endothelial growth factor (VEGF) is expressed in human bladder tumors. A phase II study was conducted to assess the VEGF inhibitor pazopanib in patients with metastatic, urothelial carcinoma. Nineteen patients with one prior systemic therapy were enrolled. No objective responses were observed and median progression-free survival was 1.9 months. The role of anti-VEGF therapies in urothelial carcinoma remains to be determined. Background Vascular endothelial growth factor (VEGF) is produced by bladder cancer cell lines in vitro and expressed in human bladder tumor tissues. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and anti-tumor activity in several preclinical models. A 2-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib in patients with metastatic, urothelial carcinoma. Methods Patients with one prior systemic therapy for metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally for a 4-week cycle. Results Nineteen patients were enrolled. No grade 4 or 5 events were experienced. Nine patients experienced 11 grade 3 adverse events. Most common toxicities were anemia, thrombocytopenia, leucopenia, and fatigue. For stage I, none of the first 16 evaluable patients were deemed a success (complete response or partial response) by the Response Evaluation Criteria In Solid Tumors criteria during the first four 4-week cycles of treatment. Median progression-free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore the trial was recommended to be permanently closed. Conclusions Pazopanib did not show significant activity in patients with urothelial carcinoma. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. PMID:23891158

CT differentiation of infiltrating renal cell carcinoma and renal urothelial tumor

International Nuclear Information System (INIS)

Choi, Hyo Kyeong; Goo, Dong Erk; Bang, Sun Woo; Lee, Moon Gyu; Cho, Kyoung Sik; Auh, Yong Ho

1994-01-01

It may be difficult to differentiate renal cell carcinoma involving collecting system from renal urothelial tumor invading into renal parenchyma. The purpose of this study was to assess the differences of CT findings between two conditions. CT findings of 5 cases of renal cell carcinoma involving the renal collecting systems and 10 cases of renal urothelial tumors invading the renal parenchyma were compared, and analyzed about the presence or absence of hydronephrosis, normal or abnormal CT nephrogram, renal contour changes due to mass and tentative diagnosis. The diagnoses were confirmed at surgery. Renal cell carcinoma showed hydronephrosis in only 20% and normal CT nephrogram and outward contour bulging in all cases. In contrast, renal urothelial tumor showed hydronephrosis(70%), abnormal CT nephrogram(60%), and preservation of reinform shape(100%). Renal contour changes and CT nephrogram may be useful in distinguishing both disease entities

Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

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Bartsch, Georg; Mitra, Anirban P; Mitra, Sheetal A; Almal, Arpit A; Steven, Kenneth E; Skinner, Donald G; Fry, David W; Lenehan, Peter F; Worzel, William P; Cote, Richard J

2016-02-01

Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor.

Science.gov (United States)

Vandeveer, Amanda J; Fallon, Jonathan K; Tighe, Robert; Sabzevari, Helen; Schlom, Jeffrey; Greiner, John W

2016-05-01

Bacillus Calmette-Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49(luc)), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49(luc) murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49(luc) bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452-62. ©2016 AACR. ©2016 American Association for Cancer Research.

An uncommon manifestation of paraneoplastic cerebellar degeneration in a patient with high grade urothelial, carcinoma with squamous differentiation: A case report and literature review

International Nuclear Information System (INIS)

Zhu, Yaofeng; Chen, Shouzhen; Chen, Songyu; Song, Jing; Chen, Fan; Guo, Hu; Shang, Zhenhua; Wang, Yong; Zhou, Changkuo; Shi, Benkang

2016-01-01

Paraneoplastic neurological syndromes (PNS) are rare disorders associated with malignant tumours, which are triggered by autoimmune reactions. Paraneoplastic cerebellar degeneration (PCD) is the PNS type most commonly associated with ovarian and breast cancer. Two bladder cancers manifesting in PCD were previously reported. However, the cancers in these cases had poor outcomes. Here, we present a 68-year old man with history of high-grade papillary urothelial carcinoma of the bladder. The patient suffered from persistent cerebellar ataxia accompanied by bladder cancer recurrence five months after transurethral resection of the bladder tumour (TURBt). Laboratory screening for the specific antibodies of paraneoplastic neurological syndromes revealed no positive results. Symptoms were not remitted after a 7-day-course of high-dose glucocorticoid therapy. To our surprise, the patient recovered fully after laparoscopic radical cystectomy. Postoperative pathology revealed that surgical specimens were urothelial carcinoma in situ (CIS) and squamous cell carcinoma of the bladder. The patient remained asymptomatic and there was no evidence of recurrence after the followup period of 11 months. To our knowledge, this is the third report of PCD in a patient with bladder cancer. This case showed that tumour resection cured the PCD. To assist clinical evaluation and management, literature regarding basic PNS characteristics and bladder cancers was reviewed

Exosomal protein interactors as emerging therapeutic targets in urothelial bladder cancer

International Nuclear Information System (INIS)

Kumari, N.; Saxena, S.; Agrawal, U.

2015-01-01

Background: Exosomes are rich sources of biological material (proteins and nucleic acids) secreted by both tumor and normal cells, and found in urine of urinary bladder cancer patients. Objective: The objective of the study was to identify interacting exosomal proteins in bladder cancer for future use in targeted therapy. Methods: The Exocarta database (www.exocarta.org) was mined for urinary bladder cancer specific exosomal proteins. The urinary bladder cancer specific exosomal proteins (n = 248) were analyzed to identify enriched pathways by Onto-tool Pathway Express (http://vortex.cs.wayne.edu/ ontoexpress). Results: Enriched pathways included cellular architecture, motility, cell to cell adhesion, tumorigenesis and metastasis. Proteins in the 9 top-ranked pathways included CTNNA1 (alpha-catenin), CTNNB1 (beta-catenin), VSAP, ITGA4, PAK1, DDR1, CDC42, RHOA, NRAS, RHO, PIK3AR1, MLC1, MMRN1, and CTTNBP2 and network analysis revealed 10 important hub proteins and identified inferred interactor NF2. Conclusions: The importance of identifying interactors is that that they can be used as targets for therapy, for example, using Bevacizumab (avastin - an angiogenesis inhibitor) against NF2 to inhibit protein-protein interactions will inhibit tumor growth and progression by hindering the exosome biogenesis

Construction and evaluation of urinary bladder bioreactor for urologic tissue-engineering purposes.

LENUS (Irish Health Repository)

Davis, Niall F

2012-01-31

OBJECTIVE: To design and construct a urinary bladder bioreactor for urologic tissue-engineering purposes and to compare the viability and proliferative activity of cell-seeded extracellular matrix scaffolds cultured in the bioreactor with conventional static growth conditions. MATERIALS AND METHODS: A urinary bladder bioreactor was designed and constructed to replicate physiologic bladder dynamics. The bioreactor mimicked the filling pressures of the human bladder by way of a cyclical low-delivery pressure regulator. In addition, cell growth was evaluated by culturing human urothelial cells (UCs) on porcine extracellular matrix scaffolds in the bioreactor and in static growth conditions for 5 consecutive days. The attachment, viability, and proliferative potential were assessed and compared with quantitative viability indicators and by fluorescent markers for intracellular esterase activity and plasma membrane integrity. Scaffold integrity was characterized with scanning electron microscopy and 4\\

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

OpenAIRE

Wallard, M J; Pennington, C J; Veerakumarasivam, A; Burtt, G; Mills, I G; Warren, A; Leung, H Y; Murphy, G; Edwards, D R; Neal, D E; Kelly, J D

2006-01-01

The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and ...

Cytotoxicity and regenerative proliferation as the mode of action for diuron-induced urothelial carcinogenesis in the rat.

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da Rocha, Mitscheli S; Nascimento, Merielen G; Cardoso, Ana Paula F; de Lima, Patrícia L A; Zelandi, Edneia A; de Camargo, João Lauro V; de Oliveira, Maria Luiza C S

2010-01-01

Diuron, a substituted urea herbicide, is carcinogenic to the urinary bladder of rats at high dietary levels. Its proposed carcinogenic mode of action (MOA) includes urothelial cytotoxicity and necrosis followed by regenerative cell proliferation and sustained urothelial hyperplasia. Cytotoxicity could be induced either by urinary solids or by chemical toxicity by diuron and/or metabolites excreted in the urine. Diuron was not genotoxic in a previous single-cell gel (comet) assay, but possible cross-linking activity remained to be evaluated. The present study explored the MOA of diuron and the effect of urinary acidification on the development of urothelial lesions. Male Wistar rats were fed diuron (2500 ppm, about 130 mg/kg of body weight) either with or without NH(4)Cl 10,000 ppm to acidify the urine. Reversibility of urothelial changes was also examined. The animals were euthanized after 15, 25, or 30 weeks. Diuron-fed rats had urinary amorphous precipitate and magnesium ammonium phosphate crystals similar to control animals. Groups treated with diuron + NH(4)Cl showed decreased urinary pH and reduced amounts of urinary crystals and precipitate. Urothelial necrosis and simple hyperplasia were observed by light microscopy and scanning electron microscopy both in diuron- and in diuron + NH(4)Cl-treated groups. Cytotoxicity and proliferative changes were mostly reversible. A modified comet assay developed in vitro with Chinese hamster ovary cells showed that diuron did not induce DNA cross-links. These data suggest that cytotoxicity with consequent regenerative cell proliferation is the predominant MOA for diuron rat urothelial carcinogenesis, the cytotoxicity being chemically induced and not due to urinary solids.

Interleukin-8 (IL-8) over-production and autocrine cell activation are key factors in monomethylarsonous acid [MMA(III)]-induced malignant transformation of urothelial cells

International Nuclear Information System (INIS)

Escudero-Lourdes, C.; Wu, T.; Camarillo, J.M.; Gandolfi, A.J.

2012-01-01

The association between chronic human exposure to arsenicals and bladder cancer development is well recognized; however, the underlying molecular mechanisms have not been fully determined. We propose that inflammatory responses can play a pathogenic role in arsenic-related bladder carcinogenesis. In previous studies, it was demonstrated that chronic exposure to 50 nM monomethylarsenous acid [MMA(III)] leads to malignant transformation of an immortalized model of urothelial cells (UROtsa), with only 3 mo of exposure necessary to trigger the transformation-related changes. In the three-month window of exposure, the cells over-expressed pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), consistent with the sustained activation of NFKβ and AP1/c-jun, ERK2, and STAT3. IL-8 was over-expressed within hours after exposure to MMA(III), and sustained over-expression was observed during chronic exposure. In this study, we profiled IL-8 expression in UROtsa cells exposed to 50 nM MMA(III) for 1 to 5 mo. IL-8 expression was increased mainly in cells after 3 mo MMA(III) exposure, and its production was also found increased in tumors derived from these cells after heterotransplantation in SCID mice. UROtsa cells do express both receptors, CXCR1 and CXCR2, suggesting that autocrine cell activation could be important in cell transformation. Supporting this observation and consistent with IL-8 over-expression, CXCR1 internalization was significantly increased after three months of exposure to MMA(III). The expression of MMP-9, cyclin D1, bcl-2, and VGEF was significantly increased in cells exposed to MMA(III) for 3 mo, but these mitogen-activated kinases were significantly decreased after IL-8 gene silencing, together with a decrease in cell proliferation rate and in anchorage-independent colony formation. These results suggest a relevant role of IL-8 in MMA(III)-induced UROtsa cell transformation. -- Highlights: ► IL-8 is over-expressed in human MMA(III)-exposed urothelial

An ancillary method in urine cytology: Nucleolar/nuclear volume ratio for discrimination between benign and malignant urothelial cells.

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Tone, Kiyoshi; Kojima, Keiko; Hoshiai, Keita; Kumagai, Naoya; Kijima, Hiroshi; Kurose, Akira

2016-06-01

The essential of urine cytology for the diagnosis and the follow-up of urothelial neoplasia has been widely recognized. However, there are some cases in which a definitive diagnosis cannot be made due to difficulty in discriminating between benign and malignant. This study evaluated the practicality of nucleolar/nuclear volume ratio (%) for the discrimination. Using Papanicolaou-stained slides, 253 benign urothelial cells and 282 malignant urothelial cells were selected and divided into a benign urothelial cell and an urothelial carcinoma (UC) cell groups. Three suspicious cases and four cases in which discrimination between benign and malignant was difficult were prepared for verification test. Subject cells were decolorized and stained with 4',6-diamidino-2-phenylindole for detection of the nuclei and the nucleoli. Z-stack method was performed to analyze. When the cutoff point of 1.514% discriminating benign urothelial cells and UC cells from nucleolar/nuclear volume ratio (%) was utilized, the sensitivity was 56.0%, the specificity was 88.5%, the positive predictive value was 84.5%, and the negative predictive value was 64.4%. Nuclear and nucleolar volume, number of the nucleoli, and nucleolar/nuclear volume ratio (%) were significantly higher in the UC cell group than in the benign urothelial cell group (P benign and malignant urothelial cells, providing possible additional information in urine cytology. Diagn. Cytopathol. 2016;44:483-491. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mechanism of cisplatin resistance in human urothelial carcinoma cells.

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Yu, Hui-Min; Wang, Tsing-Cheng

2012-05-01

An isogenic pair of cisplatin-susceptible (NTUB1) and -resistant (NTUB1/P) human urothelial carcinoma cell lines was used to elucidate the mechanism of cisplatin resistance. The significantly lower intracellular platinum (IP) concentration, which resulted from the decreased cisplatin uptake, was found in NTUB1/P cells. The enhancement of IP concentration did not increase the susceptibility of NTUB1/P cells to cisplatin treatment. The reduction of IP concentration as well was unable to enhance the cisplatin-resistance in susceptible NTUB1 cells. This indicated that reduction of IP concentration was not the account for the development of cisplatin resistance here. Instead, the over expression of anti-apoptotic Bcl-2, anti-oxidative heme oxygenase-1 (HO-1) and cell cycle regulator p16INK4 seemed to be more important for the gaining of cisplatin in these human urothelial carcinoma cell. Copyright © 2012 Elsevier Ltd. All rights reserved.

Inhalation of tobacco smoke induces increased proliferation of urinary bladder epithelium and endothelium in female C57BL/6 mice

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Ohnishi, Takamasa; Arnold, Lora L.; He, Jun; Clark, Nicole M.; Kawasaki, Shin; Rennard, Stephen I.; Boyer, Craig W.; Cohen, Samuel M.

2007-01-01

Cigarette smoking is the major environmental risk factor for bladder cancer in humans. Aromatic amines, potent DNA-reactive bladder carcinogens present in cigarette smoke, contribute significantly. However, increased cell proliferation, caused by direct mitogenesis or in response to cytotoxicity, may also play a role since urothelial hyperplasia has been observed in human cigarette smokers. We examined the urothelial effects of cigarette smoke (whole body inhalation exposure (Teague) system) in female C57BL/6 mice at various times in two studies, including reversibility evaluations. In both studies, no urothelial hyperplasia was observed by light microscopy in any group. However, in study 1, the Ki-67 labeling index (LI) of the urothelium was significantly increased in the smoke exposed group compared to controls through 3 months, but was not present at 6, 9 or 12 months even with continued exposures. In the groups that discontinued smoke exposure, it returned to the same levels as controls or lower. In study 2, the bromodeoxyuridine LI was similar to controls on day 1 but significantly increased at 5 days in the smoke exposed group. In the group that discontinued smoke exposure for 2 days, the LI was increased compared to controls but not significantly. Superficial urothelial cell cytotoxicity and necrosis were detectable by scanning electron microscopy at 5 days. Changes in LI of submucosal endothelial cells generally followed those of the urothelium and effects were reversible upon cessation of exposure. The increased urothelial proliferation appeared to be due to superficial cell cytotoxicity with consequent regeneration

Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737.

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Mani, Jens; Antonietti, Patrick; Rakel, Stefanie; Blaheta, Roman; Bartsch, Georg; Haferkamp, Axel; Kögel, Donat

2016-02-01

BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer.

Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes.

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Ma, B; Li, H; Zhang, C; Yang, K; Qiao, B; Zhang, Z; Xu, Y

2013-10-01

To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients. We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT2-3N0M0) between 2000 and 2010. The log-rank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival. With a median follow-up of 53.0 months (range 9-120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder. Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease. The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS. Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes. Copyright © 2013 Elsevier Ltd. All rights reserved.

Determining the origin of synchronous multifocal bladder cancer by exome sequencing

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Acar, Ömer; Özkurt, Ezgi; Demir, Gulfem; Saraç, Hilal; Alkan, Can; Esen, Tarık; Somel, Mehmet; Lack, Nathan A.

2015-01-01

Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC* dinucleotides (Fisher’s exact test p < 10 −41 ), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC* type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10 −4 ) suggesting that TpC* mutations largely occurred early in the development of the tumour. These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer. The online version of this article (doi:10.1186/s12885-015-1859-8) contains supplementary material, which is available to authorized users

Androgen receptor activation: a prospective therapeutic target for bladder cancer?

Science.gov (United States)

Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

2017-03-01

Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

Role of the chronic bacterial infection in urinary bladder carcinogenesis

International Nuclear Information System (INIS)

Higgy, N.A.

1985-01-01

The purpose of this thesis was to determine whether or not bacterial infection of the urinary bladder had a role in urinary bladder carcinogenesis. To investigate this proposition, four separate studies were conducted. The first study developed an experimental animal model where bacterial infection of the urinary bladder could be introduced and maintained for a period in excess of one year. The method of infection, inoculation of bacteria (Escherichia coli type 04) subserosally into the vesical wall, successfully caused persistent infection in the majority of animals. In the second study the temporal effects of bacterial infection on the induction of urothelial ornithine decarboxylase (ODC) and 3 H-thymidine uptake and DNA synthesis were examined. Bacterial infection of the urinary bladder induced urothelial ODC with a peak in enzyme activity 6 hr after infection. 3 H-Thymidine uptake and DNA synthesis peaked 48 hr after infection and coincided with the urothelial hyperplasia that occurred in response to the infection. In the third study the specific bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was given to rats concurrent with the urinary bacterial infection. In the fourth study rats were administered sodium nitrate and either dibutylamine or piperazine in the drinking water. The infected group developed bladder tumors while none were detected in the non-infected rats. From these studies it may be concluded that bacterial infection may have a significant role in the process of urinary bladder carcinogenesis

De novo reconstitution of a functional mammalian urinary bladder by tissue engineering.

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Oberpenning, F; Meng, J; Yoo, J J; Atala, A

1999-02-01

Human organ replacement is limited by a donor shortage, problems with tissue compatibility, and rejection. Creation of an organ with autologous tissue would be advantageous. In this study, transplantable urinary bladder neo-organs were reproducibly created in vitro from urothelial and smooth muscle cells grown in culture from canine native bladder biopsies and seeded onto preformed bladder-shaped polymers. The native bladders were subsequently excised from canine donors and replaced with the tissue-engineered neo-organs. In functional evaluations for up to 11 months, the bladder neo-organs demonstrated a normal capacity to retain urine, normal elastic properties, and histologic architecture. This study demonstrates, for the first time, that successful reconstitution of an autonomous hollow organ is possible using tissue-engineering methods.

[Myofibroblasts and afferent signalling in the urinary bladder. A concept].

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Neuhaus, J; Scholler, U; Freick, K; Schwalenberg, T; Heinrich, M; Horn, L C; Stolzenburg, J U

2008-09-01

Afferent signal transduction in the urinary bladder is still not clearly understood. An increasing body of evidence supports the view of complex interactions between urothelium, suburothelial myofibroblasts, and sensory nerves. Bladder tissue from tumour patients was used in this study. Methods included confocal immunofluorescence, polymerase chain reaction, calcium imaging, and fluorescence recovery after photobleaching (FRAP).Myofibroblasts express muscarinic and purinergic receptors. They show constitutive spontaneous activity in calcium imaging, which completely depends on extracellular calcium. Stimulation with carbachol and ATP-evoked intracellular calcium transients also depend on extracellular calcium. The intensive coupling between the cells is significantly diminished by incubation with TGF-beta 1. Myofibroblasts form an important cellular element within the afferent signalling of the urinary bladder. They possess all features required to take part in the complex interactions with urothelial cells and sensory nerves. Modulation of their function by cytokines may provide a pathomechanism for bladder dysfunction.

The water avoidance stress induces bladder pain due to a prolonged alpha1A adrenoceptor stimulation.

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Matos, Rita; Serrão, Paula; Rodriguez, Larissa; Birder, Lori Ann; Cruz, Francisco; Charrua, Ana

2017-08-01

Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) remains an elusive disease with the cause for the pain unclear. BPS/IC patients present increased sympathetic activity and high levels of urinary noradrenaline. At the experimental level, it has been shown that chronic adrenergic stimulation produces pain and bladder changes through an alpha 1A adrenoceptor mediated mechanism. Water avoidance stress (WAS) in rodents reproduces signs of nociception and bladder changes seen in BPS/IC patients. In this study, we explore the possible role of alpha 1A adrenoceptor in bladder pain and morphological changes. WAS was induced in a group of female Wistar rats. A separate WAS group received 0.2 mg/kg day silodosin (WAS + S). Lower abdominal pain was determined by performing sensitivity to Von Frey filaments. Bladder reflex activity was determined by cystometry in anaesthetised animals. Urine was collected for noradrenaline quantification by HPLC. Bladders were harvested and stained with Haematoxylin-eosin (to analyse urothelial morphology and to determine the disruption of surface umbrella cells) or with Toluidine Blue 0.1% to analyse mast cell infiltration. WAS increased urinary noradrenaline level and bladder frequency and decreased mechanical pain threshold, which was reversed by silodosin. WAS induced lymphocytic and mast cells infiltration in the mucosa and mild urothelial disruption, which was absent in WAS + S group. Alpha 1A adrenoceptor stimulation has an important role in the appearance of bladder pain in rats. Since BPS/IC patients present high levels of noradrenaline, alpha 1A stimulation may be an additional trigger for bladder dysfunction presented by these patients. Further studies will determine the clinical relevance of this finding in the treatment of BPS/IC patients.

Molecular subtype classification of urothelial carcinoma in Lynch syndrome

DEFF Research Database (Denmark)

Therkildsen, Christina; Eriksson, Pontus; Höglund, Mattias

2018-01-01

Lynch syndrome confers an increased risk for urothelial carcinoma (UC). Molecular subtypes may be relevant to prognosis and therapeutic possibilities, but have to date not been defined in Lynch syndrome-associated urothelial cancer. We aimed to provide a molecular description of Lynch syndrome......-associated UC. Thus, Lynch syndrome-associated UC of the upper urinary tract and the urinary bladder were identified in the Danish hereditary non-polyposis colorectal cancer (HNPCC) register and were transcriptionally and immunohistochemically profiled and further related to data from 307 sporadic urothelial...... carcinomas. Whole genome mRNA expression profiles of 41 tumors and immunohistochemical stainings against FGFR3, KRT5, CCNB1, RB1, and CDKN2A (p16) of 37 tumors from Lynch syndrome patients were generated. Pathological data, microsatellite instability, anatomic location, and overall survival data was analyzed...

Paraneoplastic syndrome in urothelial carcinoma of the kidney: difficulty in diagnosis and deterioration in prognosis

Directory of Open Access Journals (Sweden)

I. E. Mamaev

2015-01-01

Full Text Available Paraneoplastic syndrome is not a common concomitance of urothelial tumors. The literature describes a few tens of clinical cases in which urothelial cancer has become a cause of marked nonspecific tumor-associated reactions, associated with the presence of the tumor. Bladder tumors are at stake in all cases. The given clinical observation describes paraneoplastic manifestations in high-grade urothelial carcinoma of the kidney. It demonstrates difficulties in differential diagnosis and gives a retrospective estimate of diagnostic and therapeutic tactics.

Upper Tract Urothelial Carcinomas Accompanied by Previous or Synchronous Nonmuscle-Invasive Bladder Cancer and Preoperative Hydronephrosis Might Have Worse Oncologic Outcomes After Radical Nephroureterectomy.

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Liang, Chengcai; Chi, Runmin; Huang, Liqun; Wang, Jinliang; Liu, Hailong; Xu, Ding; Qian, Subo; Qian, Xiaoqiang; Qi, Jun

2016-10-01

The purpose of the study was to identify predictors of clinicopathologic features and oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy (RNU). The medical records of 172 patients treated with RNU from January 2001 to September 2014 were retrospectively reviewed. Logistic regression and survival analysis methodology were respectively used to evaluate predictors of clinicopathologic features and oncologic outcomes. Of the enrolled 172 patients, 80 (46.5%) had renal pelvic tumors, 67 (39%) had ureteral tumors, and the remaining 25 (14.5%) patients had multifocal tumors. Compared with patients with renal pelvic tumors, those with ureteral and multifocal tumors were more likely to have previous or synchronous nonmuscle-invasive bladder cancer (NMIBC) and severe hydronephrosis (P = .001 and P hydronephrosis independently predicted worse renal function and positive lymph node or lymphovascular invasion status (P = .001 and P = .007, respectively). Moreover, severe hydronephrosis was an independent risk factor for overall survival and cancer-specific survival in multivariate analysis (P = .025 and P = .045, respectively). Multifocality and previous or synchronous NMIBC were significantly associated with bladder-recurrence-free survival (P = .023 and P = .001, respectively). Upper tract urothelial carcinoma accompanied by previous or synchronous NMIBC and preoperative severe hydronephrosis could have worse oncologic outcomes after RNU. These common accompanied diagnoses could be valuable for guiding preoperative planning and postoperative adjuvant therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors

DEFF Research Database (Denmark)

Ostenfeld, Marie Stampe; Bramsen, Jesper Bertram; Lamy, Philippe

2010-01-01

hybridization. Ectopic expression of miR-145 induced extensive apoptosis in urothelial carcinoma cell lines (T24 and SW780) as characterized by caspase activation, nuclear condensation and fragmentation, cellular shrinkage, and detachment. However, cell death also proceeded upon caspase inhibition...... sites. Among these, direct targeting of CBFB, PPP3CA, and CLINT1 was confirmed by a luciferase reporter assay. Notably, a 22-gene signature targeted on enforced miR-145 expression in T24 cells was significantly (P

Urinary bladder tumors among atomic bomb survivors Hiroshima and Nagasaki, 1961-1972

International Nuclear Information System (INIS)

Sanefuji, Hayato; Ishimaru, Toranosuke.

1980-03-01

A study was made of the relationship of radiation dose to the incidence of urinary bladder tumors among atomic bomb survivors and controls in the RERF Life Span Study extended sample. A total of 112 cases of urinary bladder tumors was identified among approximately 99,000 subjects in this fixed cohort during 1961-72. Morphologic diagnoses were available for 86 cases (76.8%), cystoscopy alone for 21 cases (18.7%), and only the cause of death recorded on death certificates for 5 cases (4.5%). Urothelial carcinoma (transitional cell carcinoma) is the most common type of urinary bladder tumor for which morphologic diagnoses are available. The 1961-72 incidence rate was calculated using 106 cases identified as urinary bladder tumors. Although the crude annual incidence rate in the high dose group (100 rad or more) is elevated in both cities and both sexes, all nine cases with this dose were aged 40 years or more at the time of the bomb (ATB). The standardized relative risk adjusted for city and sex for those of age 40 or more ATB in the high dose group is 1.8 in comparison with the control group and this is a suggestive statistical difference. A statistically significant elevation of risk occurs in the high dose group for urothelial carcinoma and adenocarcinoma of the urinary bladder among those aged 40 or more ATB. (author)

Diagnostic and Prognostic Significance of Serum and Tissue Galectin 3 Expression in Patients with Carcinoma of the Bladder

Science.gov (United States)

Gendy, Hoda El; Madkour, Bothina; Abdelaty, Sara; Essawy, Fayza; Khattab, Dina; Hammam, Olfat; Nour, Hani H.

2014-01-01

Background Galectins are group of proteins found in the cytoplasm, nucleus, cell surface and extracellular matrix. Galectin 3 (Gal-3) displays pathological expression in a variety of processes such as tumorigenesis. Patients and Method 70 patients classified into the control group, cystitis group, transitional cell carcinoma group, and squamous cell carcinoma group were enrolled in this study which aimed to detect the serum level and the intensity of tissue expression of Gal-3. Results Both serum level and tissue expression of Gal-3 were statistically higher in bladder cancer patients compared to the other groups. Gal-3 level expression increased from low to high grade urothelial tumors, with a statistically significant increase of its level and expression between muscle invasive and non-muscle invasive Ta urothelial tumors. Conclusion The serum Gal-3 level is sensitive and specific for the diagnosis of bladder cancer. The prognostic significance of tissue expression is to be confirmed. PMID:26195948

Sarcomatoid carcinoma associated with small cell carcinoma of the urinary bladder: a series of 28 cases.

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Urrea, Yuly Ramirez; Epstein, Jonathan I

2017-09-01

The association of sarcomatoid carcinoma (SC) with small cell carcinoma (SCC) has not been systematically studied. We identified 39 consult cases between 2001 and 2016 with available slides for review in 28 cases. There were 19 men and 9 women (mean age: 78 years [51-89]). In 26 (92.8%) cases, the sarcomatoid component had nonspecific malignant spindle cells, 4 (14%) chondrosarcoma, 2 (7%) myxoid sarcomatous, 1 (3.5%) osteosarcoma, and 1 (3.5%) rhabdomyosarcoma. The predominant component was SCC in 11 (39%) cases, urothelial carcinoma in 6 (21%), sarcomatoid in 3 (10%), and equal sarcomatoid and SCC in 8 (29%). There were 3 morphological groups: group 1 (18/28 [64%]) showed a gradual transition from SCC to other components; group 2 (5/28 [18%]) had an abrupt transition from SCC to other components; and in group 3 (5/28 [18%]), the SCC was separate from other components. In group 1, 12 (66%) cases of SCC showed a gradual transition to sarcomatoid areas; 3 (17%) to urothelial carcinoma; and 3 (17%) to multiple components including squamous cell carcinoma, urothelial carcinoma, and sarcomatoid. Mortality did not differ based on pathological groups. The 36-month actuarial risk of death was 64.3%. The multitude of different components in these tumors is further evidence of the remarkable ability of carcinoma of the bladder to show divergent differentiation with, in some cases, gradual transition between SCC and other elements including sarcomatoid. Greater recognition of this entity with chemotherapy targeted to the various histological elements may have important therapeutic implications. Copyright © 2017 Elsevier Inc. All rights reserved.

Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM.

Science.gov (United States)

Bryan, R T; Regan, H L; Pirrie, S J; Devall, A J; Cheng, K K; Zeegers, M P; James, N D; Knowles, M A; Ward, D G

2015-03-17

Better biomarkers must be found to develop clinically useful urine tests for bladder cancer. Proteomics can be used to identify the proteins released by cancer cell lines and generate candidate markers for developing such tests. We used shotgun proteomics to identify proteins released into culture media by eight bladder cancer cell lines. These data were compared with protein expression data from the Human Protein Atlas. Epidermal growth factor receptor (EGFR) was identified as a candidate biomarker and measured by ELISA in urine from 60 noncancer control subjects and from 436 patients with bladder cancer and long-term clinical follow-up. Bladder cancer cell lines shed soluble EGFR ectodomain. Soluble EGFR is also detectable in urine and is highly elevated in some patients with high-grade bladder cancer. Urinary EGFR is an independent indicator of poor bladder cancer-specific survival with a hazard ratio of 2.89 (95% CI 1.81-4.62, Pbladder cancer-specific survival and have prognostic value over and above that provided by standard clinical observations. Measuring urinary EGFR and EpCAM may represent a simple and useful approach for fast-tracking the investigation and treatment of patients with the most aggressive bladder cancers.

Role of interleukin-8 in onset of the immune response in intravesical BCG therapy for superficial bladder cancer

NARCIS (Netherlands)

de Boer, E. C.; Somogyi, L.; de Ruiter, G. J.; de Reijke, T. M.; Kurth, K. H.; Schamhart, D. H.

1997-01-01

In intravesical therapy for superficial bladder carcinoma urothelial cells may, through the production of cytokines, contribute to the bacillus Calmette-Guerin (BCG)-induced local immunological reaction and associated antitumor efficacy. The aim of this study was to investigate such a role for the

Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis

Directory of Open Access Journals (Sweden)

Yuh-Shyan Tsai

2012-01-01

Full Text Available The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5–8.4 and 1.1 (95% CI: 0.6–1.9, and the risks of mortality were 3.0 (95% CI: 1.6–5.9 and 1.1 (95% CI: 1.0–1.2, respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

[Expression and clinical significance of 5hmC in bladder urothelial carcinoma].

Science.gov (United States)

Li, Jie; Xu, Yuqiao; Zhang, Zhiwen; Zhang, Ming; Zhang, Zhekai; Zhang, Feng; Li, Qing

2016-02-01

To investigate the expression of 5-hydroxymethylcytosine (5hmC) in bladder urothelial carcinoma (UC) and its clinical significance. The expression of 5hmC in 21 cases of UC tissues and pericarcinous urinary tract epithelium was detected by immunohistochemical staining. Then the expression of 5hmC in the surgical resection of UC tissues in 92 cases was also surveyed. Non parametric U Mann-Whitney test was used to analyze the correlation between 5hmC expression and clinical data. Single factor survival analysis was performed by Kaplan-Meier test. The expression of 5hmC in normal urinary tract epithelium and UC tissues was significantly different, but there was no significant difference in the expression of 5hmC between low and high grades of UC tissues as well as between different TNM grades. Kaplan-Meier single factor survival analysis showed that there was no significant correlation between the 5hmC expression level and the survival rate or the recurrence-free survival of UC patients. The expression level of 5hmC in UC tissues is significantly lower than that in pericarcinous urinary tract epithelium. There is no correlation between the 5hmC expression and the progression, prognosis and recurrence of UC.

Lactobacillus rhamnosus GR-1 enhances NF-kappaB activation in Escherichia coli-stimulated urinary bladder cells through TLR4

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Karlsson Mattias

2012-01-01

Full Text Available Abstract Background Epithelial cells of the urinary tract recognize pathogenic bacteria through pattern recognition receptors on their surface, such as toll-like receptors (TLRs, and mount an immune response through the activation of the NF-kappaB pathway. Some uropathogenic bacteria can subvert these cellular responses, creating problems with how the host eliminates pathogens. Lactobacillus is a genus of lactic acid bacteria that are part of the microbiota and consist of many probiotic strains, some specifically for urogenital infections. Immunomodulation has emerged as an important mode of action of probiotic and commensal lactobacilli and given the importance of epithelial cells, we evaluated the effect of the urogenital probiotic Lactobacillus rhamnosus GR-1 on epithelial immune activation. Results Immune activation through the NF-kappaB pathway was initiated by stimulation of T24 urothelial cells with heat-killed Escherichia coli and this was further potentiated when cells were co-cultured with live L. rhamnosus GR-1. Heat-killed lactobacilli were poor activators of NF-kappaB. Concomitant stimulation of bladder cells with E. coli and L. rhamnosus GR-1 increased the levels of the pro-inflammatory cytokine TNF, whereas IL-6 and CXCL8 levels were reduced. Another probiotic, L. rhamnosus GG, was also able to potentiate NF-kappaB in these cells although at a significantly reduced level compared to the GR-1 strain. The transcript numbers and protein levels of the lipopolysaccharide receptor TLR4 were significantly increased after co-stimulation with E. coli and lactobacilli compared to controls. Furthermore, inhibition of TLR4 activation by polymixin B completely blocked the lactobacilli potentiation of NF-kappaB. Conclusions The immunological outcome of E. coli challenge of bladder cells was influenced by probiotic L. rhamnosus GR-1, by enhancing the activation of NF-kappaB and TNF release. Thus the urogenital probiotic L. rhamnosus GR-1

Diuron-induced rat bladder epithelial cytotoxicity.

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Da Rocha, Mitscheli S; Arnold, Lora L; Pennington, Karen L; Muirhead, David; Dodmane, Puttappa R; Anwar, Muhammad M; Battalora, Michael; De Camargo, João Lauro V; Cohen, Samuel M

2012-12-01

Diuron, a substituted urea herbicide, is carcinogenic to the rat urinary bladder at high dietary levels (2500 ppm). To further elucidate the mode of action, this study aimed to determine the time course and sequence of bladder cytotoxic and proliferative changes induced by diuron treatment of male Wistar rats. Rats were randomized into two groups (control and 2500 ppm diuron) and treated for 28 days. Ten rats from each group were terminated on each of study days 1, 3, 7, or 28. Scanning electron micro scopy (SEM) showed urothelial cell swelling beginning on day 1, and by day 28, showed extensive necrosis, exfoliation and piling up of cells suggestive of hyperplasia. No difference in the bromo deoxyuridine labeling index was detected. In a second experiment, rats were randomized into control and diuron-treated groups and treated for 7 days or 8 weeks. After 7 days, transmission electron microscopy showed cell degenerative changes and distention of the cytoplasm, organelles, and nuclei characteristic of cytolysis. This resulted in protrusion of the superficial cells into the lumen, corresponding to the cell swelling observed previously by SEM. After 8 weeks, bladders in the diuron-treated group showed an increased incidence of simple hyperplasia by light microscopy (6/10, p diuron exposure in rats.

A Novel Risk Stratification to Predict Local-Regional Failures in Urothelial Carcinoma of the Bladder After Radical Cystectomy

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Baumann, Brian C. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Guzzo, Thomas J. [Department of Urology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); He Jiwei [Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Keefe, Stephen M. [Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Tucker, Kai; Bekelman, Justin E. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Hwang, Wei-Ting [Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Vaughn, David J. [Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Malkowicz, S. Bruce [Department of Urology, University of Pennsylvania, Philadelphia, Pennsylvania (United States); Christodouleas, John P., E-mail: christojo@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania (United States)

2013-01-01

Purpose: Local-regional failures (LF) following radical cystectomy (RC) plus pelvic lymph node dissection (PLND) with or without chemotherapy for invasive urothelial bladder carcinoma are more common than previously reported. Adjuvant radiation therapy (RT) could reduce LF but currently has no defined role because of previously reported morbidity. Modern techniques with improved normal tissue sparing have rekindled interest in RT. We assessed the risk of LF and determined those factors that predict recurrence to facilitate patient selection for future adjuvant RT trials. Methods and Materials: From 1990-2008, 442 patients with urothelial bladder carcinoma at University of Pennsylvania were prospectively followed after RC plus PLND with or without chemotherapy with routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI). One hundred thirty (29%) patients received chemotherapy. LF was any pelvic failure detected before or within 3 months of distant failure. Competing risk analyses identified factors predicting increased LF risk. Results: On univariate analysis, pathologic stage {>=}pT3, <10 nodes removed, positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology significantly predicted LF; node density was marginally predictive, but use of chemotherapy, number of positive nodes, type of surgical diversion, age, gender, race, smoking history, and body mass index were not. On multivariate analysis, only stage {>=}pT3 and <10 nodes removed were significant independent LF predictors with hazard ratios of 3.17 and 2.37, respectively (P<.01). Analysis identified 3 patient subgroups with significantly different LF risks: low-risk ({<=}pT2), intermediate-risk ({>=}pT3 and {>=}10 nodes removed), and high-risk ({>=}pT3 and <10 nodes) with 5-year LF rates of 8%, 23%, and 42%, respectively (P<.01). Conclusions: This series using routine CT and MRI surveillance to detect LF confirms that such failures are relatively common

A Novel Risk Stratification to Predict Local-Regional Failures in Urothelial Carcinoma of the Bladder After Radical Cystectomy

International Nuclear Information System (INIS)

Baumann, Brian C.; Guzzo, Thomas J.; He Jiwei; Keefe, Stephen M.; Tucker, Kai; Bekelman, Justin E.; Hwang, Wei-Ting; Vaughn, David J.; Malkowicz, S. Bruce; Christodouleas, John P.

2013-01-01

Purpose: Local-regional failures (LF) following radical cystectomy (RC) plus pelvic lymph node dissection (PLND) with or without chemotherapy for invasive urothelial bladder carcinoma are more common than previously reported. Adjuvant radiation therapy (RT) could reduce LF but currently has no defined role because of previously reported morbidity. Modern techniques with improved normal tissue sparing have rekindled interest in RT. We assessed the risk of LF and determined those factors that predict recurrence to facilitate patient selection for future adjuvant RT trials. Methods and Materials: From 1990-2008, 442 patients with urothelial bladder carcinoma at University of Pennsylvania were prospectively followed after RC plus PLND with or without chemotherapy with routine pelvic computed tomography (CT) or magnetic resonance imaging (MRI). One hundred thirty (29%) patients received chemotherapy. LF was any pelvic failure detected before or within 3 months of distant failure. Competing risk analyses identified factors predicting increased LF risk. Results: On univariate analysis, pathologic stage ≥pT3, <10 nodes removed, positive margins, positive nodes, hydronephrosis, lymphovascular invasion, and mixed histology significantly predicted LF; node density was marginally predictive, but use of chemotherapy, number of positive nodes, type of surgical diversion, age, gender, race, smoking history, and body mass index were not. On multivariate analysis, only stage ≥pT3 and <10 nodes removed were significant independent LF predictors with hazard ratios of 3.17 and 2.37, respectively (P<.01). Analysis identified 3 patient subgroups with significantly different LF risks: low-risk (≤pT2), intermediate-risk (≥pT3 and ≥10 nodes removed), and high-risk (≥pT3 and <10 nodes) with 5-year LF rates of 8%, 23%, and 42%, respectively (P<.01). Conclusions: This series using routine CT and MRI surveillance to detect LF confirms that such failures are relatively common in

p-Benzoquinone initiates non-invasive urothelial cancer through aberrant tyrosine phosphorylation of EGFR, MAP kinase activation and cell cycle deregulation: Prevention by vitamin C

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Shinjini Ganguly

Full Text Available According to WHO classification system, non-invasive urothelial carcinoma represents urothelial carcinoma in situ (CIS and dysplasia. Dysplastic urothelium often progresses to CIS that further advances to urothelial carcinoma (UC. The strongest risk factor for UC is cigarette smoking. However, the pathogenesis of cigarette smoke (CS-induced UC is poorly understood. Earlier we had shown that p-benzoquinone (p-BQ, a major toxic quinone derived from p-benzosemiquinone of CS in vivo, is a causative factor for various CS-induced diseases. Here, using a guinea pig model we showed that prolonged treatment with p-BQ led to non-invasive UC, specifically carcinoma in situ (CIS of the renal pelvis and dysplasia in the ureter and bladder. The mechanisms of carcinogenesis were p-BQ-induced oxidative damage and apoptosis that were later suppressed and followed by activation of epidermal growth factor receptor, aberrant phosphorylation of intracellular tyrosine residues, activation of MAP kinase pathway and persistent growth signaling. This was accompanied by deregulation of cell cycle as shown by marked decrease in the expression of p21waf1/cip1 and cyclin D1 proteins as well as hyperphosphorylation of pRb. UC has been characterised by histopathology and immunohistochemistry showing aberrant CK20, increased Ki-67, and marked p53 nuclear immunopositivity with uniformly negative labelling of CD44. Oral supplementation of vitamin C (30 mg/kg body weight/day prevented CIS of the renal pelvis and dysplasia in the ureter and bladder. Since majority of non-invasive UC progresses to invasive cancer with increased risk of mortality, our preclinical study might help to devise effective strategies for early intervention of the disease. Abbreviations: Bax, Bcl-2, CS, DNPH, GAPDH, IARC, p-BQ, p-BSQ, PAHs, PBS, ROS, SDS PAGE, TUNEL, WHO, UC, CIS, EGFR, MAPK, Keywords: p-Benzoquinone, Carcinoma in situ, Dysplasia, Aberrant EGFR activation, Cell cycle deregulation

microRNA-145 promotes differentiation in human urothelial carcinoma through down-regulation of syndecan-1

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Fujii, Tomomi; Shimada, Keiji; Tatsumi, Yoshihiro; Hatakeyama, Kinta; Obayashi, Chiho; Fujimoto, Kiyohide; Konishi, Noboru

2015-01-01

A new molecular marker of carcinoma in the urinary bladder is needed as a diagnostic tool or as a therapeutic target. Potential markers include microRNAs (miRNAs), which are short, low molecular weight RNAs 19–24 nt long that regulate genes associated with cell proliferation, differentiation, and development in various cancers. In this study, we investigated the molecular mechanisms by which miR-145 promotes survival of urothelial carcinoma cells and differentiation into multiple lineages. We found miR-145 to regulate expression of syndecan-1, a heparin sulfate proteoglycan. Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7 was assessed by MTS assay. Cellular senescence and apoptosis were measured by senescence-associated β-galactosidase (SA-β-gal) and TUNEL assay, respectively. Quantitative RT-PCR was used to measure mRNA expression of various genes, including syndecan-1, stem cell factors, and markers of differentiation into squamous, glandular, or neuroendocrine cells. Overexpression of miR-145 induced cell senescence, and thus significantly inhibited cell proliferation in T24 and KU7 cells. Syndecan-1 expression diminished, whereas stem cell markers such as SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated markers of differentiation into squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5 AC), and neuroendocrine cells (NSE and UCHL-1). Finally, expression of miR-145 was down-regulated in high-grade urothelial carcinomas, but not in low-grade tumors. Results indicate that miR-145 suppresses syndecan-1 and, by this mechanism, up-regulates stem cell factors and induces cell senescence and differentiation. We propose that miR-145 may confer stem cell-like properties on urothelial carcinoma cells and thus facilitate differentiation into multiple cell types. The online version of this article (doi:10.1186/s12885-015-1846-0) contains supplementary material, which is available to authorized users

Urology and nephrology update: bladder and kidney cancer.

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Fiore, David C; Fox, Cara-Louise

2014-01-01

It has been estimated that bladder and kidney cancers would be diagnosed in approximately 140,000 Americans in 2013, with approximately 30,000 dying from these cancers. Urinary tract cancers affect men more commonly than they do women, and the median age at diagnosis is 65 years. Major risk factors for these cancers include tobacco smoking, certain chemical exposures, family history, age, and obesity. Unexplained hematuria in adults should be evaluated to exclude bladder and kidney cancer. Staging of bladder and kidney cancer should be based on the TNM staging system, which, along with tumor grade, provides important treatment and prognostic information. Urothelial cell carcinoma is the most common type of bladder cancer; it also can occur in the kidneys or ureters. Renal cell carcinoma is the most common type of kidney cancer. Treatment options for bladder cancer vary widely, depending on the grade of the cancer. Early non-muscle-invasive bladder cancer may be removed cystoscopically and/or treated with intravesical immunotherapy or chemotherapy, whereas patients with muscle-invasive bladder tumors typically require surgery. Management of kidney cancer is almost always surgical, unless the patient is too ill to undergo surgery or chooses palliative care. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.

Primary Signet-Ring Carcinoma in the Bladder Presenting as a Hypervascular Luminal Polypoid Mass

International Nuclear Information System (INIS)

Jeong, Min Sun; Choi, Seung A; Jung, Yoon Young; Cho, Young Kwon; Lee, Won Mi; Lee, Seung Wook

2012-01-01

Primary signet-ring carcinoma is a very aggressive and rare variant of a primary urinary bladder cancer, accounting for less than 1% of cases. We reported on a 76-year-old patient with primary signet-ring carcinoma who occurred metastatic lymphadenopathy with extranodal invasion causing intraluminal tumor thrombi in the adjacent vein, and pulmonary metastasis over the course of three months. We demonstrated the computed tomography findings of primary signet-ring carcinoma of the bladder and correlated the imaging findings with the pathologic features. We reviewed the distinguishing imaging findings of the primary signet-ring carcinoma compared with urothelial cell carcinoma, the most common subtype of the bladder cancer.

Thrombomodulin expression regulates tumorigenesis in bladder cancer

International Nuclear Information System (INIS)

Wu, Chun-Te; Chang, Ying-Hsu; Lin, Paul- Yang; Chen, Wen-Cheng; Chen, Miao-Fen

2014-01-01

The identification of potential tumor markers will help improve therapeutic planning and patient management. Thrombomodulin (TM) is a sensitive urothelial marker. TM was reported to be one of the endogenous anti-metastatic factors and has diagnostic and prognostic values for the progression of carcinoma. In the present study, we examine the role of TM in bladder cancer. We studied the role of TM in tumor behavior and related signaling pathways in vitro using the human bladder cancer cell lines HT1376, HT1197, J82 and T24, and in vivo using animal models. We also selected clinical specimens from 100 patients with bladder cancer for immunohistochemical staining to evaluate the predictive capacity of TM in tumor invasiveness. The data revealed that positive immunoreactivity for TM was inversely correlated with clinical stage and DNA methyltransferase 1 immunoreactivity. Decreased TM expression could predict the aggressive tumor growth and advanced clinical stage in bladder cancer. When TM was inhibited, tumor growth rate and invasion ability were augmented in vitro and in vivo. The underlying changes included increased cell proliferation, enhanced epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, inhibition of NF-κB activation significantly increased TM expression and attenuated tumor aggressiveness in bladder cancer. TM plays an important role in bladder cancer tumor aggressiveness in vitro and in vivo and is a clinically significant predictor that may represent a suitable therapeutic target for bladder cancer

Bladder uptake of liposomes after intravesical administration occurs by endocytosis.

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Bharathi Raja Rajaganapathy

Full Text Available Liposomes have been used therapeutically and as a local drug delivery system in the bladder. However, the exact mechanism for the uptake of liposomes by bladder cells is unclear. In the present study, we investigated the role of endocytosis in the uptake of liposomes by cultured human UROtsa cells of urothelium and rat bladder. UROtsa cells were incubated in serum-free media with liposomes containing colloidal gold particles for 2 h either at 37°C or at 4°C. Transmission Electron Microscopy (TEM images of cells incubated at 37°C found endocytic vesicles containing gold inside the cells. In contrast, only extracellular binding was noticed in cells incubated with liposomes at 4°C. Absence of liposome internalization at 4°C indicates the need of energy dependent endocytosis as the primary mechanism of entry of liposomes into the urothelium. Flow cytometry analysis revealed that the uptake of liposomes at 37°C occurs via clathrin mediated endocytosis. Based on these observations, we propose that clathrin mediated endocytosis is the main route of entry for liposomes into the urothelial layer of the bladder and the findings here support the usefulness of liposomes in intravesical drug delivery.

miR-34a Inhibits Proliferation and Invasion of Bladder Cancer Cells by Targeting Orphan Nuclear Receptor HNF4G

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Huaibin Sun

2015-01-01

Full Text Available miR-34a is a member of the miR-34 family and acts as a tumor suppressor in bladder cancer. This study explored the regulative role of miR-34a on an orphan nuclear receptor HNF4G, which has a well-confirmed role in bladder tumor growth and invasion. qRT-PCR analysis was applied to measure miR-34a expression in two tumorigenic bladder cancer cell lines 5637 and T24 and one normal human urothelial cell line SV-HUC-1. Luciferase assay was performed to verify the putative binding between miR-34a and HNF4G. The influence of miR-34a-HNF4G axis on cell viability, colony formation, and invasion was assessed with loss- and gain-of-function analysis. This study observed that the miR-34a expressions in 5637 and T24 cells were significantly lower than in SV-HUC-1, while the muscle invasive cell sublines 5637-M and T24-M had even lower miR-34a expression than in the nonmuscle invasive sublines. HNF4G has a 3′-UTR binding site with miR-34a and is a direct downstream target of miR-34a. miR-34a can directly downregulate the expression of HNF4G and thus inhibit tumor cell viability, colony formation, and invasion. Therefore, miR-34a-HNF4G axis is an important pathway modulating cell viability, proliferation, and invasion of bladder cancer cells.

Identification of nine genomic regions of amplification in urothelial carcinoma, correlation with stage, and potential prognostic and therapeutic value.

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Yvonne Chekaluk

Full Text Available We performed a genome wide analysis of 164 urothelial carcinoma samples and 27 bladder cancer cell lines to identify copy number changes associated with disease characteristics, and examined the association of amplification events with stage and grade of disease. Multiplex inversion probe (MIP analysis, a recently developed genomic technique, was used to study 80 urothelial carcinomas to identify mutations and copy number changes. Selected amplification events were then analyzed in a validation cohort of 84 bladder cancers by multiplex ligation-dependent probe assay (MLPA. In the MIP analysis, 44 regions of significant copy number change were identified using GISTIC. Nine gene-containing regions of amplification were selected for validation in the second cohort by MLPA. Amplification events at these 9 genomic regions were found to correlate strongly with stage, being seen in only 2 of 23 (9% Ta grade 1 or 1-2 cancers, in contrast to 31 of 61 (51% Ta grade 3 and T2 grade 2 cancers, p<0.001. These observations suggest that analysis of genomic amplification of these 9 regions might help distinguish non-invasive from invasive urothelial carcinoma, although further study is required. Both MIP and MLPA methods perform well on formalin-fixed paraffin-embedded DNA, enhancing their potential clinical use. Furthermore several of the amplified genes identified here (ERBB2, MDM2, CCND1 are potential therapeutic targets.

Molecular markers for urothelial bladder cancer prognosis: toward implementation in clinical practice.

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van Rhijn, Bas W G; Catto, James W; Goebell, Peter J; Knüchel, Ruth; Shariat, Shahrokh F; van der Poel, Henk G; Sanchez-Carbayo, Marta; Thalmann, George N; Schmitz-Dräger, Bernd J; Kiemeney, Lambertus A

2014-10-01

To summarize the current status of clinicopathological and molecular markers for the prediction of recurrence or progression or both in non-muscle-invasive and survival in muscle-invasive urothelial bladder cancer, to address the reproducibility of pathology and molecular markers, and to provide directions toward implementation of molecular markers in future clinical decision making. Immunohistochemistry, gene signatures, and FGFR3-based molecular grading were used as molecular examples focussing on prognostics and issues related to robustness of pathological and molecular assays. The role of molecular markers to predict recurrence is limited, as clinical variables are currently more important. The prediction of progression and survival using molecular markers holds considerable promise. Despite a plethora of prognostic (clinical and molecular) marker studies, reproducibility of pathology and molecular assays has been understudied, and lack of reproducibility is probably the main reason that individual prediction of disease outcome is currently not reliable. Molecular markers are promising to predict progression and survival, but not recurrence. However, none of these are used in the daily clinical routine because of reproducibility issues. Future studies should focus on reproducibility of marker assessment and consistency of study results by incorporating scoring systems to reduce heterogeneity of reporting. This may ultimately lead to incorporation of molecular markers in clinical practice. Copyright © 2014 Elsevier Inc. All rights reserved.

Bovine papillomavirus type 2 (BPV-2) E5 oncoprotein binds to the subunit D of the V₁-ATPase proton pump in naturally occurring urothelial tumors of the urinary bladder of cattle.

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Roperto, Sante; Russo, Valeria; Borzacchiello, Giuseppe; Urraro, Chiara; Lucà, Roberta; Esposito, Iolanda; Riccardi, Marita Georgia; Raso, Cinzia; Gaspari, Marco; Ceccarelli, Dora Maria; Galasso, Rocco; Roperto, Franco

2014-01-01

Active infection by bovine papillomavirus type 2 (BPV-2) was documented for fifteen urinary bladder tumors in cattle. Two were diagnosed as papillary urothelial neoplasm of low malignant potential (PUNLMP), nine as papillary and four as invasive urothelial cancers. In all cancer samples, PCR analysis revealed a BPV-2-specific 503 bp DNA fragment. E5 protein, the major oncoprotein of the virus, was shown both by immunoprecipitation and immunohistochemical analysis. E5 was found to bind to the activated (phosphorylated) form of the platelet derived growth factor β receptor. PDGFβR immunoprecipitation from bladder tumor samples and from normal bladder tissue used as control revealed a protein band which was present in the pull-down from bladder cancer samples only. The protein was identified with mass spectrometry as "V₁-ATPase subunit D", a component of the central stalk of the V₁-ATPase vacuolar pump. The subunit D was confirmed in this complex by coimmunoprecipitation investigations and it was found to colocalize with the receptor. The subunit D was also shown to be overexpressed by Western blot, RT-PCR and immunofluorescence analyses. Immunoprecipitation and immunofluorescence also revealed that E5 oncoprotein was bound to the subunit D. For the first time, a tri-component complex composed of E5/PDGFβR/subunit D has been documented in vivo. Previous in vitro studies have shown that the BPV-2 E5 oncoprotein binds to the proteolipid c ring of the V₀-ATPase sector. We suggest that the E5/PDGFβR/subunit D complex may perturb proteostasis, organelle and cytosol homeostasis, which can result in altered protein degradation and in autophagic responses.

Current status of tissue engineering applied to bladder reconstruction in humans.

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Gasanz, C; Raventós, C; Morote, J

2018-01-11

Bladder reconstruction is performed to replace or expand the bladder. The intestine is used in standard clinical practice for tissue in this procedure. The complications of bladder reconstruction range from those of intestinal resection to those resulting from the continuous contact of urine with tissue not prepared for this contact. In this article, we describe and classify the various biomaterials and cell cultures used in bladder tissue engineering and reviews the studies performed with humans. We conducted a review of literature published in the PubMed database between 1950 and 2017, following the principles of the PRISM declaration. Numerous in vitro and animal model studies have been conducted, but only 18 experiments have been performed with humans, with a total of 169 patients. The current evidence suggests that an acellular matrix, a synthetic polymer with urothelial and autologous smooth muscle cells attached in vitro or stem cells would be the most practical approach for experimental bladder reconstruction. Bladder replacement or expansion without using intestinal tissue is still a challenge, despite progress in the manufacture of biomaterials and the development of cell therapy. Well-designed studies with large numbers of patients and long follow-up times are needed to establish an effective clinical translation and standardisation of the check-up functional tests. Copyright © 2017 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

DMAV in Drinking Water Activated NF-κB Signal Pathway and Increased TGF-β and IL-1β Expressions in Bladder Epithelial Cells of Rats

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Siqi Cao

2015-01-01

Full Text Available Dimethylarsinic acid (DMAV is the main product of arsenic methylation metabolism in vivo and is rat bladder carcinogen and tumor promoting agent. In this study, we measured the expressions of mRNA and proteins of NF-κB pathway members, IKKα, IKKβ, p65, and p50 in rat bladder epithelium by qRT-PCR and immunohistochemical analysis after rats received drinking water containing 100 and 200 ppm DMAV for 10 weeks. Transforming growth factor-β (TGF-β immunoexpression in rat bladder epithelium and urine level of IL-1β also were determined. We found that DMAV dramatically increased the mRNA levels of NF-κB p50 and IKKα in the bladder epithelium of rats compared to the control group. Immunohistochemical examinations showed that DMAV increased immunoreactivities of IKKα, IKKβ, and phospho-NF-κB p50 in the cytoplasm and phospho-NF-κB p50 and p65 in nucleus of rat urothelial cells. In addition, DMAV treated rats exhibited significantly increased inflammatory factor TGF-β immunoreactivity in bladder epithelium and IL-1β secretion in urine. These data suggest that DMAV could activate NF-κB signal pathway and increase TGF-β and IL-1β expressions in bladder epithelial cells of rats.

Analysis of the interaction of extracellular matrix and phenotype of bladder cancer cells

International Nuclear Information System (INIS)

Dozmorov, Mikhail G; Kyker, Kimberly D; Saban, Ricardo; Knowlton, Nicholas; Dozmorov, Igor; Centola, Michael B; Hurst, Robert E

2006-01-01

The extracellular matrix has a major effect upon the malignant properties of bladder cancer cells both in vitro in 3-dimensional culture and in vivo. Comparing gene expression of several bladder cancer cells lines grown under permissive and suppressive conditions in 3-dimensional growth on cancer-derived and normal-derived basement membrane gels respectively and on plastic in conventional tissue culture provides a model system for investigating the interaction of malignancy and extracellular matrix. Understanding how the extracellular matrix affects the phenotype of bladder cancer cells may provide important clues to identify new markers or targets for therapy. Five bladder cancer cell lines and one immortalized, but non-tumorigenic, urothelial line were grown on Matrigel, a cancer-derived ECM, on SISgel, a normal-derived ECM, and on plastic, where the only ECM is derived from the cells themselves. The transcriptomes were analyzed on an array of 1186 well-annotated cancer derived cDNAs containing most of the major pathways for malignancy. Hypervariable genes expressing more variability across cell lines than a set expressing technical variability were analyzed further. Expression values were clustered, and to identify genes most likely to represent biological factors, statistically over-represented ontologies and transcriptional regulatory elements were identified. Approximately 400 of the 1186 total genes were expressed 2 SD above background. Approximately 100 genes were hypervariable in cells grown on each ECM, but the pattern was different in each case. A core of 20 were identified as hypervariable under all 3 growth conditions, and 33 were hypervariable on both SISgel and Matrigel, but not on plastic. Clustering of the hypervariable genes showed very different patterns for the same 6 cell types on the different ECM. Even when loss of cell cycle regulation was identified, different genes were involved, depending on the ECM. Under the most permissive conditions

Dose-Dependent Response to 3-Nitrobenzanthrone Exposure in Human Urothelial Cancer Cells.

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Pink, Mario; Verma, Nisha; Zerries, Anna; Schmitz-Spanke, Simone

2017-10-16

A product of incomplete combustion of diesel fuel, 3-nitrobenzanthrone (3-NBA), has been classified as a cancer-causing substance. It first gained attention as a potential urinary bladder carcinogen due to the presence of its metabolite in urine and formation of DNA adducts. The aim of the present study was to characterize the dose-response relationship of 3-NBA in human urothelial cancer cell line (RT4) exposed to concentrations ranging from 0.0003 μM (environmentally relevant) to 80 μM by utilizing toxicological and metabolomic approaches. We observed that the RT4 cells were capable of bioactivation of 3-NBA within 30 min of exposure. Activity measurements of various enzymes involved in the conversion of 3-NBA in RT4 cells demonstrated NAD(P)H:quinone oxidoreductase (NQO1) as the main contributor for its bioactivation. Moreover, cytotoxicity assessment exhibited an initiation of adaptive mechanisms at low dosages, which diminished at higher doses, indicating that the capacity of these mechanisms no longer suffices, resulting in increased levels of intracellular reactive oxygen species, reduced proliferation, and hyperpolarisation of the mitochondrial membrane. To characterize the underlying mechanisms of this cellular response, the metabolism of 3-NBA and metabolomic changes in the cells were analyzed. The metabolomic analysis of the cells (0.0003, 0.01, 0.08, 10, and 80 μM 3-NBA) showed elevated levels of various antioxidants at low concentrations of 3-NBA. However, at higher exposure concentrations, it appeared that the cells reprogrammed their metabolism to maintain the cell homeostasis via activation of pentose phosphate pathway (PPP).

Expression profiles of variation integration genes in bladder urothelial carcinoma.

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Wang, J M; Wang, Y Q; Gao, Z L; Wu, J T; Shi, B K; Yu, C C

2014-04-30

Bladder cancer is a common cancer worldwide and its incidence continues to increase. There are approximately 261,000 cases of bladder cancer resulting in 115,000 deaths annually. This study aimed to integrate bladder cancer genome copy number variation information and bladder cancer gene transcription level expression data to construct a causal-target module network of the range of bladder cancer-related genomes. Here, we explored the control mechanism underlying bladder cancer phenotype expression regulation by the major bladder cancer genes. We selected 22 modules as the initial module network to expand the search to screen more networks. After bootstrapping 100 times, we obtained 16 key regulators. These 16 key candidate regulatory genes were further expanded to identify the expression changes of 11,676 genes in 275 modules, which may all have the same regulation. In conclusion, a series of modules associated with the terms 'cancer' or 'bladder' were considered to constitute a potential network.

Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro

International Nuclear Information System (INIS)

Varley, Claire; Hill, Gemma; Pellegrin, Stephanie; Shaw, Nicola J.; Selby, Peter J.; Trejdosiewicz, Ludwik K.; Southgate, Jennifer

2005-01-01

Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are mitotically quiescent and G0 arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing. Transcripts for HER-1, HER-2, and HER-3 were expressed by quiescent human urothelium in situ. Expression of HER-1 was upregulated in proliferating cultures, whereas HER-2 and HER-3 were more associated with a growth-arrested phenotype. NHU cells could be propagated in the absence of exogenous EGF, but autocrine signaling through HER-1 via the MAPK and PI3-kinase pathways was essential for proliferation and migration during urothelial wound repair. HB-EGF was expressed by urothelium in situ and HB-EGF, epiregulin, TGF-α, and amphiregulin were expressed by proliferating NHU cells. Urothelial wound repair in vitro was attenuated by neutralizing antibodies against HER-1 ligands, particularly amphiregulin. By contrast, the same ligands applied exogenously promoted migration, but inhibited proliferation, implying that HER-1 ligands provoke differential effects in NHU cells depending upon whether they are presented as soluble or juxtacrine ligands. We conclude that proliferation and migration during wound healing in NHU cells are mediated through an EGFR autocrine signalling loop and our results implicate amphiregulin as a key mediator

Recurrent and multiple bladder tumors show conserved expression profiles

International Nuclear Information System (INIS)

Lindgren, David; Fioretos, Thoas; Månsson, Wiking; Höglund, Mattias; Gudjonsson, Sigurdur; Jee, Kowan Ja; Liedberg, Fredrik; Aits, Sonja; Andersson, Anna; Chebil, Gunilla; Borg, Åke; Knuutila, Sakari

2008-01-01

Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin. However, the genetic relationship among consecutive tumors has been shown to be complex in as much as the genetic evolution does not adhere to the chronological appearance of the metachronous tumors. Consequently, genetically less evolved tumors may appear chronologically later than genetically related but more evolved tumors. Forty-nine meta- or synchronous urothelial tumors from 22 patients were analyzed using expression profiling, conventional CGH, LOH, and mutation analyses. We show by CGH that partial chromosomal losses in the initial tumors may not be present in the recurring tumors, by LOH that different haplotypes may be lost and that detected regions of LOH may be smaller in recurring tumors, and that mutations present in the initial tumor may not be present in the recurring ones. In contrast we show that despite apparent genomic differences, the recurrent and multiple bladder tumors from the same patients display remarkably similar expression profiles. Our findings show that even though the vast majority of the analyzed meta- and synchronous tumors from the same patients are not likely to have originated directly from the preceding tumor they still show remarkably similar expressions profiles. The presented data suggests that an expression profile is established early in tumor development and that this profile is stable and maintained in recurring tumors

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

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Davis Carole A

2007-03-01

Full Text Available Abstract Background In general, inflammation plays a role in most bladder pathologies and represents a defense reaction to injury that often times is two edged. In particular, bladder neurogenic inflammation involves the participation of mast cells and sensory nerves. Increased mast cell numbers and tryptase release represent one of the prevalent etiologic theories for interstitial cystitis and other urinary bladder inflammatory conditions. The activity of mast cell-derived tryptase as well as thrombin is significantly increased during inflammation. Those enzymes activate specific G-protein coupled proteinase-activated receptors (PARs. Four PARs have been cloned so far, and not only are all four receptors highly expressed in different cell types of the mouse urinary bladder, but their expression is altered during experimental bladder inflammation. We hypothesize that PARs may link mast cell-derived proteases to bladder inflammation and, therefore, play a fundamental role in the pathogenesis of cystitis. Results Here, we demonstrate that in addition to the mouse urinary bladder, all four PA receptors are also expressed in the J82 human urothelial cell line. Intravesical administration of PAR-activating peptides in mice leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS, substance P, and antigen was strongly attenuated by PAR1-, and to a lesser extent, by PAR2-deficiency. Conclusion Our results reveal an overriding participation of PAR1 in bladder inflammation, provide a working model for the involvement of downstream signaling, and evoke testable hypotheses regarding the role of PARs in bladder inflammation. It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis.

Fluorescent imaging of high-grade bladder cancer using a specific antagonist for chemokine receptor CXCR4.

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Nishizawa, Koji; Nishiyama, Hiroyuki; Oishi, Shinya; Tanahara, Noriko; Kotani, Hirokazu; Mikami, Yoshiki; Toda, Yoshinobu; Evans, Barry J; Peiper, Stephen C; Saito, Ryoichi; Watanabe, Jun; Fujii, Nobutaka; Ogawa, Osamu

2010-09-01

We previously reported that the expression of CXC chemokine receptor-4 (CXCR4) was upregulated in invasive bladder cancers and that the small peptide T140 was a highly sensitive antagonist for CXCR4. In this study, we identified that CXCR4 expression was induced in high-grade superficial bladder tumors, including carcinoma in situ and invasive bladder tumors. To visualize the bladder cancer cells using urinary sediments from the patients and chemically induced mouse bladder cancer model, a novel fluorescent CXCR4 antagonist TY14003 was developed, that is a T140 derivative. TY14003 could label bladder cancer cell lines expressing CXCR4, whereas negative-control fluorescent peptides did not label them. When labeling urinary sediments from patients with invasive bladder cancer, positive-stained cells were identified in all patients with bladder cancer and positive urine cytology but not in controls. Although white blood cells in urine were also labeled with TY14003, they could be easily discriminated from urothelial cells by their shape and size. Finally, intravesical instillation of TY14003 into mouse bladder, using N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer model, demonstrated that fluorescent signals were detected in the focal areas of bladder of all mice examined at 12 weeks of BBN drinking by confocal microscopy and fluorescent endoscopy. On the contrary, all the normal bladders were found to be negative for TY14003 staining. In conclusion, these results indicate that TY14003 is a promising diagnostic tool to visualize small or flat high-grade superficial bladder cancer.

Microcystic Variant of Urothelial Carcinoma

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Anthony Kodzo-Grey Venyo

2013-01-01

Full Text Available Background. Microcystic variant of urothelial carcinoma is one of the new variants of urothelial carcinoma that was added to the WHO classification in 2004. Aims. To review the literature on microcystic variant of urothelial carcinoma. Methods. Various internet search engines were used to identify reported cases of the tumour. Results. Microscopic features of the tumour include: (i Conspicuous intracellular and intercellular lumina/microcysts encompassed by malignant urothelial or squamous cells. (ii The lumina are usually empty; may contain granular eosinophilic debris, mucin, or necrotic cells. (iii The cysts may be variable in size; round, or oval, up to 2 mm; lined by urothelium which are either flattened cells or low columnar cells however, they do not contain colonic epithelium or goblet cells; are infiltrative; invade the muscularis propria; mimic cystitis cystica and cystitis glandularis; occasionally exhibit neuroendocrine differentiation. (iv Elongated and irregular branching spaces are usually seen. About 17 cases of the tumour have been reported with only 2 patients who have survived. The tumour tends to be of high-grade and high-stage. There is no consensus opinion on the best option of treatment of the tumour. Conclusions. It would prove difficult at the moment to be dogmatic regarding its prognosis but it is a highly aggressive tumour. New cases of the tumour should be reported in order to document its biological behaviour.

Urothelial Carcinoma Recurrence at an Ileal Orthotopic Neobladder and Unilateral Lower Ureter After Surgery

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Bunya Kawamoto

2016-11-01

Full Text Available The recurrence of urothelial carcinoma in an orthotopic neobladder is rare. We report the case of a 61-year-old man with a muscle-invasive bladder tumor that was treated using radical cystectomy and the creation of a Studer's orthotopic neobladder. However, nine years after the cystectomy, we detected a mass at the left ureteroileal anastomosis. We successfully performed Studer's neobladder resection, urethrectomy, and left nephroureterectomy to remove the entire mass. Pathological examination revealed urothelial carcinoma with adenocarcinoma in the neobladder and adenocarcinomatous metastasis in the mesenteric lymph node.

Appraisal of diagnostic ability of UCA1 as a biomarker of carcinoma of the urinary bladder.

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Srivastava, A K; Singh, P K; Rath, S K; Dalela, D; Goel, M M; Bhatt, M L B

2014-11-01

Initial diagnosis of carcinoma of the urinary bladder remains to be a challenge. Urine cytology, as an adjunct to cystoscopy, is less sensitive for low-grade tumors. Urothelial cancer associated 1 (UCA1) is a novel non-coding RNA gene, which plays a pivotal role in bladder cancer progression. Our aim is to investigate the significance of urinary UCA1 for the non-invasive diagnosis of transitional cell carcinoma (TCC) of the urinary bladder. We examined UCA1 expression in a bladder cancer cell line (T24) and in urine of 28 healthy individuals, 46 patients of non-malignant disorders, and 117 cases (69 primary and 48 recurrent cases) of histologically proven TCC prior to transurethral resection by using real-time PCR and compared it with voided urinary cytology. UCA1 expression was found in T24 cell line and also found to be significantly higher in the cancer group as compared to the controls (p0.05). UCA1 can be used as a non-invasive diagnostic biomarker for TCC bladder as an adjunct to cytology in the early diagnosis of primary urinary bladder cancer.

CD73 Predicts Favorable Prognosis in Patients with Nonmuscle-Invasive Urothelial Bladder Cancer

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Marian S. Wettstein

2015-01-01

Full Text Available Aims. CD73 is a membrane associated 5′-ectonucleotidase that has been proposed as prognostic biomarker in various solid tumors. The aim of this study is to evaluate CD73 expression in a cohort of patients with primary bladder cancer in regard to its association with clinicopathological features and disease course. Methods. Tissue samples from 174 patients with a primary urothelial carcinoma were immunohistochemically assessed on a tissue microarray. Associations between CD73 expression and retrospectively obtained clinicopathological data were evaluated by contingency analysis. Survival analysis was performed to investigate the predictive value of CD73 within the subgroup of pTa and pT1 tumors in regard to progression-free survival (PFS. Results. High CD73 expression was found in 46 (26.4% patients and was significantly associated with lower stage, lower grade, less adjacent carcinoma in situ and with lower Ki-67 proliferation index. High CD73 immunoreactivity in the subgroup of pTa and pT1 tumors (n=158 was significantly associated with longer PFS (HR: 0.228; p=0.047 in univariable Cox regression analysis. Conclusion. High CD73 immunoreactivity was associated with favorable clinicopathological features. Furthermore, it predicts better outcome in the subgroup of pTa and pT1 tumors and may thus serve as additional tool for the selection of patients with favorable prognosis.

Construction of ureteral grafts by seeding urothelial cells and bone marrow mesenchymal stem cells into polycaprolactone-lecithin electrospun fibers.

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Shen, Jie; Fu, Xiaoling; Ou, Lailiang; Zhang, Min; Guan, Yong; Wang, Kai; Che, Yongzhe; Kong, Deling; Steinhof, Gustav; Li, Wenzhong; Yu, Yaoting; Ma, Nan

2010-03-01

The aim of the present study was to investigated the construction of polycaprolactone-lecithin (PCL-L) electrospun fibers as a novel scaffold material for a tissue-engineered ureter. The effect of bone marrow mesenchymal stem cells (BM-MSCs) on the neovascularization of the scaffolds and the viability of planted urothelial cells (UCs) on PCL-L were also studied. UCs were obtained from New Zealand rabbit bladders, cultured and then seeded onto the lumen of the tubular scaffolds before being subcutaneously transplanted into the space of nude mice. The cultured UCs showed vacuolar degeneration after 7 days of transplantation and they gradually degraded thereafter. To facilitate the regeneration of the tissue-engineered ureter and the survival of UCs in the implant, MSCs were seeded into the tubular grafts by rolling up the nanofibrous membrane, followed by the seeding of UCs. This facilitated the survival of the UCs, which formed several cellular layers after 30 days. The mean microvessel density was significantly increased in tissues seeded with MSCs. Cell-tracking experiments revealed that the transplanted MSCs did not integrate directly into capillaries for angiogenesis. Our results demonstrated that the PCL-L electrospun fibrous scaffold has a high potential for a tissue-engineered ureter especially when seeded with BM-MSCs, which enhanced angiogenesis.

Morphological examination of the effects of defibrotide on experimentally induced bladder injury and its relation to interstitial cystitis.

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Aydin, H; Ercan, F; Cetinel, S; San, T

2001-08-01

This morphological study aims to investigate the effects of defibrotide, a deoxyribonucleic acid derivative drug with cytoprotective, immunosuppressive and vasorelaxant effects, on protamine sulfate induced bladder injury. Wistar albino female rats were catheterized and intravesically infused with phosphate buffered solution (control group) or, either protamine sulfate (bladder injury group) or protamine sulfate+defibrotide (bladder injury+defibrotide group) dissolved in phosphate buffered solution. The morphology of the urinary bladder was investigated using light and electron microscopy. The number of mast cells in the mucosa, mucosal alterations, intercellular junctions, surface topography and the glycosaminoglycan (GAG) layer as well as microvillus formation on the luminal surface were evaluated. In the bladder injury group, ulcerated areas, irregularity of the GAG layer, increased number of mast cells, vacuole formation, dilated perinuclear cistern, formation of pleomorphic and uniform microvilli and dilatations in the intercellular spaces in the urothelium were observed. In the bladder injury+defibrotide group a relatively normal urothelial topography, GAG layer and a few mast cells in the mucosa, some dilatations between the intercellular areas, less uniform microvilli, regular perinuclear cistern and tight junctions were observed. These results show that defibrotide can inhibit PS induced bladder damage.

Progression of urothelial carcinoma in situ of the urinary bladder: a switch from luminal to basal phenotype and related therapeutic implications.

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Barth, Isabella; Schneider, Ursula; Grimm, Tobias; Karl, Alexander; Horst, David; Gaisa, Nadine T; Knüchel, Ruth; Garczyk, Stefan

2018-05-01

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0-3) multiplied with percentage of positive cells (0-4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

What are the currently available and in development molecular markers for bladder cancer? Will they prove to be useful in the future?

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Abdulmajed, Mohamed Ismat; Sancak, Eyüp Burak; Reşorlu, Berkan; Al-Chalaby, Gydhia Zuhair

2014-12-01

Urothelial carcinoma is the 9(th) most common cancer worldwide. Most urothelial tumors are non-muscle invasive on presentation. However, two-thirds of non-invasive bladder cancers will eventually recur with a 25% risk of progression to muscle-invasive bladder cancer. Tumor stage, histological grade and pathological invasion of blood vessels and lymphatic tissue are the main indicators for urothelial cancer prognosis. The gold standard for diagnosing bladder cancer is conventional white-light cystoscopy and biopsy. Urine cytology is a highly specific, sensitive test for high-grade tumors or carcinoma in situ (CIS). Urinary NMP22 has an overall sensitivity and specificity for detecting bladder cancer of 49% and 87%, respectively. However, there are false-positive results in the presence of urinary tract infection or hematuria. The detection of specific gene mutations related to urothelial cancers has been studied and employed to reproduce markers helpful for diagnosis. According to current studies, molecular markers can be used to predict tumor recurrence. From a prognostic point of view, new molecular markers have yet to be established as reliable indicators of tumor aggressiveness. We aimed to review the molecular markers with possible prognostic significance that have been discussed in the literature. This review examined the literature for various molecular markers under development for bladder cancer in an attempt to optimize patient care and reduce the costs of treating these patients.

Modulated Raman spectroscopy for enhanced identification of bladder tumor cells in urine samples.

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Canetta, Elisabetta; Mazilu, Michael; De Luca, Anna Chiara; Carruthers, Antonia E; Dholakia, Kishan; Neilson, Sam; Sargeant, Harry; Briscoe, Tina; Herrington, C Simon; Riches, Andrew C

2011-03-01

Standard Raman spectroscopy (SRS) is a noninvasive technique that is used in the biomedical field to discriminate between normal and cancer cells. However, the presence of a strong fluorescence background detracts from the use of SRS in real-time clinical applications. Recently, we have reported a novel modulated Raman spectroscopy (MRS) technique to extract the Raman spectra from the background. In this paper, we present the first application of MRS to the identification of human urothelial cells (SV-HUC-1) and bladder cancer cells (MGH) in urine samples. These results are compared to those obtained by SRS. Classification using the principal component analysis clearly shows that MRS allows discrimination between Raman spectra of SV-HUC-1 and MGH cells with high sensitivity (98%) and specificity (95%). MRS is also used to distinguish between SV-HUC-1 and MGH cells after exposure to urine for up to 6 h. We observe a marked change in the MRS of SV-HUC-1 and MGH cells with time in urine, indicating that the conditions of sample collection will be important for the application of this methodology to clinical urine samples.

Tissue responses to hexyl 5-aminolevulinate-induced photodynamic treatment in syngeneic orthotopic rat bladder cancer model: possible pathways of action

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Arum, Carl-Jørgen; Gederaas, Odrun A.; Larsen, Eivind L. P.; Randeberg, Lise L.; Hjelde, Astrid; Krokan, Hans E.; Svaasand, Lars O.; Chen, Duan; Zhao, Chun-Mei

2011-02-01

Orthotopic bladder cancer model in rats mimics human bladder cancer with respect to urothelial tumorigenesis and progression. Utilizing this model at pT1 (superficial stage), we analyze the tissue responses to hexyl 5-aminolevulinate-induced photodynamic therapy (HAL-PDT). In comparison to untreated rats, HAL-PDT causes little change in tumor-free rat bladder but induces inflammatory changes with increased lymphocytes and mononuclear cell infiltration in rat bladders with tumor. Immunohistochemistry reveals that HAL-PDT is without effect on proliferating cell nuclear antigen expression within the tumor and increases caspase-3 expression in both normal urothelium and the tumor. Transmission electron microscopy reveals severe mitochondrial damage, formations of apoptotic bodies, vacuoles, and lipofuscin bodies, but no microvillus-formed niches in HAL-PDT-treated bladder cancer rats. Bioinformatics analysis of the gene expression profile indicates an activation of T-cell receptor signaling pathway in bladder cancer rats without PDT. HAL-PDT increases the expression of CD3 and CD45RA in the tumor (determined by immunohistochemistry). We suggest that pathways of action of HAL-PDT may include, at least, activations of mitochondrial apoptosis and autophagy, breakdown of cancer stem cell niches, and importantly, enhancement of T-cell activation.

Pathobiology and Chemoprevention of Bladder Cancer

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Tanaka, Takuji; Miyazawa, Katsuhito; Tsukamoto, Tetsuya; Kuno, Toshiya; Suzuki, Koji

2011-01-01

Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer. PMID:21941546

Repeated Treatments with Chitosan in Combination with Antibiotics Completely Eradicate Uropathogenic Escherichia coli From Infected Mouse Urinary Bladders.

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Erman, Andreja; Hergouth, Veronika Križan; Blango, Matthew G; Kos, Mojca Kerec; Mulvey, Matthew A; Veranic, Peter

2017-08-01

Uropathogenic Escherichia coli (UPEC), the primary causative agents of urinary tract infections, colonize and invade the epithelial cells of the bladder urothelium. Infection of immature urothelial cells can result in the formation of persistent intracellular reservoirs that are refractory to antibiotic treatments. Previously, we defined a novel therapeutic strategy that used the bladder cell exfoliant chitosan to deplete UPEC reservoirs. However, although a single treatment of chitosan followed by ciprofloxacin administration had a marked effect on reducing UPEC titers within the bladder, this treatment failed to prevent relapsing bacteriuria. We show here that repeated use of chitosan in conjunction with the antibiotic ciprofloxacin completely eradicates UPEC from the urinary tract and prevents the development of relapsing bouts of bacteriuria. In addition, microscopy revealed rapid restoration of bladder integrity following chitosan treatment, indicating that chitosan can be used to effectively combat recalcitrant bladder infections without causing lasting harm to the urothelium. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis

OpenAIRE

Zhou, Haiping; Wang, Xing; Mo, Lan; Liu, Yan; He, Feng; Zhang, Fenglin; Huang, Kuo-How; Wu, Xue-Ru

2016-01-01

The conversion of precancerous lesions to full-fledged cancers requires the affected cells to surpass certain rate-limiting steps. We recently showed that activation of HRAS proto-oncogene in urothelial cells of transgenic mice causes simple urothelial hyperplasia (SUH) which is persistent and whose transition to low-grade papillary urothelial carcinoma (UC) must undergo nodular urothelial hyperplasia (NUH). We hypothesized that NUH, which has acquired fibrovascular cores, plays critical role...

Prognostic factors in non-muscle-invasive bladder tumors - I. Clinical prognostic factors: A review of the experience of the EORTC genito-urinary group - II. Biologic prognostic markers

NARCIS (Netherlands)

Kurth, Karl-Heinz; Sylvester, Richard J.

2007-01-01

Objectives: To summarize the most important clinical prognostic factors of non-muscle-invasive bladder cancer, as assessed by the European organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Group, to present biologic markers involved in urothelial cell carcinoma, and to address

Safety and Efficacy of Durvalumab (MEDI4736), an Anti–Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

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Massard, Christophe; Gordon, Michael S.; Sharma, Sunil; Rafii, Saeed; Wainberg, Zev A.; Luke, Jason; Curiel, Tyler J.; Colon-Otero, Gerardo; Hamid, Omid; Sanborn, Rachel E.; O’Donnell, Peter H.; Drakaki, Alexandra; Tan, Winston; Kurland, John F.; Rebelatto, Marlon C.; Jin, Xiaoping; Blake-Haskins, John A.; Gupta, Ashok

2016-01-01

Purpose To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). Methods A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1–positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. Results A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). Conclusion Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily pretreated. PMID:27269937

Differential induction of micronuclei in peripheral lymphocytes and exfoliated urothelial cells of workers exposed to 4,4'-methylenebis-(2-chloroaniline) (MOCA) and bitumen fumes.

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Murray, E B; Edwards, J W

2005-01-01

Cytogenetic end-points used to estimate risk of genotoxic events in workers include the measurement of micronuclei (MN) in exfoliated cells, lymphocytes, and other tissues. Micronuclei are chromatin-containing bodies outside the cell nucleus resulting from contaminant-induced DNA damage. A review of 71 reports of human genotoxic responses to chemical or physical agents published between 1999 and 2001 revealed that 14% of such studies measured genotoxicity endpoints in specific target tissues relevant to the site of disease for the agent examined; 18% used endpoints in surrogate or non-target tissues but considered the relations between endpoints in surrogate and disease target tissues, and 68% measured genotoxicity endpoints in accessible tissues without reference to specific targets for disease. Methylenebis-(2-chloroaniline) (MOCA), used in polyurethane manufacture, is a suspected bladder carcinogen. Bitumen, used in road surfacing, contains skin and lung carcinogens. In this study, we aimed to compare genotoxicity in urothelial cells and in lymphocytes of workers exposed to these materials. Twelve men employed in polyurethane manufacture, twelve bitumen road layers, and eighteen hospital stores personnel (controls) were recruited and all provided blood and urine samples on the same day. Blood cultures were prepared using a cytochalasin B-block method. Exfoliated urothelial cells were collected from urine and stained for light microscopy. The number of MN in urothelial cells was higher in MOCA-exposed (14.27 +/- 0.56 MN/1000, 9.69 +/- 0.32 MN cells/1000) than in bitumen exposed workers (11.99 +/- 0.65 MN/1000, 8.66 +/- 0.46 MN cells/1000) or in control subjects (6.88 +/- 0.18 MN/1000, 5.17 +/- 0.11 MN cells/1000). Conversely, in lymphocytes, MN were higher in bitumen-exposed (16.24 +/- 0.63 MN/1000, 10.65 +/- 0.24 MN cells/1000) than in MOCA-exposed workers (13.25 +/- 0.48 MN/1000, 8.54 +/- 0.14 MN cells/1000) or in control subjects (9.24 +/- 0.29 MN/ 1000, 5

TRPV2 activation induces apoptotic cell death in human T24 bladder cancer cells: a potential therapeutic target for bladder cancer.

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Yamada, Takahiro; Ueda, Takashi; Shibata, Yasuhiro; Ikegami, Yosuke; Saito, Masaki; Ishida, Yusuke; Ugawa, Shinya; Kohri, Kenjiro; Shimada, Shoichi

2010-08-01

To investigate the functional expression of the transient receptor potential vanilloid 2 (TRPV2) channel protein in human urothelial carcinoma (UC) cells and to determine whether calcium influx into UC cells through TRPV2 is involved in apoptotic cell death. The expression of TRPV2 mRNA in bladder cancer cell lines (T24, a poorly differentiated UC cell line and RT4, a well-differentiated UC cell line) was analyzed using reverse transcriptase-polymerase chain reaction. The calcium permeability of TRPV2 channels in T24 cells was investigated using a calcium imaging assay that used cannabidiol (CBD), a relatively selective TRPV2 agonist, and ruthenium red (RuR), a nonselective TRPV channel antagonist. The death of T24 or RT4 cells in the presence of CBD was evaluated using a cellular viability assay. Apoptosis of T24 cells caused by CBD was confirmed using an annexin-V assay and small interfering RNA (siRNA) silencing of TRPV2. TRPV2 mRNA was abundantly expressed in T24 cells. The expression level in UC cells was correlated with high-grade disease. The administration of CBD increased intracellular calcium concentrations in T24 cells. In addition, the viability of T24 cells progressively decreased with increasing concentrations of CBD, whereas RT4 cells were mostly unaffected. Cell death occurred via apoptosis caused by continuous influx of calcium through TRPV2. TRPV2 channels in UC cells are calcium-permeable and the regulation of calcium influx through these channels leads directly to the death of UC cells. TRPV2 channels in UC cells may be a potential new therapeutic target, especially in higher-grade UC cells. Copyright 2010 Elsevier Inc. All rights reserved.

Overexpression of high mobility group box 1 contributes to progressive clinicopathological features and poor prognosis of human bladder urothelial carcinoma

Directory of Open Access Journals (Sweden)

Huang CK

2018-04-01

Full Text Available Changkun Huang,* Zhichao Huang,* Xiaokun Zhao, Yinhuai Wang, Hongqing Zhao, Zhaohui Zhong, Lang Wang Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China *These authors contributed equally to this work Background: High mobility group box 1 (HMGB1, a versatile protein with intranuclear and extracellular functions, plays an important role in a variety of human cancers. However, the clinical/prognostic significance of HMGB1 expression in human bladder urothelial carcinoma (BUC remains unclear. The aim of this study was to investigate the HMGB1 expression in human BUC with regard to its clinical and prognostic significance.Patients and methods: HMGB1 mRNA and protein expressions in tumor and paired normal bladder tissues were detected in 20 BUC cases by quantitative real-time polymerase chain reaction (qRT-PCR and Western blot. HMGB1 protein expression in 165 primary BUC tissues was evaluated by immunohistochemistry (IHC, and its correlations with clinicopathological characteristics and prognosis were also analyzed. Student’s t-test, χ2 test, Kaplan–Meier plots, and Cox proportional hazard regression model were performed to analyze the data. Results: By using qRT-PCR and Western blot, the upregulated expression of HMGB1 mRNA and protein was detected in BUC, compared with paired normal tissue (P<0.05. By using IHC, high HMGB1 expression was examined in 84 of 165 (51.0% BUC cases. High HMGB1 expression was significantly correlated with poorer differentiation and higher T and N classification (all P<0.05. Univariate analysis showed that high HMGB1 expression was significantly associated with a shortened patients’ overall survival (OS and disease-free survival (DFS; both P<0.001. In different subgroups of BUC patients, HMGB1 expression was a prognostic factor in patients with different histological grades or T classification (all P<0.05, pN− (both P<0.001 for OS and DFS, and

Pathology outcomes in patients with transurethral bladder tumour resection in a Turkish population: A retrospective analysis

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Salih Budak

2018-03-01

Full Text Available Objectives: Transurethral bladder tumour resection (TURBT is the common surgical method used in the diagnosis, staging and treatment of patients with bladder tumour. Most of the rare tumours other than the urothelial carcinomas of the bladder are in advanced stage on diagnosis and necessitate aggressive treatment. In our study, we aimed to the histologic types of bladder cancer and to determine the regional incidence of rare bladder cancer types in our region. Materials and methods: We retrospectively evaluated 815 patients who underwent TURBT surgery between January 2010 and March 2016 in our clinic with a diagnosis of bladder cancer and at least 1 year follow-up. Patients with tumour histopathological examination including histological tumour type, grade and were reported. Thirty-nine patients with an unclear pathology report (neighboring organ invasion, cautery artifact, etc and 17 patients whose data could not be accessed were excluded from the study. The patients who had received chemotherapy or radiotherapy due to any type of malignancy (23 were also excluded from the study. Results: The outcomes of 736 patients operated in our clinics due to bladder tumour were evaluated. The mean age was 65.2 ± 8.4; 135 were female and 601 were male. Among them 711 patients with urothelial carcinoma were reported (94.2%. According to TNM classification, stage Ta was observed in 270 patients (37.9%, stage T1 in 297 (41.7%, and stage T2 in 144 (20.3%. Non-urothelial cancers were reported in 25 cases (3.3%. Conclusion: The incidence of bladder carcinoma varies between regions. The results of our study are similar to those of the western countries. Increased smoking and exposure to environmental carcinogenetic agents may lead to altered incidences and histological types of bladder tumours. Revision of regional tumour records may be useful to develop and evaluate future treatment strategies.

Differential effects of selective frankincense (Ru Xiang) essential oil versus non-selective sandalwood (Tan Xiang) essential oil on cultured bladder cancer cells: a microarray and bioinformatics study

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2014-01-01

Background Frankincense (Boswellia carterii, known as Ru Xiang in Chinese) and sandalwood (Santalum album, known as Tan Xiang in Chinese) are cancer preventive and therapeutic agents in Chinese medicine. Their biologically active ingredients are usually extracted from frankincense by hydrodistillation and sandalwood by distillation. This study aims to investigate the anti-proliferative and pro-apoptotic activities of frankincense and sandalwood essential oils in cultured human bladder cancer cells. Methods The effects of frankincense (1,400–600 dilutions) (v/v) and sandalwood (16,000–7,000 dilutions) (v/v) essential oils on cell viability were studied in established human bladder cancer J82 cells and immortalized normal human bladder urothelial UROtsa cells using a colorimetric XTT cell viability assay. Genes that responded to essential oil treatments in human bladder cancer J82 cells were identified using the Illumina Expression BeadChip platform and analyzed for enriched functions and pathways. The chemical compositions of the essential oils were determined by gas chromatography–mass spectrometry. Results Human bladder cancer J82 cells were more sensitive to the pro-apoptotic effects of frankincense essential oil than the immortalized normal bladder UROtsa cells. In contrast, sandalwood essential oil exhibited a similar potency in suppressing the viability of both J82 and UROtsa cells. Although frankincense and sandalwood essential oils activated common pathways such as inflammatory interleukins (IL-6 signaling), each essential oil had a unique molecular action on the bladder cancer cells. Heat shock proteins and histone core proteins were activated by frankincense essential oil, whereas negative regulation of protein kinase activity and G protein-coupled receptors were activated by sandalwood essential oil treatment. Conclusion The effects of frankincense and sandalwood essential oils on J82 cells and UROtsa cells involved different mechanisms leading to

Canine urothelial carcinoma: genomically aberrant and comparatively relevant.

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Shapiro, S G; Raghunath, S; Williams, C; Motsinger-Reif, A A; Cullen, J M; Liu, T; Albertson, D; Ruvolo, M; Bergstrom Lucas, A; Jin, J; Knapp, D W; Schiffman, J D; Breen, M

2015-06-01

Urothelial carcinoma (UC), also referred to as transitional cell carcinoma (TCC), is the most common bladder malignancy in both human and canine populations. In human UC, numerous studies have demonstrated the prevalence of chromosomal imbalances. Although the histopathology of the disease is similar in both species, studies evaluating the genomic profile of canine UC are lacking, limiting the discovery of key comparative molecular markers associated with driving UC pathogenesis. In the present study, we evaluated 31 primary canine UC biopsies by oligonucleotide array comparative genomic hybridization (oaCGH). Results highlighted the presence of three highly recurrent numerical aberrations: gain of dog chromosome (CFA) 13 and 36 and loss of CFA 19. Regional gains of CFA 13 and 36 were present in 97 % and 84 % of cases, respectively, and losses on CFA 19 were present in 77 % of cases. Fluorescence in situ hybridization (FISH), using targeted bacterial artificial chromosome (BAC) clones and custom Agilent SureFISH probes, was performed to detect and quantify these regions in paraffin-embedded biopsy sections and urine-derived urothelial cells. The data indicate that these three aberrations are potentially diagnostic of UC. Comparison of our canine oaCGH data with that of 285 human cases identified a series of shared copy number aberrations. Using an informatics approach to interrogate the frequency of copy number aberrations across both species, we identified those that had the highest joint probability of association with UC. The most significant joint region contained the gene PABPC1, which should be considered further for its role in UC progression. In addition, cross-species filtering of genome-wide copy number data highlighted several genes as high-profile candidates for further analysis, including CDKN2A, S100A8/9, and LRP1B. We propose that these common aberrations are indicative of an evolutionarily conserved mechanism of pathogenesis and harbor genes

Molecular Characterization of Urothelial Carcinoma of the Bladder and Upper Urinary Tract

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Ji Yun Lee

2018-02-01

Full Text Available PURPOSE: A better understanding of the molecular basis of urothelial carcinoma (UC is needed to refine the clinical decision-making process. METHODS AND MATERIALS: We performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes in UC using Ampliseq v2. Copy number variations (CNVs were detected with nCounter assay. Genetic alterations between upper tract UC (UTUC and urinary bladder UC (UBUC were compared. RESULTS: Tumor samples from 31 UTUC and 61 UBUC patients were included in analysis. The two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was longer in UTUC than UBUC patients, though this was statistically nonsignificant (59 vs 41 months, P = .137. In total, we found 982 genetic alterations from 92 samples: single nucleotide variants were the most common type of somatic mutation (479/508, 94.3%. Frequently detected somatic mutations included TP53 (68.5%, KDR (41.3%, and PIK3CA (17.4%. Notably, RB1 mutations were the only mutations significantly different between the UBUC and UTUC groups (19.7% vs. 0%, P = .020. The most common types of CNVs included amplifications (56/62, 90.3%: 17.7% of patients identified amplifications in NOTCH1. We also identified five translocations in the entire study population, including one case with FGFR3-TACC3 (Chr4 fusion. CONCLUSION: Within a small study population, we identified similar genetic alterations in both UTUC and UBUC patients, indicating a basis for similar management strategies.

Interleukin-17-positive mast cells influence outcomes from BCG for patients with CIS: Data from a comprehensive characterisation of the immune microenvironment of urothelial bladder cancer.

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Alexander C Dowell

Full Text Available The tumour immune microenvironment is considered to influence cancer behaviour and outcome. Using a panel of markers for innate and adaptive immune cells we set out to characterise and understand the bladder tumour microenvironment of 114 patients from a prospective multicentre cohort of newly-diagnosed bladder cancer patients, followed-up for 4.33±1.71 years. We found IL-17-positive cells were significantly increased in primary and concomitant carcinoma in situ (CIS, p<0.0001, a highly malignant lesion which is the most significant single risk factor for disease progression. Further characterisation of the tumour immunophenotype identified IL-17+ cells as predominantly mast cells rather than T-cells, in contrast to most other tumour types. Expression of the IL-17-receptor in bladder tumours, and functional effects and gene expression changes induced by IL-17 in bladder tumour cells in vitro suggest a role in tumour behaviour. Finally, we assessed the effects of IL-17 in the context of patient outcome, following intravesical BCG immunotherapy which is the standard of care; higher numbers of IL-17+ cells were associated with improved event-free survival (p = 0.0449, HR 0.2918, 95% CI 0.08762-0.9721 in patients with primary and concomitant CIS (n = 41, we propose a model of IL-17+ Mast cells mechanism of action. Thus, in the context of bladder CIS, IL-17+ mast cells predict favourable outcome following BCG immunotherapy indicative of a novel mechanism of BCG immunotherapy in UBC and could form the basis of a stratified approach to treatment.

Screening for Bladder and Other Urothelial Cancers

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... cancer is the focus of this summary. Enlarge Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. Urine is made in ...

Dynamic Change in p63 Protein Expression during Implantation of Urothelial Cancer Clusters

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Takahiro Yoshida

2015-07-01

Full Text Available Although the dissemination of urothelial cancer cells is supposed to be a major cause of the multicentricity of urothelial tumors, the mechanism of implantation has not been well investigated. Here, we found that cancer cell clusters from the urine of patients with urothelial cancer retain the ability to survive, grow, and adhere. By using cell lines and primary cells collected from multiple patients, we demonstrate that △Np63α protein in cancer cell clusters was rapidly decreased through proteasomal degradation when clusters were attached to the matrix, leading to downregulation of E-cadherin and upregulation of N-cadherin. Decreased △Np63α protein level in urothelial cancer cell clusters was involved in the clearance of the urothelium. Our data provide the first evidence that clusters of urothelial cancer cells exhibit dynamic changes in △Np63α expression during attachment to the matrix, and decreased △Np63α protein plays a critical role in the interaction between cancer cell clusters and the urothelium. Thus, because △Np63α might be involved in the process of intraluminal dissemination of urothelial cancer cells, blocking the degradation of △Np63α could be a target of therapy to prevent the dissemination of urothelial cancer.

Whyever bladder tissue engineering clinical applications still remain unusual even though many intriguing technological advances have been reached?

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Alberti, C

2016-01-01

To prevent problematic outcomes of bowel-based bladder reconstructive surgery, such as prosthetic tumors and systemic metabolic complications, research works, to either regenerate and strengthen failing organ or build organ replacement biosubstitute, have been turned, from 90s of the last century, to both regenerative medicine and tissue engineering.Various types of acellular matrices, naturally-derived materials, synthetic polymers have been used for either "unseeded" (cell free) or autologous "cell seeded" tissue engineering scaffolds. Different categories of cell sources - from autologous differentiated urothelial and smooth muscle cells to natural or laboratory procedure-derived stem cells - have been taken into consideration to reach the construction of suitable "cell seeded" templates. Current clinically validated bladder tissue engineering approaches essentially consist of augmentation cystoplasty in patients suffering from poorly compliant neuropathic bladder. No clinical applications of wholly tissue engineered neobladder have been carried out to radical-reconstructive surgical treatment of bladder malignancies or chronic inflammation-due vesical coarctation. Reliable reasons why bladder tissue engineering clinical applications so far remain unusual, particularly imply the risk of graft ischemia, hence its both fibrous contraction and even worse perforation. Therefore, the achievement of graft vascular network (vasculogenesis) could allow, together with the promotion of host surrounding vessel sprouting (angiogenesis), an effective graft blood supply, so avoiding the ischemia-related serious complications.

Risk factors and prognosis of intravesical recurrence after surgical management of upper tract urothelial carcinoma: A 30-year single centre experience

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Mohamed Mohamed Elawdy

2017-09-01

Conclusions: In our present series, bladder cancer recurrence of urothelial malignancy occurred in nearly half of the patients after surgical management of UTUC. Ureteric tumour was the only identifiable risk factor, thus patients with ureteric tumours may benefit from prophylactic intravesical chemoimmunotherapy. Bladder recurrence does not appear to affect the cancer-specific survival after surgical management of UTUC.

[Atypical urothelial cells (AUC): A Bethesda-derived wording applicable to urinary cytopathology].

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Piaton, Eric; Advenier, Anne-Sophie; Benaïm, Gilles; Petrucci, Myriam Decaussin; Lechevallier, Florence Mege; Ruffion, Alain

2011-02-01

To investigate (1) whether sparse nuclear atypias involving deep urothelial cells have a diagnostic or prognostic value in urinary cytology, and (2) whether the terms atypical urothelial cells "of undetermined significance" (AUC-US) or "cannot exclude high grade" (AUC-H) might be used to standardize urinary cytology reports. Atypical urothelial cells (AUC) were defined as deep cells with nuclear abnormalities (increased N/C ratio, eccentric nucleus, hyperchromatism and/or irregular shape) in small number not allowing their categorization as malignant, high grade. We studied 435 urinary samples from 126 patients with AUC at any step of their clinical history, followed up over a 10-year period (1999-2009). Every case was compared with histopathology within 6 months and to long term follow-up including cystoscopy and histopathology combined. A total of 183 AUC was recorded. AUC were associated with negative, benign or low grade histological results in 36 of 106 cases (33.9 %) within 6 months, but a high grade was simultaneously documented in 70 cases (66 %). AUC preceded high-grade lesions in 66 cases (36.1 % of all AUC) in a mean interval of 10.5±12.0 months. Overall, AUC were associated with or predictive of high-grade lesions in 135 cases (73.8 %). AUC have a diagnostic and prognostic value. Applying the terms AUC-US and AUC-H to urinary cytopathology reports would allow, as for the Bethesda system for cervical or vaginal cytologic diagnoses, better appreciation of the risk of progression to high grade tumours in cases with atypias. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Arsenic and urinary bladder cell proliferation

International Nuclear Information System (INIS)

Luster, Michael I.; Simeonova, Petia P.

2004-01-01

Epidemiologic studies have demonstrated that a close association exists between the elevated levels of arsenic in drinking water and the incidence of certain cancers, including transitional cell carcinomas of the urinary bladder. We have employed in vitro and in vivo models to examine the effects of sodium arsenite on the urinary bladder epithelium. Mice exposed to 0.01% sodium arsenite in drinking water demonstrated hyperproliferation of the bladder uroepithelium within 4 weeks after initiating treatment. This occurred in the absence of amorphous precipitates and was accompanied by the accumulation of trivalent arsenite (iAs 3+ ), and to a lesser extent dimethylarsenic (DMA), arsenate (iAs 5+ ), and monomethylarsenic (MMA) in bladder tissue. In contrast to the bladder, urinary secretion was primarily in the form of DMA and MMA. Arsenic-induced cell proliferation in the bladder epithelium was correlated with activation of the MAP kinase pathway, leading to extracellular signal-regulated kinase (ERK) kinase activity, AP-1 activation, and expression of AP-1-associated genes involved in cell proliferation. Activation of the MAP kinase pathway involved both epidermal growth factor (EGF) receptor-dependent and -independent events, the latter involving Src activation. Studies summarized in this review suggest that arsenic accumulates in urinary bladder epithelium causing activation of specific signaling pathways that lead to chronic increased cell proliferation. This may play a non-epigenetic role in carcinogenesis by increasing the proliferation of initiated cells or increasing the mutational rate

Review: Application of Nanoparticles in Urothelial Cancer of the Urinary Bladder

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Chen, Chieh-Hsiao; Chan, Tzu-Min; Wu, Yi-Jhen; Chen, Jia-Jin

2015-01-01

Bladder cancer is a common malignancy of the urinary tract, which generally develops in the epithelial lining of the urinary bladder. The specific course of treatment depends on the stage of bladder cancer; however, therapeutic strategies typically involve intravesical drug delivery to reduce toxicity and increase therapeutic effects. Recently, metallic, polymeric, lipid, and protein nanoparticles have been introduced to aid in the treatment of bladder cancer. Nanoparticles are also commonly ...

Pretreatment Neutrophil-Lymphocyte Ratio as a Predictor in Bladder Cancer and Metastatic or Unresectable Urothelial Carcinoma Patients: a Pooled Analysis of Comparative Studies.

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Wu, Shuiqing; Zhao, Xiaokun; Wang, Yinhuai; Zhong, Zhaohui; Zhang, Lei; Cao, Jian; Ai, Kai; Xu, Ran

2018-01-01

Emerging studies have shown that the neutrophil-lymphocyte ratio (NLR) is a potential predictor in various tumors. Our study was conducted to assess the prognostic value of the pretreatment NLR in bladder cancer and metastatic or unresectable urothelial carcinoma (mUC or uUC) patients up to July 2017. The correlation between the pretreatment NLR and pathological characteristics was also evaluated in bladder cancer patients. The hazard ratio (HR) and odds ratio (OR) with the 95% confidence interval (CI) were extracted or calculated from the included studies for further pooled analysis. A total of 21 studies were included in a pooled analysis. The pooled results indicated that a high pretreatment NLR was associated with reduced overall survival (OS) (HR=1.27, 95% CI=1.12-1.43), relapse-free survival (RFS) (HR=1.41, 95% CI=1.23-1.60), progression-free survival (PFS) (HR=1.75, 95% CI=1.36-2.15), disease-specific survival (DSS) and cancer-specific survival (CSS) (HR=1.27, 95% CI=1.19-1.35) in the bladder cancer patients. Additionally, an elevated pretreatment NLR suggested a worse OS rate in the mUC or uUC patients (HR=1.63, 95% CI=1.34-1.91). The pooled ORs and 95% CIs showed that a high pretreatment NLR could be a risk indicator for certain pathological features, such as lymphovascular invasion, a positive margin status and advanced tumor stage. our results showed that a high pretreatment NLR predicted poor prognosis in bladder cancer, mUC and uUC patients. © 2018 The Author(s). Published by S. Karger AG, Basel.

Mucinous urothelial carcinoma of the renal pelvis

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Kemal Behzatoğlu

2014-12-01

Full Text Available Urothelial carcinoma with abundant myxoid stroma is a newly-described and extremely rare entity. Since only very few cases have been reported, there is no consensus on its nomenclature. Microscopic examination revealed invasive urothelial carcinoma with widespread low-grade noninvasive areas. There were focal invasive areas in the neighborhood of the renal parenchyma. Malignant urothelial tumor/cell groups localized in the stroma had abundant myxoid/mucinous background in the invasive areas. The cytoplasm of the tumoral cells was more eosinophilic in these areas and the cells formed small groups and cords. Histochemically, PAS and Alcian Blue were positive in the cytoplasm of the tumoral cells and in the stroma while negative in the non-mucinous areas. Immunohistochemically, the tumoral cells of the mucinous invasive areas diffusely expressed MUC1 and MUC2. We discuss the origin of the mucinous/myxoid stroma, the tumor’s nature and its nomenclature with histochemical and immunohistochemical features.

The antidiabetic drug ciglitazone induces high grade bladder cancer cells apoptosis through the up-regulation of TRAIL.

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Marie-Laure Plissonnier

Full Text Available Ciglitazone belongs to the thiazolidinediones class of antidiabetic drug family and is a high-affinity ligand for the Peroxisome Proliferator-Activated Receptor γ (PPARγ. Apart from its antidiabetic activity, this molecule shows antineoplastic effectiveness in numerous cancer cell lines.Using RT4 (derived from a well differentiated grade I papillary tumor and T24 (derived from an undifferentiated grade III carcinoma bladder cancer cells, we investigated the potential of ciglitazone to induce apoptotic cell death and characterized the molecular mechanisms involved. In RT4 cells, the drug induced G2/M cell cycle arrest characterized by an overexpression of p53, p21(waf1/CIP1 and p27(Kip1 in concomitance with a decrease of cyclin B1. On the contrary, in T24 cells, it triggered apoptosis via extrinsic and intrinsic pathways. Cell cycle arrest and induction of apoptosis occurred at high concentrations through PPARγ activation-independent pathways. We show that in vivo treatment of nude mice by ciglitazone inhibits high grade bladder cancer xenograft development. We identified a novel mechanism by which ciglitazone kills cancer cells. Ciglitazone up-regulated soluble and membrane-bound TRAIL and let TRAIL-resistant T24 cells to respond to TRAIL through caspase activation, death receptor signalling pathway and Bid cleavage. We provided evidence that TRAIL-induced apoptosis is partially driven by ciglitazone-mediated down-regulation of c-FLIP and survivin protein levels through a proteasome-dependent degradation mechanism.Therefore, ciglitazone could be clinically relevant as chemopreventive or therapeutic agent for the treatment of TRAIL-refractory high grade urothelial cancers.

New Aspects in the Differential Diagnosis and Therapy of Bladder Pain Syndrome/Interstitial Cystitis

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Jochen Neuhaus

2011-01-01

Full Text Available Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical “columns”: (i clinical diagnostics, (ii histopathology, and (iii molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC.

New Aspects in the Differential Diagnosis and Therapy of Bladder Pain Syndrome/Interstitial Cystitis

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Neuhaus, Jochen; Schwalenberg, Thilo; Horn, Lars-Christian; Alexander, Henry; Stolzenburg, Jens-Uwe

2011-01-01

Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical “columns”: (i) clinical diagnostics, (ii) histopathology, and (iii) molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC. PMID:22028706

New aspects in the differential diagnosis and therapy of bladder pain syndrome/interstitial cystitis.

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Neuhaus, Jochen; Schwalenberg, Thilo; Horn, Lars-Christian; Alexander, Henry; Stolzenburg, Jens-Uwe

2011-01-01

Diagnosis of bladder pain syndrome/interstitial cystitis (BPS/IC) is presently based on mainly clinical symptoms. BPS/IC can be considered as a worst-case scenario of bladder overactivity of unknown origin, including bladder pain. Usually, patients are partially or completely resistant to anticholinergic therapy, and therapeutical options are especially restricted in case of BPS/IC. Therefore, early detection of patients prone to develop BPS/IC symptoms is essential for successful therapy. We propose extended diagnostics including molecular markers. Differential diagnosis should be based on three diagnostical "columns": (i) clinical diagnostics, (ii) histopathology, and (iii) molecular diagnostics. Analysis of molecular alterations of receptor expression in detrusor smooth muscle cells and urothelial integrity is necessary to develop patient-tailored therapeutical concepts. Although more research is needed to elucidate the pathomechanisms involved, extended BPS/IC diagnostics could already be integrated into routine patient care, allowing evidence-based pharmacotherapy of patients with idiopathic bladder overactivity and BPS/IC.

Angiogenesis in urinary bladder carcinoma as defined by ...

African Journals Online (AJOL)

Background: Among the patients with bladder cancer, a group is still at risk of disease recurrence, progression, and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial carcinoma and is a potential therapeutic target. Objectives: To quantify tumor ...

Urinary Bladder Cancer in Egypt: Are There Gender Differences in Its Histopathological Presentation?

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Fiorina Kyritsi

2018-01-01

Full Text Available We investigated gender differences in the histopathologic presentation of bladder cancer cases in Egypt, where both urothelial cell carcinoma (UC and squamous cell carcinoma (SCC types are highly prevalent. We used logistic regression to estimate the unadjusted (OR and adjusted odds ratio (AOR and 95% confidence interval (CI of the associations between gender and different histopathologic and sociodemographic parameters of 2,186 confirmed cases of primary bladder cancer (1,775 males and 411 females; 784 SCC and 1,402 UC. There were no statistically significant gender differences in tumor grade, stage, mucosal ulcer, or inflammatory cystitis, regardless of the cancer type, but men were less likely than women to have undergone cystectomy with pelvic lymphadenectomy. Having Schistosoma haematobium (SH ova in the bladder tissue was significantly associated with male gender in the fully adjusted model of either SCC (AOR (95% CI = 2.12 (1.15–3.89 or UC cases (3.78 (1.89–7.55. Compared to females, male cases were significantly older at time of diagnosis and smokers. In Egypt, regardless of the type of bladder cancer (SCC or UC, male more than female cases had evidence of SH infection, but not other histopathologic differences, in bladder tissue specimens.

Immunoglobulin G4-associated inflammatory pseudotumor of urinary bladder: a case report.

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Park, Sanghui; Ro, Jae Y; Lee, Dong Hyeon; Choi, Sun Young; Koo, Heasoo

2013-12-01

A previously healthy 72-year old woman was admitted with a chief complaint of gross hematuria and fecaluria for 4 months. On initial computed tomographic examination, a lobulated shaped intravesical protruding mass with adhesion to the sigmoid colon was identified. Under a clinical diagnosis of bladder cancer with vesicosigmoid fistula vs sigmoid colon cancer with vesicosigmoid fistula, a frozen section evaluation of the bladder mass was performed to determine the origin of the tumor. Because the frozen section diagnosis of the bladder mass was an inflammatory origin, a partial cystectomy with segmental resection of the adherent sigmoid colon was elected. The microscopic examination of the partial resection of the urinary bladder revealed suburothelial inflammatory mass lesion, involving the entire wall of bladder with extension to the sigmoid colon, which was composed of spindle cells without significant atypia admixed with many lymphocytes, plasma cells, and some scattered eosinophils. Chronic inflammation around nerve bundles, sclerotic fibrosis, and prominent lymphoid follicles with plasma cells were the main features of the mass. No urothelial dysplasia or malignancy was seen. An average of 57 plasma cells per 1 high-power field was immunoreactive for immunoglobulin (Ig) G4 with IgG4/IgG ratio of more than 40%, a diagnostic feature of IgG4-associated inflammatory pseudotumor (IPT), arising in the bladder with the secondary involvement of the sigmoid colon. Recent studies reported many IPTs associated with IgG4 in other locations; however, to the best of our knowledge, IgG4-associated IPT in the urinary bladder has not been reported. We describe herein the first case of IgG4-associated IPT, lymphoplasmacytic type in the urinary bladder. Copyright © 2013 Elsevier Inc. All rights reserved.

Expression of CD74 in bladder cancer and its suppression in association with cancer proliferation, invasion and angiogenesis in HT-1376 cells

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Gai, Jun-Wei; Wahafu, Wasilijiang; Song, Liming; Ping, Hao; Wang, Mingshuai; Yang, Feiya; Niu, Yinong; Qing, Wei; Xing, Nianzeng

2018-01-01

The aim of the present study was to investigate the expression and potential roles of CD74 in human urothelial cell carcinoma of the bladder (UCB) in vitro and in vivo. CD74 and macrophage migration inhibitory factor (MIF) were located and assayed in normal and UCB samples and cell lines using immunostaining. CD74 was knocked down using CD74 shRNA lentiviral particles in HT-1376 cells. The proliferative, invasive potential and microvessel density (MVD) of knockdown-CD74 HT-1376 cells were analyzed in vitro or in vivo. The expression of CD74 in an additional high grade UCB J82 cell line was also verified in vivo. All experiments were repeated at least 3 times. The majority of muscle-invasive bladder cancer (MIBC) samples, and only one high grade UCB cell line, HT-1376, expressed CD74, compared with normal, non-muscle-invasive bladder cancer (NMIBC) samples and other cell lines. The levels of proliferation and invasion were decreased in the CD74 knockdown-HT-1376 cells, and western blotting assay indicated that the levels of proteins associated with proliferation, apoptosis and invasion in the cells were affected correspondingly by different treatments in vitro. The tumorigenesis and MVD assays indicated less proliferation and angiogenesis in the knockdown-HT-1376 cells compared with the scramble cells. Notably, J82 cells exhibiting no signal of CD74 in vitro presented the expression of CD74 in vivo. The present study revealed the potential roles of CD74 in the proliferation, invasion and angiogenesis of MIBC, and that it may serve as a potential therapeutic target for UCB, but additional studies are required.

FLUORESCENCE DIAGNOSIS FOR RECURRENT BLADDER CANCER

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R. V. Ulyanov

2017-01-01

Full Text Available The clinical case of successful use of local fluorescence spectroscopy combined with fluorescence imaging during cystoscopy for diagnosis of recurrent bladder cancer is represented in the article. Histological study of fluorescent foci confirmed tumor growth (urothelial carcinoma in all areas with high levels of diagnostic parameter. In the fluorescent focus with low diagnostic parameter inflammation was detected.

In vivo fluorescence imaging of an orthotopic rat bladder tumor model indicates differential uptake of intravesically instilled near-infrared labeled 2-deoxyglucose analog by neoplastic urinary bladder tissues

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Piao, Daqing; Davis, Carole A.; Hurst, Robert E.; Slaton, Joel W.

2017-02-01

Bladder cancer is one of the most expensive cancers to manage due to frequent recurrences requiring life-long surveillance and treatment. A near-infrared labeled 2-deoxy-d-glucose probe IRDye800CW-DG targeting glucose metabolism pathway has shown to enhance the sensitivity of diagnosing several types of cancers as tested on tumor models not including bladder tumor. This pilot study has explored differential uptake of intravesically administered IRDye800CW-DG in an orthotopic rat bladder tumor model. Twenty-five female Fischer rats were randomly grouped to four conditions: no-tumor-control (n=3), no-tumor-control intravesically instilled with IRDye800CWDG (n=6), rats bearing GFP-labeled AY-27 rat bladder urothelial cell carcinoma cells and washed with saline (n=5), and rats bearing AY-27 tumors and intravesically instilled with IRDye800CW-DG (n=11). Near-infrared fluorescence was measured from the opened bladder wall of anesthetized rat at an excitation wavelength of 750nm and an emission wavelength of 776nm, by using an in-house fluorescence imaging system. There is no statistically significant difference of the peak fluorescence intensity among the no-tumor-control bladders (n=3), the no-tumorcontrol bladders instilled with IRDye800CW-DG (n=6), and the GFP-labeled AY-27 treated bladders washed by saline (n=5). When compared to that of the no-tumor-control bladders instilled with IRDye800CW-DG (n=6), the fluorescence intensity of GFP-labeled AY-27 treated bladders instilled with IRDye800CW-DG and with histology confirmed neoplastic bladder tissue (n=11) was remarkably more intense (3.34 fold of over the former) and was also statistically significant (pbladder tissues suggests the potential for cystoscopy-adaptation to enhance diagnosis and guiding surgical management of flat urinary bladder cancer.

External Beam Radiotherapy for Focal Lymphoepithelioma-Like Carcinoma in the Urinary Bladder: A Case Report and Literature Review

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Nobuhiro Kushida

2015-01-01

Full Text Available Lymphoepithelioma is a malignant epithelial tumor in the nasopharynx characterized by prominent lymphoid infiltration. Carcinomas that resemble lymphoepitheliomas have been called lymphoepithelioma-like carcinomas and have been reported in other organs. A tumor in the bladder is categorized by the percentage of the total area occupied by the lymphoepithelioma-like carcinoma pattern, with the prognosis dependent on the percentage. We present an 81-year-old man with stage 3 chronic obstructive pulmonary disease and a history of aortic aneurysm repair. The computed tomography scans indicated thickening and irregularity of the bladder wall, with left external iliac lymph node metastasis. His diagnosis was bladder cancer, and the clinical stage was evaluated as T3N1M0. Transurethral resection of the bladder tumor was performed, and the pathological specimen showed that the tumor was composed of undifferentiated malignant cells with sheets and nests arranged in a syncytial pattern, as well as an urothelial carcinoma lesion. A prominent lymphoid reaction accompanied the tumor. The pathological diagnosis was focal-type lymphoepithelioma-like carcinoma containing a component of urothelial carcinoma G3>G2. His general condition was such that he could not tolerate radical cystectomy or systemic chemotherapy. External beam radiotherapy (total 60 Gy was given to the bladder, including the lymph node metastatic lesion. No cancer recurrence was detected by regular follow-up computed tomography and cystoscopy. He eventually died of other causes 48 months later. Although treatment for focal lymphoepithelioma-like carcinoma generally requires multifocal therapies, in the present case, the bladder became tumor free. We also summarize previously reported lymphoepithelioma-like carcinoma cases treated with radiotherapy.

Immunohistochemical detection of hTERT in urothelial lesions: a potential adjunct to urine cytology

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Khalbuss Walid

2006-08-01

Full Text Available Abstract Background Urine cytology has a critical role in evaluation for bladder carcinoma. Due to the low sensitivity of this technique, ancillary modalities such as the detection of markers of malignancy by immunochemistry are desirable. Promising factors in this context are components of the human telomerase enzyme complex. Telomerase repairs and extend telomeres, which when eroded beyond a critical limit trigger a senescence checkpoint. Accordingly, while absent in normal somatic cells, telomerase activity has been detected in the great majority of malignant tumor specimens tested, and so has potential value for the recognition of malignant cells in clinical specimens. Methods In this study, we investigated whether the immunohistochemical detection of the catalytic subunit of telomerase (hTERT can aid cytology in the diagnosis of bladder lesions. Findings from the retrospective evaluation of over 100 cell blocks, including urine sediments from confirmed malignant and benign conditions, were compared with routine urine cytology data. Results The presence of hTERT protein was indicative of the transformation of urothelia to a malignant phenotype. Nucleolar hTERT was expressed in 27 (93% of 29 samples obtained from patients with confirmed primary bladder cancer. Conversely, hTERT was detectable in only 3 (0.8% of 39 samples from benign conditions. The hTERT assay showed higher diagnostic sensitivity (84.8% than published urine cytology data (~65% for confirmed bladder carcinoma, however, the hTERT assay was less specific than cytology (65.2% vs. ~95% respectively. Conclusion As a highly sensitive marker, immunohistochemical hTERT detection in urine sediments represents a reliable adjunct to cytology in the accurate diagnosis of urothelial neoplasms.

Bladder cancer: Analysis of the 2004 WHO classification in ...

African Journals Online (AJOL)

Objectives: Bladder cancer (BCA) is aworldwide disease and shows a wide range of geographical variation. The aim of this study is to analyze the prevalence of schistosomal and non-schistosomal associated BCA as well as compare our findings with the 2004 WHO consensus classification of urothelial neoplasms and ...

Understanding the biology of urothelial cancer metastasis

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Takashi Kobayashi

2016-10-01

Full Text Available Management of unresectable urothelial cancer (UC has been a clinical challenge for decades. While drug resistance is a key issue, precise understanding of biology of UC metastasis is another challenge for the improvement of treatment outcome of UC patients. Introduction of the cell biology concepts including epithelial-mesenchymal transition (EMT and cancer stemness seems to explain UC metastasis. Molecular genetics based on gene expression profiling, next generation sequencing, and explosion of non-coding RNA world has opened the door to intrinsic molecular subtyping of UC. Next steps include, based on the recently accumulated understanding, the establishment of novel disease models representing UC metastasis in various experimental platforms, particularly in vivo animal systems. Indeed, novel knowledge molecular genetics has not been fully linked to the modeling of UC metastasis. Further understanding of bladder carcinogenesis is needed particularly with regard to cell of origin related to tumor characteristics including driver gene alterations, pathological differentiations, and metastatic ability. Then we will be able to establish better disease models, which will consequently lead us to further understanding of biology and eventually the development of novel therapeutic strategies for UC metastasis.

Differences in the epigenetic regulation of MT-3 gene expression between parental and Cd+2 or As+3 transformed human urothelial cells

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Ajjimaporn Amornpan

2011-02-01

Full Text Available Abstract Background Studies have shown that metallothionein 3 (MT-3 is not expressed in normal urothelium or in the UROtsa cell line, but is expressed in urothelial cancer and in tumors generated from the UROtsa cells that have been transformed by cadmium (Cd+2 or arsenite (As+3.The present study had two major goals. One, to determine if epigenetic modifications control urothelial MT-3 gene expression and if regulation is altered by malignant transformation by Cd+2 or As+3. Two, to determine if MT-3 expression might translate clinically as a biomarker for malignant urothelial cells released into the urine. Results The histone deacetylase inhibitor MS-275 induced MT-3 mRNA expression in both parental UROtsa cells and their transformed counterparts. The demethylating agent, 5-Aza-2'-deoxycytidine (5-AZC had no effect on MT-3 mRNA expression. ChIP analysis showed that metal-responsive transformation factor-1 (MTF-1 binding to metal response elements (MRE elements of the MT-3 promoter was restricted in parental UROtsa cells, but MTF-1 binding to the MREs was unrestricted in the transformed cell lines. Histone modifications at acetyl H4, trimethyl H3K4, trimethyl H3K27, and trimethyl H3K9 were compared between the parental and transformed cell lines in the presence and absence of MS-275. The pattern of histone modifications suggested that the MT-3 promoter in the Cd+2 and As+3 transformed cells has gained bivalent chromatin structure, having elements of being "transcriptionally repressed" and "transcription ready", when compared to parental cells. An analysis of MT-3 staining in urinary cytologies showed that a subset of both active and non-active patients with urothelial cancer shed positive cells in their urine, but that control patients only rarely shed MT-3 positive cells. Conclusion The MT-3 gene is silenced in non-transformed urothelial cells by a mechanism involving histone modification of the MT-3 promoter. In contrast, transformation of the

Co-cultures provide a new tool to probe communication between adult sensory neurons and urothelium.

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O'Mullane, Lauren M; Keast, Janet R; Osborne, Peregrine B

2013-08-01

Recent evidence suggests that the urothelium functions as a sensory transducer of chemical, mechanical or thermal stimuli and signals to nerve terminals and other cells in the bladder wall. The cellular and molecular basis of neuro-urothelial communication is not easily studied in the intact bladder. This led us to establish a method of co-culturing dorsal root ganglion sensory neurons and bladder urothelial cells. Sensory neurons and urothelial cells obtained from dorsal root ganglia and bladders dissected from adult female Sprague-Dawley® rats were isolated by enzyme treatment and mechanical dissociation. They were plated together or separately on collagen coated substrate and cultured in keratinocyte medium for 48 to 72 hours. Retrograde tracer labeling was performed to identify bladder afferents used for functional testing. Neurite growth and complexity in neurons co-cultured with urothelial cells was increased relative to that in neuronal monocultures. The growth promoting effect of urothelial cells was reduced by the tyrosine kinase inhibitor K252a but upstream inhibition of nerve growth factor signaling with TrkA-Fc had no effect. Fura-2 calcium imaging of urothelial cells showed responses to adenosine triphosphate (100 μM) and activation of TRPV4 (4α-PDD, 10 μM) but not TRPV1 (capsaicin, 1 μM), TRPV3 (farnesyl pyrophosphate, 1 μM) or TRPA1 (mustard oil, 100 μM). In contrast, co-cultured neurons were activated by all agonists except farnesyl pyrophosphate. Co-culturing provides a new methodology for investigating neuro-urothelial interactions in animal models of urological conditions. Results suggest that neuronal properties are maintained in the presence of urothelium and neurite growth is potentiated by a nerve growth factor independent mechanism. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Increased risks of upper tract urothelial carcinoma in male and female chinese herbalists.

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Yang, Hsiao-Yu; Wang, Jung-Der; Lo, Tsai-Chang; Chen, Pau-Chung

2011-03-01

It has been shown that herbs that contain aristolochic acid induce urological cancer. Chinese herbalists have easy access to such herbs. Our previous mortality study has shown a significantly increased risk of urological cancer in female but not male herbalists. To re-examine this risk in male herbalists, the incidence of urological cancer was analyzed. We enrolled all 6550 Chinese herbalists in Taiwan registered during 1985-2000, and we retrospectively followed the development of cancer until 2001 by analysis of data collected from the Taiwan Cancer Registry. Standardized incidence ratios (SIRs) were calculated for urological cancers in herbalists and compared with those for the general population in Taiwan. There were 30 newly diagnosed cases of urological cancer and most of them were transitional cell carcinoma (93.1%). The mean age at diagnosis for urothelial carcinoma was 51.6 years, and 51.9% were in the upper urinary tract. After adjustment for age and sex, the SIR for all urological cancers was 3.51 [(95% confidence interval (CI): 2.37-5.01]. When stratified by location, the SIRs for kidney and upper urinary tract cancers and bladder cancer were 4.24 (95% CI: 2.47-6.80) and 2.86 (95% CI: 1.52-4.89), respectively. When analyzed by sex, the SIRs for all urological cancers, kidney and upper urinary tract cancers, and bladder cancer were also significantly increased in male herbalists. The significant risk of urothelial carcinoma noted in male herbalists increases our suspicion that this is an occupational disease that renders regular health assessment of herbalists an urgent necessity. Copyright © 2011 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.

Role of isoenzyme M2 of pyruvate kinase in urothelial tumorigenesis.

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Zhou, Haiping; Wang, Xing; Mo, Lan; Liu, Yan; He, Feng; Zhang, Fenglin; Huang, Kuo-How; Wu, Xue-Ru

2016-04-26

The conversion of precancerous lesions to full-fledged cancers requires the affected cells to surpass certain rate-limiting steps. We recently showed that activation of HRAS proto-oncogene in urothelial cells of transgenic mice causes simple urothelial hyperplasia (SUH) which is persistent and whose transition to low-grade papillary urothelial carcinoma (UC) must undergo nodular urothelial hyperplasia (NUH). We hypothesized that NUH, which has acquired fibrovascular cores, plays critical roles in mesenchymal-to-epithelial signaling, breaching the barriers of urothelial tumor initiation. Using proteomics involving two-dimensional gel electrophoresis, immunoblotting with pan-phosphotyrosine antibody and MALDI-mass spectrometry, we identified isoform 2 of pyruvate kinase (PKM2) as the major tyrosine-phosphorylated protein switched on during NUH. We extended this finding using specimens from transgenic mice, human UC and UC cell lines, establishing that PKM2, but not its spliced variant PKM1, was over-expressed in low-grade and, more prominently, high-grade UC. In muscle-invasive UC, PKM2 was co-localized with cytokeratins 5 and 14, UC progenitor markers. Specific inhibition of PKM2 by siRNA or shRNA suppressed UC cell proliferation via increased apoptosis, autophagy and unfolded protein response. These results strongly suggest that PKM2 plays an important role in the genesis of low-grade non-invasive and high-grade invasive urothelial carcinomas.

Levels of tissue inhibitor of metalloproteinases 1 in plasma and urine frompatients with bladder cancer

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Holten Andersen, MN; Brunner, N; Nielsen, HJ

2006-01-01

Aim: To assess the potential use of plasma and urine levels of tissue inhibitor of metalloproteinases 1 (TIMP-1) in urothelial cancer. Methods: TIMP-1 levels were determined in urine and plasma from healthy donors (n=26), patients with bacterial bladder infection (n=24), urothelial bladder adenoma...... (n=3) or adenocarcinoma (n=7). Results: Free and total TIMP-1 in plasma were weakly but significantly correlated with age; urinary TIMP-1 was not. A strong correlation between free and total TIMP-1 in plasma was observed, with an average ratio of 0.85. No correlation between total TIMP-1 in urine...... and plasma was found (p=0.55). No significant differences in free or total TIMP-1 in plasma were found between healthy individuals, patients with cystitis or bladder cancer (p=0.4). Urinary TIMP-1 levels were significantly increased in patients with cystitis (p=0.001). No apparent differences in TIMP-1...

Bladder Cancer in HIV-infected Adults: An Emerging Issue? Case-Reports and Systematic Review.

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Sylvain Chawki

Full Text Available Non-AIDS-related malignancies now represent a frequent cause of death among HIV-infected patients. Albeit bladder cancer is one of the most common malignancies worldwide, it has been rarely reported among HIV-infected patients. We wished to assess the prevalence and characteristics of bladder cancer in HIV-infected patients.We conducted a single center retrospective study from 1998 to 2013 in a university hospital in Paris. Cases of bladder cancer among HIV-infected patients were identified using the electronic records of the hospital database and of the HIV-infected cohort. Patient characteristics and outcomes were retrieved from patients charts. A systematic review of published cases of bladder cancers in patients with HIV-infection was also performed.During the study period we identified 15 HIV-infected patients (0.2% of the cohort with a bladder cancer. Patients were mostly men (73% and smokers (67%, with a median age of 56 years at cancer diagnosis. Bladder cancer was diagnosed a median of 14 years after HIV-infection. Most patients were on ART (86% with median current and nadir CD4 cell counts of 506 and 195 cells/mm3, respectively. Haematuria (73% was the most frequent presenting symptom and HPV-associated lesions were seen in 6/10 (60% patients. Histopathology showed transitional cell carcinoma in 80% and a high proportion of tumors with muscle invasion (47% and high histologic grade (73%. One-year survival rate was 74.6%. The systematic review identified 13 additional cases of urothelial bladder cancers which shared similar features.Bladder cancers in HIV-infected patients remain rare but may occur in relatively young patients with a low nadir CD4 cell count, have aggressive pathological features and can be fatal.

Protoporphyrin IX induced by 5-aminolevulinic acid in bladder cancer cells in voided urine can be extracorporeally quantified using a spectrophotometer.

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Nakai, Yasushi; Anai, Satoshi; Onishi, Sayuri; Masaomi, Kuwada; Tatsumi, Yoshihiro; Miyake, Makito; Chihara, Yoshitomo; Tanaka, Nobumichi; Hirao, Yoshihiko; Fujimoto, Kiyohide

2015-06-01

We evaluated the feasibility of photodynamic diagnosis of bladder cancer by spectrophotometric analysis of voided urine samples after extracorporeal treatment with 5-aminolevulinic acid (ALA). Sixty-one patients with bladder cancer, confirmed histologically after the transurethral resection of a bladder tumor, were recruited as the bladder cancer group, and 50 outpatients without history of urothelial carcinoma or cancer-related findings were recruited as the control group. Half of the voided urine sample was incubated with ALA (ALA-treated sample), and the rest was incubated without treatment (ALA-untreated sample). For detecting cellular protoporphyrin IX levels, intensity of the samples at the excitation wavelength of 405 nm was measured using a spectrophotometer. The difference between the intensity of the ALA-treated and ALA-untreated samples at 635 nm was calculated. The differences in the bladder cancer group were significantly greater than those in the control group (p spectrophotometer in patients with bladder cancer. Therefore, this cancer detection system has a potential for clinical use. Copyright © 2015 Elsevier B.V. All rights reserved.

Characteristics of bladder neoplasms in the young population of Saudi Arabia

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Abdulrahman I Alabdulkareem

2017-01-01

Conclusions: Bladder malignancies at the early fourth decade of life tend to be a low stage and low grade. The most common histopathology was papillary urothelial carcinoma. Management should be based on the clinical and histopathological features. However, most of the patient underwent TURBT.

Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium.

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Yu, Weiqun; Hill, Warren G; Apodaca, Gerard; Zeidel, Mark L

2011-01-01

The urothelium is proposed to be a sensory tissue that responds to mechanical stress by undergoing dynamic membrane trafficking and neurotransmitter release; however, the molecular basis of this function is poorly understood. Transient receptor potential (TRP) channels are ideal candidates to fulfill such a role as they can sense changes in temperature, osmolarity, and mechanical stimuli, and several are reported to be expressed in the bladder epithelium. However, their complete expression profile is unknown and their cellular localization is largely undefined. We analyzed expression of all 33 TRP family members in mouse bladder and urothelium by RT-PCR and found 22 specifically expressed in the urothelium. Of the latter, 10 were chosen for closer investigation based on their known mechanosensory or membrane trafficking functions in other cell types. Western blots confirmed urothelial expression of TRPC1, TRPC4, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, TRPML1, and polycystins 1 and 2 (PKD1 and PKD2) proteins. We further defined the cellular and subcellular localization of all 10 TRP channels. TRPV2 and TRPM4 were prominently localized to the umbrella cell apical membrane, while TRPC4 and TRPV4 were identified on their abluminal surfaces. TRPC1, TRPM7, and TRPML1 were localized to the cytoplasm, while PKD1 and PKD2 were expressed on the apical and basolateral membranes of umbrella cells as well as in the cytoplasm. The cellular location of TRPV1 in the bladder has been debated, but colocalization with neuronal marker calcitonin gene-related peptide indicated clearly that it is present on afferent neurons that extend into the urothelium, but may not be expressed by the urothelium itself. These findings are consistent with the hypothesis that the urothelium acts as a sentinel and by expressing multiple TRP channels it is likely it can detect and presumably respond to a diversity of external stimuli and suggest that it plays an important role in urothelial signal

Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

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Brian P. Adley

2006-12-01

Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

Biological significance of TERT promoter mutation in papillary urothelial neoplasm of low malignant potential.

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Wang, Chung-Chieh; Huang, Chao-Yuan; Jhuang, Yu-Lin; Chen, Chih-Chi; Jeng, Yung-Ming

2018-04-01

Mutations in FGFR3 and the promoter region of the telomerase reverse transcriptase (TERT) gene have been found frequently in urothelial carcinoma of the urinary bladder. However, related data for papillary urothelial neoplasm of low malignant potential (PUNLMP) are limited. In this study, we investigated the mutation status of the TERT promoter, FGFR3 and HRAS in low-grade papillary urothelial neoplasms and evaluated their prognostic significance. The cases included in this study comprised 21 inverted papillomas, 30 PUNLMPs and 34 low-grade non-invasive papillary urothelial carcinomas (NIPUCs). TERT promoter mutations were observed in 10 (33%) PUNLMPs and 17 (50%) low-grade NIPUCs, but not in any inverted papilloma. FGFR3 mutations were observed more frequently in PUNLMP and low-grade NIPUC than in inverted papillomas (P = 0.009), whereas the opposite trend was noted for HRAS mutations (P low-grade NIPUC (P = 0.530). Notably, PUNLMP cases with TERT promoter mutations had a similar recurrence rate to that in low-grade NIPUC cases (P = 0.487). Our results suggest that the status of the TERT promoter mutation may serve as a biomarker of prognostic stratification in patients with PUNLMP. © 2017 John Wiley & Sons Ltd.

Expression levels of transcription factors c-Fos and c-Jun and transmembrane protein HAb18G/CD147 in urothelial carcinoma of the bladder.

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Huhe, Muren; Liu, Shuangshuang; Zhang, Yang; Zhang, Zheng; Chen, Zhinan

2017-05-01

The aim of the present study was to investigate the prognostic significance of the expression of transcription factors, c-Fos, c-Jun and transmembrane protein CD147, in urothelial carcinoma of the bladder (UCB). The current study investigated the clinical significance of these factors in the development, progression and survival analysis of UCB. Immunohistochemistry was employed to analyze c‑Fos, c‑Jun and CD147 expression in 41 UCB cases and 34 non‑cancerous human bladder tissues. These results were scored in a semi‑quantitative manner based on the intensity and percentage of tumor cells that presented immunoreactivity. Protein levels of CD147, c‑Fos and c‑Jun expression were upregulated in 22 (53.7%), 10 (24.4%) and 9 (22.0%) UCB cases, respectively. High levels of c‑Jun correlated with the AJCC cancer staging manual (7th edition; P=0.038). Univariate analysis revealed that upregulated CD147 (P=0.038) or c‑Jun (P=0.008) was associated with poor overall survival (OS), respectively. Further analysis revealed that either CD147‑c‑Fos‑c‑Jun co‑expression (P=0.004), or CD147‑c‑Jun co‑expression (P=0.037) and c‑Fos‑c‑Jun co‑expression (PCD147, c‑Jun or c‑Fos were independent risk indicators for death in UCB patients. Increased expression of c‑Jun or CD147, as well as co‑expression of CD147‑c‑Jun, c‑Jun‑c‑Fos or CD147‑c‑Jun‑c‑Fos has prognostic significance for UCB patients. Therefore, high CD147 and c‑Jun expression may serve roles in tumor progression and may be diagnostic and therapeutic targets in UCB whether alone or in combination.

Positive Correlation between Matrix Metalloproteinases and Epithelial-to-Mesenchymal Transition and its Association with Clinical Outcome in Bladder Cancer Patients.

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Singh, R; Mandhani, A; Agrawal, V; Garg, Minal

2018-01-18

Involvement of matrix metalloproteinases (MMPs) in the pathogenesis of urothelial carcinoma elects them to be sensitive marker for clinical and prognostic implications. MMPs regulate tumor growth and invasion by inducing epithelial-to-mesenchymal transition (EMT) which is characterized by the complex reprogramming of epithelial cells and ultimately bring about major changes in the structural organization of bladder urothelium. The present study has been undertaken to evaluate the clinical relevance of MMPs in two distinct types of bladder cancer disease. Expression analysis of MMPs namely MMP-2, MMP-7, MMP-9 and EMT markers including epithelial marker, E-cadherin; mesenchymal markers, N-cadherin and Vimentin; and EMT-activating transcriptional factors (EMT-ATFs), Snail, Slug, Twist and Zeb was done in 64 cases of bladder tumor tissues [{Non-muscle invasive bladder cancer (NMIBC): 35 cases} and {Muscle invasive bladder cancer (MIBC): 29 cases}] by real-time quantitative polymerase chain reaction (RT-qPCR). Immunohistochemistry (IHC) staining was done in matched bladder tumor tissues to evaluate the protein expression and localization of E-cadherin, N-cadherin, Vimentin, Snail, and Slug. Our data showed overexpression of MMP-2, MMP-7 and MMP-9 at transcriptome level in 32.8%, 25% and 37.5% bladder tumor cases respectively. These tumor tissues were examined for higher expression of mesenchymal markers (N-cadherin and Vimentin) at mRNA and protein level and exhibited statistical association with tumor stage and tumor grade (p = 0.02, p = 0.04, Mann-Whitney test). Significant statistical correlation in tumor tissues with overexpressed MMPs has also been observed between gain of transcriptional factors and weak expression of E-cadherin with tumor stage, grade, gender, presence of hematuria and smoking history of the patients. Gene expression patterns of EMT markers in bladder tumors with overexpressed MMPs and their significant association with clinical profile

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer.

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Buss, Julieti Huch; Begnini, Karine Rech; Bender, Camila Bonemann; Pohlmann, Adriana R; Guterres, Silvia S; Collares, Tiago; Seixas, Fabiana Kömmling

2017-01-01

Mycobacterium bovis bacillus Calmette-Guerin (BCG) remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1) controlling drug release for extended time frames, (2) combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3) reducing systemic side effects, (4) increasing bioavailability, (5) and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

Nano-BCG: A Promising Delivery System for Treatment of Human Bladder Cancer

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Julieti Huch Buss

2018-01-01

Full Text Available Mycobacterium bovis bacillus Calmette–Guerin (BCG remains at the forefront of immunotherapy for treating bladder cancer patients. However, the incidence of recurrence and progression to invasive cancer is commonly observed. There are no established effective intravesical therapies available for patients, whose tumors recur following BCG treatment, representing an important unmet clinical need. In addition, there are very limited options for patients who do not respond to or tolerate chemotherapy due to toxicities, resulting in poor overall treatment outcomes. Within this context, nanotechnology is an emergent and promising tool for: (1 controlling drug release for extended time frames, (2 combination therapies due to the ability to encapsulate multiple drugs simultaneously, (3 reducing systemic side effects, (4 increasing bioavailability, (5 and increasing the viability of various routes of administration. Moreover, bladder cancer is often characterized by high mutation rates and over expression of tumor antigens on the tumor cell surface. Therapeutic targeting of these biomolecules may be improved by nanotechnology strategies. In this mini-review, we discuss how nanotechnology can help overcome current obstacles in bladder cancer treatment, and how nanotechnology can facilitate combination chemotherapeutic and BCG immunotherapies for the treatment of non-muscle invasive urothelial bladder cancer.

Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy.

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Lane, Zhaoli; Epstein, Jonathan I

2008-01-01

Pseudocarcinomatous epithelial hyperplasia in the bladder is a little known phenomenon, recognized to be associated with prior irradiation and/or chemotherapy. Whether this process can occur outside of this setting has not been studied. We identified 8 of these cases mimicking invasive urothelial carcinoma from our consultation files from 07/04 to 07/06 with no prior history of radiation or chemotherapy. The mean age at diagnosis was 65 years (range, 42 to 81 y), with 5 of the 8 males. Seven patients had a potential etiology for these changes that could either have resulted in localized ischemia or injury to the urothelium. These included case 1: atrial fibrillation, hypertension, congestive heart failure, gastrointestinal bleeding, and coronary artery vascular disease; case 2: coronary angioplasty, atrial fibrillation, hyperlipidemia, and amputation of arm for ischemia; case 3: hypertension, uncontrolled diabetes, hyperlipidemia, and atrial fibrillation; case 4: underlying arteriovenous malformation of the bladder; cases 5 to 6: history of indwelling Foley catheter; and case 7: history of radical prostatectomy for prostate cancer but no radiation. One patient had no potential contributing factors. All 8 patients presented with gross hematuria. At cystoscopy, 7 patients had polypoid lesions with 1 appearing nonpolypoid. Histologically, all cases showed epithelial proliferation of urothelium with cells having prominent eosinophilic cytoplasm. This process that mimicked invasive cancer within the lamina propria was marked in 3 cases (38%). Moderate nuclear pleomorphism was seen in 6 cases (75%). Only 1 case revealed mitotic figures. Ulceration was seen in 1 case. All cases showed some degree of hemorrhage with hemosiderin deposition identified in 3 cases (38%). Fibrin deposition was present in 1 case within the stroma, 3 cases in the vessels, and 4 cases in both. Five cases show stromal fibrosis. Edema and vascular congestion were common features (90% and 100

Histiocytic sarcoma with bladder involvement: Case report and literature review.

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Fernández-Aceñero, Mª Jesús; Pérez Alonso, Pablo; Díaz Del Arco, Cristina

We report an unusual case of histiocytic sarcoma with bladder involvement. An 80 year-old man with a previous history of diffuse large B-cell malignant lymphoma presented with hematuria and back pain. Serial urine cytologies revealed no urothelial malignant cells, but cystoscopy showed a large intravesical mass. The patient underwent transurethral resection (TUR) of the tumor. The bladder TUR specimen showed a widely infiltrating epithelioid neoplasm, with intense immunohistochemical positivity for CD45 and histiocytic markers (CD68, lysozime and fascin). Histopathological diagnosis was histiocytic sarcoma. As the patient's condition was progressively deteriorating, only palliative care was indicated and he died one month after TUR. Although histiocytic sarcoma can often be widespread at the time of diagnosis, to our knowledge, this is the first report of a case presenting with urinary symptoms. Histiocytic sarcoma can mimic many other malignant lesions, and only immunohistochemistry can define the tumor cells, allowing correct therapy. We discuss the differential diagnosis and possible associations. Copyright © 2017 Sociedad Española de Anatomía Patológica. Publicado por Elsevier España, S.L.U. All rights reserved.

Imaging of transitional cell carcinomas of the urinary tracts

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Ozmen, M.

2012-01-01

Full text: Transitional cell carcinoma (TCC) is the most common urothelial neoplasm to involve the upper urinary tract and bladder. Prognosis significantly worsens with deeper invasion. The role of imaging is to detect the tiniest urothelial neoplasms while still potentially resectable and curable. In case of advance disease, imaging should identify the extent of disease. Intravenous or retrograde urography, ultrasonography, computed tomography or magnetic resonance imaging have been used for diagnosis of TCC. The diagnostic performances of these imaging modalities differ from each other. A recent review regarding imaging of TCC by Razavi et al states that the retrieved sensitivity/specificity for the detection of TCC of upper urinary tract for CT urography (CTU), MR urography, excretory urography, and retrograde urography were 96%/99%, 69%/97%, 80%/81%, and 96%/96%, respectively. For detecting bladder cancer, the retrieved sensitivity/specificity for CT cystography, MR cystography, and ultrasonography were 94%/98%, 91%/95%, and 78%/96%, respectively. They conclude that CT urography is the best imaging technique for confirming or excluding malignancy in the upper urinary tract, whereas CT cystography has the best diagnostic performance for diagnosing bladder cancer. While cystoscopy is still considered by most to be the gold-standard for evaluation of the urinary bladder, CTU is playing an increasing role in the detection of urinary bladder urothelial neoplasms. As with the upper urinary tract, bladder urothelial neoplasms typically present as a filling defect, a focal mass, or an area of abnormal focal wall thickening. Magnetic resonance imaging is superior for evaluation of the depth of tumour invasion into the bladder wall, but this knowledge may not ultimately affect treatment as feasibility for radical cystectomy depends on staging by a combination of clinical, histopathological and imaging findings. Radical cystectomy may include resection of adjacent organs

Primary signet cell adenocarcinoma of bladder

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Prateek Kinra

2017-01-01

Full Text Available Primary signet cell cancer of the urinary bladder is a relatively rare entity. Since there is no mucinous epithelium in the bladder, It is proposed that the tumor arises from metaplastic urothelium. Two thirds of the tumours are mucin secreting, in most of which the site of the deposition is either extracellular or intracellular displacing the nucleus to a peripheral crescent, giving the cells a signet ring appearance. The tumours are most often infiltrative and diffusely involving the majority of the bladder akin to its name sake in stomach. It is essential to distinguish this carcinoma from gastrointestinal metastases as different therapeutic strategies are often necessary.

TP53 modulating agent, CP-31398 enhances antitumor effects of ODC inhibitor in mouse model of urinary bladder transitional cell carcinoma.

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Madka, Venkateshwar; Mohammed, Altaf; Li, Qian; Zhang, Yuting; Kumar, Gaurav; Lightfoot, Stan; Wu, Xueru; Steele, Vernon; Kopelovich, Levy; Rao, Chinthalapally V

2015-01-01

Mutations of the tumor suppressor p53 and elevated levels of polyamines are known to play key roles in urothelial tumorigenesis. We investigated the inhibition of polyamines biosynthesis and the restoration of p53 signaling as a possible means of preventing muscle invasive urothelial tumors using DFMO, an ODC-inhibiting agent, and CP-31398 (CP), a p53 stabilizing agent. Transgenic UPII-SV40T male mice at 6weeks age (n=15/group) were fed control diet (AIN-76A) or experimental diets containing DFMO (1000 and 2000 ppm) or 150 ppm CP or both. At 40 weeks of age, all mice were euthanized and urinary bladders were evaluated to determine tumor weight and histopathology. Low-dose DFMO had a moderate significant inhibitory effect on tumor growth (38%, P0.05). CP at 150 ppm alone had a strong inhibitory effect on tumor growth by 80% (PCP (150 ppm) led to significant decrease in tumor weight (70%, PCP and DFMO appears to be a promising strategy for urothelial TCC prevention.

Squamous cell carcinoma in bladder extrophy

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Cabral-Ribeiro, J; Silva, C; Sousa, L; Pérez García, D; Ribeiro dos Santos, A

2005-01-01

Bladder extrophy is a rare congenital malformation that nowadays is surgically corrected in neonatal period. We present a case report of a 71-year-old male with a verrucous squamous cell carcinoma arising in a classical uncorrected form of bladder extrophy.

The association of ABO blood type with disease recurrence and mortality among patients with urothelial carcinoma of the bladder undergoing radical cystectomy.

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Gershman, Boris; Moreira, Daniel M; Tollefson, Matthew K; Frank, Igor; Cheville, John C; Thapa, Prabin; Tarrell, Robert F; Thompson, Robert Houston; Boorjian, Stephen A

2016-01-01

To evaluate the association of ABO blood type with clinicopathologic outcomes and mortality among patients with urothelial carcinoma of the bladder treated with radical cystectomy (RC). We identified 2,086 consecutive patients who underwent RC between 1980 and 2008. Postoperative recurrence-free survival (RFS) and cancer-specific survival (CSS) were estimated using the Kaplan Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to evaluate the association of ABO blood type with outcomes. A total of 913 (44%), 881 (42%), 216 (10%), and 76 (4%) patients had blood type O, A, B, and AB, respectively. Median postoperative follow-up among survivors was 11.0 years (interquartile range: 7.7-15.9y). Overall, 1,561 patients died, with 770 deaths attributable to bladder cancer. Non-O blood type was associated with significantly worse 5-year RFS (65% vs. 69%; P = 0.04) and/or CSS (64% vs. 70%; P = 0.02). In particular, among patients with≤pT2N0 disease, the 5-year RFS for those with non-O vs. O blood type was 75% vs. 82%, respectively (P = 0.002), whereas the 5-year CSS was 77% vs. 85%, respectively (P = 0.001). Moreover, on multivariable analysis, blood type A remained independently associated with an increased risk of cancer-specific mortality (hazard ratio = 1.22; P = 0.01). Non-O blood type, particularly blood type A, is associated with a significantly increased risk of death from bladder cancer among patients undergoing RC. If validated, the utility of a multimodal therapy approach, including perioperative chemotherapy, or more frequent postoperative surveillance in this cohort warrants further study. Copyright © 2016 Elsevier Inc. All rights reserved.

Bladder cancer: what’s new in 2017

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O. B. Karyakin

2018-01-01

Full Text Available Treatment of bladder cancer has been a complicated problem. Low survival for regional and metastatic disease remains. In recent years,  the efforts of doctors, biologists, diagnosticians were aimed at development of new technologies in these spheres and improvement of treatment results for this pathology. In this review, current views on diagnosis, the role of repeated surgical interventions in non-muscle-invasive bladder cancer, etc. are presented. Advances in molecular biology allowed to differentiate subtypes of urothelial bladder cancer. Importantly, the results of biomolecular studies allowed to identify different responses to drug treatment. Moreover, in some cases these results have a follow-up period of up to 3 years. Based on other data characterizing the tumor, the effectiveness of new drugs for treatment of regional, metastatic and post-cisplatin therapy bladder cancer was evaluated. These results allow to hope for increased life span and quality of life for patients with this severe disease.

Hypoxic exosomes facilitate bladder tumor growth and development through transferring long non-coding RNA-UCA1.

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Xue, Mei; Chen, Wei; Xiang, An; Wang, Ruiqi; Chen, He; Pan, Jingjing; Pang, Huan; An, Hongli; Wang, Xiang; Hou, Huilian; Li, Xu

2017-08-25

To overcome the hostile hypoxic microenvironment of solid tumors, tumor cells secrete a large number of non-coding RNA-containing exosomes that facilitate tumor development and metastasis. However, the precise mechanisms of tumor cell-derived exosomes during hypoxia are unknown. Here, we aim to clarify whether hypoxia affects tumor growth and progression by transferring long non-coding RNA-urothelial cancer-associated 1 (lncRNA-UCA1) enriched exosomes secreted from bladder cancer cells. We used bladder cancer 5637 cells with high expression of lncRNA-UCA1 as exosome-generating cells and bladder cancer UMUC2 cells with low expression of lncRNA-UCA1 as recipient cells. Exosomes derived from 5637 cells cultured under normoxic or hypoxic conditions were isolated and identified by transmission electron microscopy, nanoparticle tracking analysis and western blotting analysis. These exosomes were co-cultured with UMUC2 cells to evaluate cell proliferation, migration and invasion. We further investigated the roles of exosomal lncRNA-UCA1 derived from hypoxic 5637 cells by xenograft models. The availability of lncRNA-UCA1 in serum-derived exosomes as a biomarker for bladder cancer was also assessed. We found that hypoxic exosomes derived from 5637 cells promoted cell proliferation, migration and invasion, and hypoxic exosomal RNAs could be internalized by three bladder cancer cell lines. Importantly, lncRNA-UCA1 was secreted in hypoxic 5637 cell-derived exosomes. Compared with normoxic exosomes, hypoxic exosomes derived from 5637 cells showed the higher expression levels of lncRNA-UCA1. Moreover, Hypoxic exosomal lncRNA-UCA1 could promote tumor growth and progression though epithelial-mesenchymal transition, in vitro and in vivo. In addition, the expression levels of lncRNA-UCA1 in the human serum-derived exosomes of bladder cancer patients were higher than that in the healthy controls. Together, our results demonstrate that hypoxic bladder cancer cells remodel tumor

Molecular targets in urothelial cancer: detection, treatment, and animal models of bladder cancer

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Smolensky, Dmitriy; Rathore, Kusum; Cekanova, Maria

2016-01-01

Bladder cancer remains one of the most expensive cancers to treat in the United States due to the length of required treatment and degree of recurrence. In order to treat bladder cancer more effectively, targeted therapies are being investigated. In order to use targeted therapy in a patient, it is important to provide a genetic background of the patient. Recent advances in genome sequencing, as well as transcriptome analysis, have identified major pathway components altered in bladder cancer. The purpose of this review is to provide a broad background on bladder cancer, including its causes, diagnosis, stages, treatments, animal models, as well as signaling pathways in bladder cancer. The major focus is given to the PI3K/AKT pathway, p53/pRb signaling pathways, and the histone modification machinery. Because several promising immunological therapies are also emerging in the treatment of bladder cancer, focus is also given on general activation of the immune system for the treatment of bladder cancer. PMID:27784990

Reduced glucocorticoid receptor expression predicts bladder tumor recurrence and progression.

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Ishiguro, Hitoshi; Kawahara, Takashi; Zheng, Yichun; Netto, George J; Miyamoto, Hiroshi

2014-08-01

To assess the levels of glucocorticoid receptor (GR) expression in bladder tumors because the status and its prognostic value remain largely unknown. We immunohistochemically stained for GR in bladder tumor and matched non-neoplastic bladder tissue specimens. Overall, GR was positive in 129 (87%) of 149 urothelial tumors, which was significantly (P=.026) lower than in non-neoplastic urothelium (90 [96%] of 94). Forty-two (79%) of 53 low-grade tumors vs 45 (47%) of 96 high-grade carcinomas (Pcancer-specific survival of MI tumors (P=.067). Multivariate analysis identified low GR expression as a strong predictor for recurrence of NMI tumors (P=.034). GR expression was downregulated in bladder tumors compared with nonneoplastic bladder tumors and in high-grade/MI tumors compared with low-grade/NMI tumors. Decreased expression of GR, as an independent prognosticator, predicted recurrence of NMI tumors. These results support experimental evidence suggesting an inhibitory role of GR signals in bladder cancer outgrowth. Copyright© by the American Society for Clinical Pathology.

Immunohistochemical positive stained p53 protein in bladder transitional cell carcinoma

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Halimi Monireh

2009-04-01

Full Text Available Background: Molecular genetics and immunopathologic analysis of bladder cancer have shown some abnormalities in a number of genes and proteins that have been implicated in the development and progression of such tumors, mainly in the p53 pathway. Aims: To investigate the rate of positively stained p53 protein in patients with urothelial papillary carcinoma of the bladder (UCB by immunohistochemistry and its relationship with tumor grade, gender and age of the patients. Settings and Design: During the present cross-sectional study, 100 paraffin-embedded specimens of UCB, which were provided from biopsies of the bladder by transurethral access, were immunohistochemically stained and studied for p53 protein from May 2006 to May 2007 in our referral center pathology laboratory. Materials and Methods: First, 4 µm slices of paraffin sections were provided and then stained by the avidin-biotin peroxidase method. The rate of positively stained p53 protein (defined as positive nuclear staining in over 10% of the cells was assessed. This rate was also estimated and compared between grades, genders and age-related groups (< 70 years, ≥70 years. Statistical Analysis: The χ2 , Fisher′s exact test and Mann-Whitney U test were used for comparing. Results: The overall rate of positively stained specimens was 11% for nuclear p53 protein. This rate was significantly higher in females (10/29 vs. 1/71; P < 0.001; odds ratio [OR]: 0.23; 95% confidence interval [CI]: 4.43-306.08, patients with 70 or older than 70 years (8/42 vs. 3/58; P = 0.04; OR: 0.55; 95% CI: 1.07-17.39 and in high-grade tumors (10/58 vs. 1/42; P = 0.02; OR: 0.59; 95% CI: 0.01-0.95. Conclusions: The rate of positively stained p53 protein for UCB was lower in our population. This rate was also higher in females, patients with 70 or older than 70 years and high grade of UCB.

Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or bladder-preservation therapy for muscle-invasive bladder cancer.

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Cahn, David B; Handorf, Elizabeth A; Ghiraldi, Eric M; Ristau, Benjamin T; Geynisman, Daniel M; Churilla, Thomas M; Horwitz, Eric M; Sobczak, Mark L; Chen, David Y T; Viterbo, Rosalia; Greenberg, Richard E; Kutikov, Alexander; Uzzo, Robert G; Smaldone, Marc C

2017-11-15

The current study was performed to examine temporal trends and compare overall survival (OS) in patients undergoing radical cystectomy (RC) or bladder-preservation therapy (BPT) for muscle-invasive urothelial carcinoma of the bladder. The authors reviewed the National Cancer Data Base to identify patients with AJCC stage II to III urothelial carcinoma of the bladder from 2004 through 2013. Patients receiving BPT were stratified as having received any external-beam radiotherapy (any XRT), definitive XRT (50-80 grays), and definitive XRT with chemotherapy (CRT). Treatment trends and OS outcomes for the BPT and RC cohorts were evaluated using Cochran-Armitage tests, unadjusted Kaplan-Meier curves, adjusted Cox multivariate regression, and propensity score matching, using increasingly stringent selection criteria. A total of 32,300 patients met the inclusion criteria and were treated with RC (22,680 patients) or BPT (9620 patients). Of the patients treated with BPT, 26.4% (2540 patients) and 15.5% (1489 patients), respectively, were treated with definitive XRT and CRT. Improved OS was observed for RC in all groups. After adjustments with more rigorous statistical models controlling for confounders and with more restrictive BPT cohorts, the magnitude of the OS benefit became attenuated on multivariate (any XRT: hazard ratio [HR], 2.115 [95% confidence interval [95% CI], 2.045-2.188]; definitive XRT: HR, 1.870 [95% CI, 1.773-1.972]; and CRT: HR, 1.578 [95% CI, 1.474-1.691]) and propensity score (any XRT: HR, 2.008 [95% CI, 1.871-2.154]; definitive XRT: HR, 1.606 [95% CI, 1.453-1.776]; and CRT: HR, 1.406 [95% CI, 1.235-1.601]) analyses. In the National Cancer Data Base, receipt of BPT was associated with decreased OS compared with RC in patients with stage II to III urothelial carcinoma. Increasingly stringent definitions of BPT and more rigorous statistical methods adjusting for selection biases attenuated observed survival differences. Cancer 2017;123:4337-45. © 2017

Water avoidance stress induces frequency through cyclooxygenase-2 expression: a bladder rat model.

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Yamamoto, Keisuke; Takao, Tetsuya; Nakayama, Jiro; Kiuchi, Hiroshi; Okuda, Hidenobu; Fukuhara, Shinichiro; Yoshioka, Iwao; Matsuoka, Yasuhiro; Miyagawa, Yasushi; Tsujimura, Akira; Nonomura, Norio

2012-02-01

Water avoidance stress is a potent psychological stressor and it is associated with visceral hyperalgesia, which shows degeneration of the urothelial layer mimicking interstitial cystitis. Cyclooxygenase-2 inhibitors have been recognized to ameliorate frequency both in clinical and experimental settings. We investigated the voiding pattern and cyclooxygenase-2 expression in a rat bladder model of water avoidance stress. After being subjected to water avoidance stress or a sham procedure, rats underwent metabolic cage analysis and cystometrography. Real time reverse transcription polymerase chain reaction was carried out to examine cyclooxygenase-2 messenger ribonucleic acid in bladders of rats. Protein expression of cyclooxygenase-2 was analyzed with immunohistochemistry and western blotting. Furthermore, the effects of the cyclooxygenase-2 inhibitor, etodolac, were investigated by carrying out cystometrography, immunohistochemistry and western blotting. Metabolic cage analysis and cystometrography showed significantly shorter intervals and less volume of voiding in water avoidance stress rats. Significantly higher expression of cyclooxygenase-2 messenger ribonucleic acid was verified by reverse transcription polymerase chain reaction. Immunohistochemistry and western blotting showed significantly higher cyclooxygenase-2 protein levels in water avoidance stress bladders. Furthermore, immunohistochemistry showed high cyclooxygenase-2 expression exclusively in smooth muscle cells. All water avoidance stress-induced changes were reduced by cyclooxygenase-2 inhibitor pretreatment. Chronic stress might cause frequency through cyclooxygenase-2 gene upregulation in bladder smooth muscle cells. Further study of cyclooxygenase-2 in the water avoidance stress bladder might provide novel therapeutic modalities for interstitial cystitis. © 2011 The Japanese Urological Association.

Comparative Tissue Proteomics of Microdissected Specimens Reveals Novel Candidate Biomarkers of Bladder Cancer*

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Chen, Chien-Lun; Chung, Ting; Wu, Chih-Ching; Ng, Kwai-Fong; Yu, Jau-Song; Tsai, Cheng-Han; Chang, Yu-Sun; Liang, Ying; Tsui, Ke-Hung; Chen, Yi-Ting

2015-01-01

More than 380,000 new cases of bladder cancer are diagnosed worldwide, accounting for ∼150,200 deaths each year. To discover potential biomarkers of bladder cancer, we employed a strategy combining laser microdissection, isobaric tags for relative and absolute quantitation labeling, and liquid chromatography-tandem MS (LC-MS/MS) analysis to profile proteomic changes in fresh-frozen bladder tumor specimens. Cellular proteins from four pairs of surgically resected primary bladder cancer tumor and adjacent nontumorous tissue were extracted for use in two batches of isobaric tags for relative and absolute quantitation experiments, which identified a total of 3220 proteins. A DAVID (database for annotation, visualization and integrated discovery) analysis of dysregulated proteins revealed that the three top-ranking biological processes were extracellular matrix organization, extracellular structure organization, and oxidation-reduction. Biological processes including response to organic substances, response to metal ions, and response to inorganic substances were highlighted by up-expressed proteins in bladder cancer. Seven differentially expressed proteins were selected as potential bladder cancer biomarkers for further verification. Immunohistochemical analyses showed significantly elevated levels of three proteins—SLC3A2, STMN1, and TAGLN2—in tumor cells compared with noncancerous bladder epithelial cells, and suggested that TAGLN2 could be a useful tumor tissue marker for diagnosis (AUC = 0.999) and evaluating lymph node metastasis in bladder cancer patients. ELISA results revealed significantly increased urinary levels of both STMN1 and TAGLN2 in bladder cancer subgroups compared with control groups. In comparisons with age-matched hernia urine specimens, urinary TAGLN2 in bladder cancer samples showed the largest fold change (7.13-fold), with an area-under-the-curve value of 0.70 (p < 0.001, n = 205). Overall, TAGLN2 showed the most significant

Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer.

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Pandith, Arshad A; Shah, Zafar A; Siddiqi, Mushtaq A

2013-05-01

Bladder cancer is the second most common genitourinary tumor and constitutes a very heterogeneous disease. Molecular and pathologic studies suggest that low-grade noninvasive and high-grade invasive urothelial cell carcinoma (UCC) arise via distinct pathways. Low-grade noninvasive UCC represent the majority of tumors at presentation. A high proportion of patients with low-grade UCC develop recurrences but usually with no progression to invasive disease. At presentation, a majority of the bladder tumors (70%-80%) are low-grade noninvasive (pTa). Several genetic changes may occur in bladder cancer, but activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are the most common and most specific genetic abnormality in bladder cancer. Interestingly, these mutations are associated with bladder tumors of low stage and grade, which makes the FGFR3 mutation the first marker that can be used for diagnosis of noninvasive bladder tumors. Since the first report of FGFR3 involvement in bladder tumors, numerous studies have been conducted to understand its function and thereby confirm the oncogenic role of this receptor particularly in noninvasive groups. Efforts are on to exploit this receptor as a therapeutic target, which holds much promise in the treatment of bladder cancer, particularly low-grade noninvasive tumors. Further studies need to explore the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer. This review focuses on the role of FGFR3 in bladder tumors in the backdrop of various studies published. Copyright © 2013 Elsevier Inc. All rights reserved.

Role of fibronectin in intravesical BCG therapy for superficial bladder cancer.

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Ratliff, T L; Kavoussi, L R; Catalona, W J

1988-02-01

Intravesical bacillus Calmette-Guerin (BCG) has been demonstrated to be effective both for prophylaxis and treatment of superficial bladder cancer. In order to identify the progression of events that result in BCG-mediated antitumor activity, studies were performed to evaluate the mechanism of binding of BCG within the bladder. Histological and quantitative studies in a mouse model revealed that BCG attached to the bladder wall only in areas of urothelial damage. Preliminary in vitro data showed that BCG attached to surfaces coated with extracellular matrix proteins. Further studies were then performed using purified extracellular matrix proteins to identify the proteins responsible for attachment. BCG were observed to attach to surfaces coated only with purified fibronectin (FN) but not to other purified proteins including laminin, collagen or fibrinogen. The attachment of BCG to purified FN in vitro was dose dependent and was inhibited by anti-FN antibodies. Moreover, BCG attachment in vivo to bladders with damaged urothelial surfaces was inhibited more than 95% by anti-FN antibodies, but binding was not affected by anti-laminin antibodies or preimmune serum. A survey of commercially available BCG vaccines (Pasteur, Tice, Glaxo, Connaught) showed that only Glaxo BCG did not attach to FN-coated surfaces. Glaxo BCG also was shown to express inferior antitumor activity suggesting that the absence of FN binding by Glaxo may have been associated with the absence of antitumor activity of the vaccine.

Characterization of Uptake and Internalization of Exosomes by Bladder Cancer Cells

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Carrie A. Franzen

2014-01-01

Full Text Available Bladder tumors represent a special therapeutic challenge as they have a high recurrence rate requiring repeated interventions and may progress to invasive or metastatic disease. Exosomes carry proteins implicated in bladder cancer progression and have been implicated in bladder cancer cell survival. Here, we characterized exosome uptake and internalization by human bladder cancer cells using Amnis ImageStreamX, an image cytometer. Exosomes were isolated by ultracentrifugation from bladder cancer culture conditioned supernatant, labeled with PKH-26, and analyzed on the ImageStreamX with an internal standard added to determine concentration. Exosomes were cocultured with bladder cancer cells and analyzed for internalization. Using the IDEAS software, we determined exosome uptake based on the number of PKH-26+ spots and overall PKH-26 fluorescence intensity. Using unlabeled beads of a known concentration and size, we were able to determine concentrations of exosomes isolated from bladder cancer cells. We measured exosome uptake by recipient bladder cancer cells, and we demonstrated that uptake is dose and time dependent. Finally, we found that uptake is active and specific, which can be partially blocked by heparin treatment. The characterization of cellular uptake and internalization by bladder cancer cells may shed light on the role of exosomes on bladder cancer recurrence and progression.

Glucocorticoid receptor beta increases migration of human bladder cancer cells.

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McBeth, Lucien; Nwaneri, Assumpta C; Grabnar, Maria; Demeter, Jonathan; Nestor-Kalinoski, Andrea; Hinds, Terry D

2016-05-10

Bladder cancer is observed worldwide having been associated with a host of environmental and lifestyle risk factors. Recent investigations on anti-inflammatory glucocorticoid signaling point to a pathway that may impact bladder cancer. Here we show an inverse effect on the glucocorticoid receptor (GR) isoform signaling that may lead to bladder cancer. We found similar GRα expression levels in the transitional uroepithelial cancer cell lines T24 and UMUC-3. However, the T24 cells showed a significant (p bladder cancer cells. Therefore, GRβ may have a significant role in bladder cancer, and possibly serve as a therapeutic target for the disease.

Diuron-induced rat urinary bladder carcinogenesis: mode of action and human relevance evaluations using the International Programme on Chemical Safety framework.

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Da Rocha, Mitscheli Sanches; Arnold, Lora L; De Oliveira, Maria Luiza Cotrim Sartor; Catalano, Shadia M Ihlaseh; Cardoso, Ana Paula Ferragut; Pontes, Merielen G N; Ferrucio, Bianca; Dodmane, Puttappa R; Cohen, Samuel M; De Camargo, João Lauro V

2014-05-01

Diuron, a high volume substituted urea herbicide, induced high incidences of urinary bladder carcinomas and low incidences of kidney pelvis papillomas and carcinomas in rats exposed to high doses (2500 ppm) in a 2-year bioassay. Diuron is registered for both occupational and residential uses and is used worldwide for more than 30 different crops. The proposed rat urothelial mode of action (MOA) for this herbicide consists of metabolic activation to metabolites that are excreted and concentrated in the urine, leading to cytotoxicity, urothelial cell necrosis and exfoliation, regenerative hyperplasia, and eventually tumors. We show evidence for this MOA for diuron using the International Programme on Chemical Safety (IPCS) conceptual framework for evaluating an MOA for chemical carcinogens, and the United States Environmental Protection Agency (USEPA) and IPCS framework for assessing human relevance.

Potential Therapeutic Roles of Tanshinone IIA in Human Bladder Cancer Cells

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Sheng-Chun Chiu

2014-09-01

Full Text Available Tanshinone IIA (Tan-IIA, one of the major lipophilic components isolated from the root of Salviae Miltiorrhizae, has been found to exhibit anticancer activity in various cancer cells. We have demonstrated that Tan-IIA induces apoptosis in several human cancer cells through caspase- and mitochondria-dependent pathways. Here we explored the anticancer effect of Tan-IIA in human bladder cancer cell lines. Our results showed that Tan-IIA caused bladder cancer cell death in a time- and dose-dependent manner. Tan-IIA induced apoptosis through the mitochondria-dependent pathway in these bladder cancer cells. Tan-IIA also suppressed the migration of bladder cancer cells as revealed by the wound healing and transwell assays. Finally, combination therapy of Tan-IIA with a lower dose of cisplatin successfully killed bladder cancer cells, suggesting that Tan-IIA can serve as a potential anti-cancer agent in bladder cancer.

Prognostic significance of atypical papillary urothelial hyperplasia.

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Swierczynski, Sharon L; Epstein, Jonathan I

2002-05-01

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia. We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis

Metastatic Gastric Linitis Plastica from Bladder Cancer Mimicking a Primary Gastric Carcinoma: a Case Report

International Nuclear Information System (INIS)

Hong, Won Sun; Chung, Dong Jin; Lee, Jae Mun; Byun, Jae Ho; Hahn, Seong Tae

2009-01-01

Primary gastric carcinoma is the most common cause of linitis plastica. Less frequently, metastatic gastric cancer from the breast, omental metastases and non-Hodgkin lymphoma involving the stomach have been reported to show similar radiographic findings as for linitis plastica. A metastatic gastric cancer from bladder cancer is extremely rare. We present an unusual case, the first to our knowledge, of gastric linitis plastica that resulted from a metastatic urothelial carcinoma of the bladder

Enzalutamide inhibits androgen receptor-positive bladder cancer cell growth.

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Kawahara, Takashi; Ide, Hiroki; Kashiwagi, Eiji; El-Shishtawy, Kareem A; Li, Yi; Reis, Leonardo O; Zheng, Yichun; Miyamoto, Hiroshi

2016-10-01

Emerging preclinical evidence suggests that androgen-mediated androgen receptor (AR) signals promote bladder cancer progression. However, little is known about the efficacy of an AR signaling inhibitor, enzalutamide, in the growth of bladder cancer cells. In this study, we compared the effects of enzalutamide and 2 other classic antiandrogens, flutamide and bicalutamide, on androgen-induced bladder cancer cell proliferation, migration, and invasion as well as tumor growth in vivo. Thiazolyl blue cell viability assay, flow cytometry, scratch wound-healing assay, transwell invasion assay, real-time polymerase chain reaction, and reporter gene assay were performed in AR-positive (e.g., UMUC3, TCCSUP, and 647V-AR) and AR-negative (e.g., UMUC3-AR-short hairpin RNA [shRNA], TCCSUP-AR-shRNA, 647V) bladder cancer lines treated with dihydrotestosterone and each AR antagonist. We also used a mouse xenograft model for bladder cancer. Dihydrotestosterone increased bladder cancer cell proliferation, migration, and invasion indicating that endogenous or exogenous AR was functional. Enzalutamide, hydroxyflutamide, and bicalutamide showed similar inhibitory effects, without significant agonist activity, on androgen-mediated cell viability/apoptosis, cell migration, and cell invasion in AR-positive lines. No significant effects of dihydrotestosterone as well as AR antagonists on the growth of AR-negative cells were seen. Correspondingly, in UMUC3 cells, these AR antagonists down-regulated androgen-induced expression of AR, matrix metalloproteinase-2, and interleukin-6. Androgen-enhanced AR-mediated transcriptional activity was also blocked by each AR antagonist exhibiting insignificant agonist activity. In UMUC3 xenograft-bearing mice, oral gavage treatment with each antiandrogen retarded tumor growth, and only enzalutamide demonstrated a statistically significant suppression compared with mock treatment. Our current data support recent observations indicating the involvement of

Nephrogenic adenoma of the bladder in a prune belly syndrome patient: case report and review of the literature.

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Broecker, Justine S; Steelman, Charlotte K; Broecker, Bruce H; Shehata, Bahig M

2011-01-01

Nephrogenic adenoma (NA) is a rare lesion of the urinary tract widely considered to be a metaplastic response to urothelial injury. Herein, we present the case of an 8-year-old male with prune belly syndrome who presented with gross hematuria. Investigation revealed a bladder mass; however, upon cystoscopic examination, multiple polypoid lesions were identified. Microscopic examination revealed NA of the bladder. To our knowledge, this is the second reported case of NA of the bladder in association with prune belly syndrome.

The evolution of bladder cancer genomics: What have we learned and how can we use it?

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Audenet, François; Attalla, Kyrollis; Sfakianos, John P

2018-03-21

With advancements in molecular biology techniques, great progress has been made in the understanding of urothelial carcinoma pathogenesis. To examine the historic description of molecular alterations in bladder cancer and their evolution towards our current comprehension of the biology of the disease. Historically, a two-pathway model was described from histological and cytogenetic studies: low-grade papillary non-muscle invasive bladder cancers (NMIBC) were described to arise from epithelial hyperplasia with loss of chromosome 9 as an early event, whereas muscle-invasive bladder cancers (MIBC) were considered to develop from dysplasia, associated with genetic instability. Although there could be connections between the 2 pathways, NMIBC and MIBC were largely believed to develop secondary to different molecular alterations. Next-generation sequencing has allowed important insights into cancer biology and a better understanding of the pathways involved in bladder cancer pathogenesis and heterogeneity. Urothelial carcinoma has been found to have a high frequency of somatic mutations compared to other solid tumors, including several mutations in multiple signaling pathways, such as cell cycle regulators (TP53, RB1), RTK/RAS/RAF pathway, PI3K/AKT/mTOR pathway and TERT gene promoter. Epigenetic changes and mutations in chromatin remodeling genes are especially frequent in bladder cancer. Mutations in FGFR3 and KDM6A are more common in NMIBC than in MIBC, whereas mutations in TP53 and KMT2D are more common in MIBC, suggesting the previously hypothesized 2 different pathways, with a subset of tumors progressing from NMIBC to MIBC. Using comprehensive RNA expression profiling studies, at least 5 subtypes of bladder cancer have been identified, the most fundamental division being Basal/Squamous-like and Luminal. These subtypes have different prognoses, natural histories and responses to systemic treatments: Luminal subtypes are enriched with papillary histology and have a

Frequency of CD4+CD25+Foxp3+ cells in peripheral blood in relation to urinary bladder cancer malignancy indicators before and after surgical removal.

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Jóźwicki, Wojciech; Brożyna, Anna A; Siekiera, Jerzy; Slominski, Andrzej T

2016-03-08

Tumor cells communicate with stromal cells, including cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), to form microenvironment inhibiting immune responses. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) stimulate immune tolerance and facilitate tumor progression. We analyzed the changes in Treg frequencies assessed using flow cytometry in the peripheral blood of patients with urothelial bladder cancer before and after tumor-removal. Changes in Treg frequency were investigated in relation to clinicopathomorphological indicators of tumor malignancy and expression of RCAS1 on CAFs and TAMs. Higher Treg frequencies were observed in early phase of tumor growth (pTa-pT2), in larger tumors, with more aggressive type of invasion, and with expression of RCAS1. The later phase of tumor development, accompanied by a nonclassic differentiations and pT3-pT4 advancement, had lower number of tumor infiltrating lymphocytes (TILs) and lower Treg frequency. Furthermore, in pT2-pT4 tumors, a decreased post-surgery Treg frequency was associated with poorer prognosis: patients with the lowest frequency of Tregs died first. These findings strongly suggest that the Treg frequencies at later phase of tumor growth, associated with a low anti-tumor response, represent a new and important prognostic indicator in urinary bladder cancer.

Effects of co-administration of dietary sodium arsenite and an NADPH oxidase inhibitor on the rat bladder epithelium

International Nuclear Information System (INIS)

Suzuki, Shugo; Arnold, Lora L.; Pennington, Karen L.; Kakiuchi-Kiyota, Satoko; Cohen, Samuel M.

2009-01-01

Arsenite (As III ), an inorganic arsenical, is a known human carcinogen, inducing tumors of the skin, urinary bladder and lung. It is metabolized to organic methylated arsenicals. Oxidative stress has been suggested as a mechanism for arsenic-induced carcinogenesis. Reactive oxygen species (ROS) can be important factors for carcinogenesis and tumor progression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is known to produce intracellular ROS, therefore, we investigated the ability of apocynin (acetovanillone), an NADPH oxidase inhibitor, to inhibit the cytotoxicity and regenerative cell proliferation of arsenic in vitro and in vivo. Apocynin had similar effects in reducing the cytotoxicity of As III and dimethylarsinous acid (DMA III ) in rat urothelial cells in vitro. When tested at the same concentrations as apocynin, other antioxidants, such as L-ascorbate and N-acetylcysteine, did not inhibit As III -induced cytotoxicity but they were more effective at inhibiting DMA III -induced cytotoxicity compared with apocynin. In vivo, female rats were treated for 3 weeks with 100 ppm As III . Immunohistochemical staining for 8-hydroxy-2'-deoxyguanosine (8-OHdG) showed that apocynin reduced oxidative stress partially induced by As III treatment on rat urothelium, and significantly reduced the cytotoxicity of superficial cells detected by scanning electron microscopy (SEM). However, based on the incidence of simple hyperplasia and the bromodeoxyuridine (BrdU) labeling index, apocynin did not inhibit As III -induced urothelial cell proliferation. These data suggest that the NADPH oxidase inhibitor, apocynin, may have the ability to partially inhibit arsenic-induced oxidative stress and cytotoxicity of the rat bladder epithelium in vitro and in vivo. However, apocynin did not inhibit the regenerative cell proliferation induced by arsenite in a short-term study.

Crude mortality and loss of life expectancy of patients diagnosed with urothelial carcinoma of the urinary bladder in Norway.

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Andreassen, Bettina K; Myklebust, Tor Å; Haug, Erik S

2017-02-01

Reports from cancer registries often lack clinically relevant information, which would be useful in estimating the prognosis of individual patients with urothelial carcinoma of the urinary bladder (UCB). This article presents estimates of crude probabilities of death due to UCB and the expected loss of lifetime stratified for patient characteristics. In Norway, 10,332 patients were diagnosed with UCB between 2001 and 2010. The crude probabilities of death due to UCB were estimated, stratified by gender, age and T stage, using flexible parametric survival models. Based on these models, the loss in expectation of lifetime due to UCB was also estimated for the different strata. There is large variation in the estimated crude probabilities of death due to UCB (from 0.03 to 0.76 within 10 years since diagnosis) depending on age, gender and T stage. Furthermore, the expected loss of life expectancy is more than a decade for younger patients with muscle-invasive UCB and between a few months and 5 years for nonmuscle-invasive UCB. The suggested framework leads to clinically relevant prognostic risk estimates for individual patients diagnosed with UCB and the consequence in terms of loss of lifetime expectation. The published probability tables can be used in clinical praxis for risk communication.

Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression

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Byler Timothy K

2012-08-01

Full Text Available Abstract Background Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium. We speculated that inhibition of angiogenesis by valproate might be mediated by this anti-angiogenic protein. Methods Bladder cancer cell lines UMUC3 and T24 were treated with valproate or another histone deacetylase inhibitor, vorinostat, in culture for a period of three days. Proliferation was assessed by alamar blue reduction. Gene expression was evaluated by reverse transcription of RNA and quantitative PCR. Results Proliferation assays showed treatment with valproate or vorinostat decreased proliferation in both cell lines. Histone deacetylase inhibition also increased relative expression of thrombospondin-1 up to 8 fold at 5 mM valproate. Conclusions Histone deacetylase inhibitors warrant further study for the prevention or treatment of bladder cancer.

Effect of sirolimus on urinary bladder cancer T24 cell line

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Oliveira Paula A

2009-01-01

Full Text Available Abstract Background Sirolimus is recently reported to have antitumour effects on a large variety of cancers. The present study was performed to investigate sirolimus's ability to inhibit growth in T24 bladder cancer cells. Methods T24 bladder cancer cells were treated with various concentrations of sirolimus. MTT assay was used to evaluate the proliferation inhibitory effect on T24 cell line. The viability of T24 cell line was determined by Trypan blue exclusion analysis. Results Sirolimus inhibits the growth of bladder carcinoma cells and decreases their viability. Significant correlations were found between cell proliferation and sirolimus concentration (r = 0.830; p Conclusion Sirolimus has an anti-proliferation effect on the T24 bladder carcinoma cell line. The information from our results is useful for a better understanding sirolimus's anti-proliferative activity in the T24 bladder cancer cell line.

Telomerase Activity, Cytokeratin 20 and Cytokeratin 19 in Urine Cells of Bladder Cancer Patients

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Morsi, M.I.; Youssef, A.I.; El-Sedafi, A.S.; Ghazal, A.A.; Zaher, E.R.; Hassouna, M.E.

2006-01-01

Aim of the Study: This work aims to search for markers suitable for the screening of bladder cancer, which should be specific, sensitive, reproducible, non-invasive and at acceptable cost. Patients and Methods: The study included 50 patients diagnosed as bladder cancer (35 TCC, 15 SCC) of different stages and grades, 30 patients with various urothelial diseases, besides 20 apparently healthy subjects of matched age and sex to the malignant group. A random midstream urine sample was collected in a sterile container for the determination of telomerase by RT-PCR, keratin 19 by ELSA CYFRA 21-1 IRMA kit, keratin 20 by RT-PCR and immunohistochemical staining, and urine cytology. Results: For all parameters (telomerase, K19, K20 and cytology) the malignant group was significantly different from both the benign and the control groups. None of the four studied parameters was correlated to the stage of the disease, and when it comes to grade, only KI9 showed a significant positive correlation with grade both in TCC and SCe. When ROC curves for all parameters were compared, K 19 had the largest area under the curve, and then comes K20 . o Conclusion: K 19 may be used as a biological marker for the diagnosis of bladder cancer. K 19 could not be used for differential diagnosis of different types of bladder cancer, meanwhile it could be a marker for differentiation that decreases in less differentiated tumors. As a tumor marker, K20 reflects inability to differentiate tumor type or grade in TCC, while in SCC of the bladder it is correlated with the grade. As a method, RT-PCR is superior to immunostaining for the detection of bladder cancer, meanwhile K20 immunohistochemistry ([HC) results were much better than urine cytology as a bladder cancer screening test. haematuria and inflammation reduced the specificity of telomerase assay, which reduced its validity as a tumor marker of bladder cancer. K 19 and K20 are the best candidates as screening tests for the diagnosis of bladder

CT in the diagnosis of squamous cell carcinoma of urinary bladder

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Narumi, Yoshifumi; Mitani, Takashi; Kuriyama, Keiko

1988-01-01

CT findings of 8 operated cases with squamous cell carcinoma of urinary bladder were reviewed. All of them had advanced stage tumor with invasion into perivesical fat or organs (≥ T3b), and with or without lymphnode involvement. We compared them with 15 operated cases with advavced transitional cell carcinoma of urinary bladder (≥ T3b) especially in regard to the direction of tumor growth, and the frequency of invasion into perivesical organs and lymphnode involvement. Futhermore, we studied a relation between CT findings and histopathological stages of the squamous cell carcinoma of urinary bladder. Squamous cell carcinoma of urinary bladder showed predominant extravesical growth as the stage advanced, while transitional cell carcinoma generally showed predominant intravesical growth. Squamous cell carcinoma invaded into perivesical organs and metastasized to lymphnodes more frequently than transitional cell carcinoma of control group. Accuracy of CT staging of squamous cell carcinoma of urinary bladder was found to be 100 % in T stage and 75 % in N stage. (author)

Vitamins C and K3 sensitize human urothelial tumors to gemcitabine.

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Kassouf, Wassim; Highshaw, Ralph; Nelkin, Gina M; Dinney, Colin P; Kamat, Ashish M

2006-10-01

We evaluated the antitumor effects of vitamins C and K3 for human urothelial carcinoma and the potential use of the combination of vitamins C plus K3 as a sensitizing agent for conventional chemotherapy for urothelial carcinoma. The antiproliferative and apoptotic effects of vitamin C alone, vitamin K3 alone, vitamins C plus K3, gemcitabine alone and gemcitabine plus vitamins C plus K3 were assessed in vitro by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, propidium iodide staining and flow cytometry. For in vivo studies we implanted UMUC-14 tumorigenic urothelial carcinoma cells into the subcutis of nude mice. One week later we treated 10 mice each with saline (control), vitamins C plus K3, gemcitabine or gemcitabine plus vitamins C plus K3. Treatment was continued for 4 weeks, followed by necropsy. Tumor volume was measured and tumor kinetics were established. Apoptosis and proliferation were evaluated in tumor sections using immunohistochemistry and TUNEL assay. Vitamins C plus K3 induced cytostasis and caused apoptosis to a greater degree than either vitamin alone (p Vitamins C plus K3 also substantially augmented the effects of gemcitabine in vitro. There were 32.3% apoptosis with gemcitabine plus vitamins C plus K3, 5.3% with gemcitabine alone and 15.8% with vitamins C plus K3 alone (p vitamins C plus K3 compared with that in the control or for either agent alone. Mean tumor weight and growth rate in the gemcitabine plus vitamins C plus K3 group (237 mg and 11.3 mm3 daily) were decreased compared with those in the control (530 mg and 34.3 mm3 daily), and those for vitamins C plus K3 alone (490 mg and 25.2 mm3 daily) and gemcitabine alone (400 mg and 21.3 mm3 daily) (p Vitamins C and K3 have significant antiproliferative and apoptotic effects when used in combination. This combination enhances the efficacy of gemcitabine against bladder cancer in vivo.

Clinico-pathological pattern, classification and staging of urinary bladder carcinomas - a five years experience at a tertiary care hospital in central punjab

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Naeem, A.

2015-01-01

In Pakistan, urinary bladder carcinoma is the 8th commonest malignancy while being the fourth commonest cancer in men. The relative occurrence of a particular histological type of bladder carcinoma depends on the clinical setting. Both grade and stage of these cancers are highly correlated with recurrence, progression and patient survival rates. Methods: This cross-sectional study comprised of 122 patients with newly diagnosed operable primary bladder carcinomas who underwent cystoscopy associated transurethral resection of bladder tumour at the Urology Department of Punjab Employees Social Security Hospital, Lahore. All participants completed a detailed questionnaire and underwent an in-depth interview to obtain data. The surgical specimens were referred to the Pathology department. Gross observations of the tumour recorded. Result: A total of 114 cases, classified according to WHO/ISUP criteria, low-grade papillary lesions, comprising Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) and Papillary Low Grade carcinomas, accounted for 43% of tumours. Male to female ratio being 5.3:1 (74%). Lateral walls were involved in 44%, posterior wall in 25.3%, trigone in 10.7%, bladder neck in 7.2%, dome in 5.8%, ureteric orifice in 4.13%, anterior wall in 2% and left ureter in 0.87% cases. Tumour staging revealed an overall 11.5% of tumours with stage Ta and 31.5% with stage T3-4. About 29% tumours were non invasive. About n=13 of low-grade carcinomas and n=68 of high-grade carcinomas were invasive. For tumours classified by WHO/ISUP criteria, the percentage of women was larger for PUNLMP than for the other categories of urothelial tumours (p-value 0.006); no statistically significant difference was found by age or gender with respect to tumour stage (p-value 0.138 and 0.452). Conclusion: Transitional Cell Carcinoma (TCC) is the commonest among middle aged men. (author)

Deep Sequencing of Urinary RNAs for Bladder Cancer Molecular Diagnostics.

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Sin, Mandy L Y; Mach, Kathleen E; Sinha, Rahul; Wu, Fan; Trivedi, Dharati R; Altobelli, Emanuela; Jensen, Kristin C; Sahoo, Debashis; Lu, Ying; Liao, Joseph C

2017-07-15

Purpose: The majority of bladder cancer patients present with localized disease and are managed by transurethral resection. However, the high rate of recurrence necessitates lifetime cystoscopic surveillance. Developing a sensitive and specific urine-based test would significantly improve bladder cancer screening, detection, and surveillance. Experimental Design: RNA-seq was used for biomarker discovery to directly assess the gene expression profile of exfoliated urothelial cells in urine derived from bladder cancer patients ( n = 13) and controls ( n = 10). Eight bladder cancer specific and 3 reference genes identified by RNA-seq were quantitated by qPCR in a training cohort of 102 urine samples. A diagnostic model based on the training cohort was constructed using multiple logistic regression. The model was further validated in an independent cohort of 101 urines. Results: A total of 418 genes were found to be differentially expressed between bladder cancer and controls. Validation of a subset of these genes was used to construct an equation for computing a probability of bladder cancer score (P BC ) based on expression of three markers ( ROBO1, WNT5A , and CDC42BPB ). Setting P BC = 0.45 as the cutoff for a positive test, urine testing using the three-marker panel had overall 88% sensitivity and 92% specificity in the training cohort. The accuracy of the three-marker panel in the independent validation cohort yielded an AUC of 0.87 and overall 83% sensitivity and 89% specificity. Conclusions: Urine-based molecular diagnostics using this three-marker signature could provide a valuable adjunct to cystoscopy and may lead to a reduction of unnecessary procedures for bladder cancer diagnosis. Clin Cancer Res; 23(14); 3700-10. ©2017 AACR . ©2017 American Association for Cancer Research.

Horseradish extract promotes urinary bladder carcinogenesis when administered to F344 rats in drinking water.

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Cho, Young-Man; Hasumura, Mai; Imai, Toshio; Takami, Shigeaki; Nishikawa, Akiyoshi; Ogawa, Kumiko

2017-07-01

Horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate and other isothiocyanates, has been used as a food additive. To evaluate the potential hazards of HRE, a 104-week chronic study, a 2-week analysis of cell proliferation in the urinary bladder and a medium-term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. In the 104-week chronic study with 32 male rats per group, no treatment-related increases in the incidences of neoplastic lesions in any organ, including urinary bladder, were observed, except for simple hyperplasia in the urinary bladder in rats treated with HRE at concentrations of more than 0.01% (5.0 mg kg -1 body weight day -1 ). In the promotion study, HRE treatment after N-butyl-N-(4-hydroxybutyl)nitrosamine initiation caused a clear increase in papillary or nodular hyperplasia, papilloma, and urothelial carcinoma of the urinary bladder in the groups given HRE for 13 weeks at doses higher than 0.005%, 0.01%, and 0.04% (2.7, 5.4 and 20.5 mg kg -1 body weight day -1 ), respectively. In the 2-week cell proliferation analysis, treatment with HRE at concentrations greater than 0.005% (3.9 mg kg -1 body weight day -1 ) caused transient increases in 5-bromo-2'-deoxyuridine labeling indices in the urothelium. Although clear tumor induction was not observed, administration of relatively low-dose HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis. Further studies are needed to elucidate the mode of action of HRE in the rat urinary bladder to facilitate data extrapolation from the present study and provide insights into risk assessment. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Discussion on the influence of HER2 status on the clinical outcome of bladder cancer continues

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Lammers, R.; Witjes, J.A.

2011-01-01

Evaluation of: Bolenz C, Shariat SF, Karakiewicz PI et al. Human epidermal growth factor receptor 2 expression status provides independent prognostic information in patients with urothelial carcinoma of the urinary bladder. BJUI 106, 1216-1222 (2010). The article under evaluation by Bolenz et al.

Overactive bladder – 18 years – Part II

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Jose Carlos Truzzi

2016-04-01

Full Text Available ABSTRACT Traditionally, the treatment of overactive bladder syndrome has been based on the use of oral medications with the purpose of reestablishing the detrusor stability. The recent better understanding of the urothelial physiology fostered conceptual changes, and the oral anticholinergics – pillars of the overactive bladder pharmacotherapy – started to be not only recognized for their properties of inhibiting the detrusor contractile activity, but also their action on the bladder afference, and therefore, on the reduction of the symptoms that constitute the syndrome. Beta-adrenergic agonists, which were recently added to the list of drugs for the treatment of overactive bladder, still wait for a definitive positioning – as either a second-line therapy or an adjuvant to oral anticholinergics. Conservative treatment failure, whether due to unsatisfactory results or the presence of adverse side effects, define it as refractory overactive bladder. In this context, the intravesical injection of botulinum toxin type A emerged as an effective option for the existing gap between the primary measures and more complex procedures such as bladder augmentation. Sacral neuromodulation, described three decades ago, had its indication reinforced in this overactive bladder era. Likewise, the electric stimulation of the tibial nerve is now a minimally invasive alternative to treat those with refractory overactive bladder. The results of the systematic literature review on the oral pharmacological treatment and the treatment of refractory overactive bladder gave rise to this second part of the review article Overactive Bladder – 18 years, prepared during the 1st Latin-American Consultation on Overactive Bladder.

Companied P16 genetic and protein status together providing useful information on the clinical outcome of urinary bladder cancer.

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Pu, Xiaohong; Zhu, Liya; Fu, Yao; Fan, Zhiwen; Zheng, Jinyu; Zhang, Biao; Yang, Jun; Guan, Wenyan; Wu, Hongyan; Ye, Qing; Huang, Qing

2018-04-01

SPEC P16/CEN3/7/17 Probe fluorescence-in-situ-hybridization (FISH) has become the most sensitive method in indentifying the urothelial tumors and loss of P16 has often been identified in low-grade urothelial lesions; however, little is known about the significations of other P16 genetic status (normal and amplification) in bladder cancer.We detected P16 gene status by FISH in 259 urine samples and divided these samples into 3 groups: 1, normal P16; 2, loss of P16; and 3, amplified P16. Meanwhile, p16 protein expression was measured by immunocytochemistry and we characterized the clinicopathologic features of cases with P16 gene status.Loss of P16 occurred in 26.2%, P16 amplification occurred in 41.3% and P16 gene normal occurred in 32.4% of all cases. P16 genetic status was significantly associated with tumor grade and primary tumor status (P = .008 and .017), but not with pathological tumor stage, overall survival, and p16 protein expression. However, P16 gene amplification accompanied protein high-expression has shorter overall survival compared with the overall patients (P = .023), and P16 gene loss accompanied loss of protein also had the tendency to predict bad prognosis (P = .067).Studies show that the genetic status of P16 has a close relation with the stages of bladder cancer. Loss of P16 is associated with low-grade urothelial malignancy while amplified P16 donotes high-grade. Neither P16 gene status nor p16 protein expression alone is an independent predictor of urothelial bladder carcinoma, but combine gene and protein status together providing useful information on the clinical outcome of these patients.

Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells

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Lin JF

2017-05-01

cisplatin toward BC cells. These results indicated that cisplatin induced protective autophagy which may contribute to the development of cisplatin resistance and resulted in treatment failure. Mechanistically, upregulation of beclin-1 (BECN1 was detected in cisplatin-treated cells, and knockdown of BECN1 using shRNA attenuated cisplatin-induced autophagy and subsequently enhanced cisplatin-induced apoptosis.Conclusion: Collectively, the study results indicated that cisplatin-induced autophagy is mediated by BECN1 in BC cells. Therefore, combinative treatment using cisplatin and autophagy inhibitors could potentially overcome cisplatin resistance related to autophagy induction. Keywords: autophagy inhibition, autophagy related genes, apoptosis, cisplatin resistance, human urinary bladder urothelial carcinoma, lentiviral-based shRNA

The Contrasting Role of the Mediator Subunit MED30 in the Progression of Bladder Cancer.

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Syring, Isabella; Weiten, Richard; Müller, Tim; Schmidt, Doris; Steiner, Susanne; Kristiansen, Glen; Müller, Stefan C; Ellinger, Jörg

2017-12-01

The Mediator complex is a key regulator of gene transcription, and several studies have demonstrated altered expression of particular subunits in diverse human diseases, especially cancer. To date, nothing is known about the role of MED30 in bladder cancer. We, therefore, performed an RNA expression and survival analysis of the subunit MED30 in 537 samples of bladder cancer by using the database cBioPortal. To validate these data on the protein level, we practiced immunohistochemical staining against MED30 on a tissue microarray containing 210 samples of all tumour stages and performed survival analyses. For functional analysis, the siRNA-mediated knockdown of MED30 was performed in the cell lines T24 and TCCSUP followed by proliferation, migration, and invasion assays. On the mRNA and protein levels, higher expression of MED30 is associated with better patient survival. In accordance with this, advanced T- and N-stages showed lower expression of MED30. In contrast, knockdown of MED30 led to reduction of the tumour parameters proliferation, migration, and invasion in the BCa cell lines. MED30 appears to be integrated in the progression of the urothelial tumour in the bladder. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Neoadjuvant and adjuvant chemotherapy for locally advanced bladder carcinoma. Development of novel bladder preservation approach, Osaka Medical College regimen

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Azuma, Haruhito; Inamoto, Teruo; Takahara, Kiyoshi; Ibuki, Naokazu; Nomi, Hayahito; Yamamoto, Kazuhiro; Narumi, Yoshihumi; Ubai, Takanobu

2012-01-01

Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of ''combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects (''Osaka Medical College regimen'' referred to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21-814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review. (author)

Evaluation of viability and proliferative activity of human urothelial cells cultured onto xenogenic tissue-engineered extracellular matrices.

LENUS (Irish Health Repository)

Davis, Niall F

2011-04-01

To evaluate the viability and proliferative activity of human urothelial cells (HUCs) cultured on tissue-engineered extracellular matrix scaffolds and to assess the potential of extracellular matrixes to support the growth of HUCs in their expected in vivo urine environment.

CXCL5 is a potential diagnostic and prognostic marker for bladder cancer patients.

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Zhu, Xi; Qiao, Yan; Liu, Weihua; Wang, Wenying; Shen, Hongliang; Lu, Yi; Hao, Gangyue; Zheng, Jiajia; Tian, Ye

2016-04-01

Chemokine C-X-C motif ligand 5 (CXCL5) is critical for bladder cancer growth and progression. Our previous study demonstrated that increase of CXCL5 in bladder cancer cell lines had an effect on tumor growth and progression. This study aims to investigate the expression of CXCL5 in tissue and urine of bladder cancer patients, in relation to clinicopathologic parameters, and as a predictive value in diagnosing and evaluating bladder cancer. Urothelial bladder cancer tissues from 255 patients were profiled for CXCL5 alterations by immunohistochemistry. Urine samples collected from patients with bladder cancer and urinary tract infections as well as healthy volunteers were analyzed by ELISA. High expression of CXCL5 in bladder cancer tissue was correlated with TNM stage (P = 0.012), cancer grade (P = 0.001), and lymph node metastasis (P = 0.007). CXCL5 alterations were associated with overall survival (P = 0.007), progression free survival (P = 0.004), and recurrence free survival in muscle invasive bladder cancers (P = 0.026). CXCL5 expression in the urine of bladder cancer patients was significantly different from urinary tract infection patients (P = 0.001) and healthy volunteers. However, urine leukocytes may predict CXCL5 levels (β = 0.56, P bladder cancer TNM stage (P = 0.039), lymph node metastasis (P = 0.023), tumor size (P = 0.007), and tumor grade (P = 0.005). The sensitivity and specificity for CXCL5/creatinine in predicting bladder cancer were 80.4 and 61.3 %, respectively. These results suggest increased CXCL5 expression in cancer tissue predicts poor survival in bladder cancer patients. CXCL5 expression in urine is useful in a minimally invasive modality for bladder cancer diagnosis. However, urine leukocytes are significant predictors of CXCL5 levels and may affect its result in bladder cancer diagnosis.

Characterization of the early proliferative response of the rodent bladder to subtotal cystectomy: a unique model of mammalian organ regeneration.

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Charles C Peyton

Full Text Available Subtotal cystectomy (STC; surgical removal of ∼75% of the rat urinary bladder elicits a robust proliferative response resulting in complete structural and functional bladder regeneration within 8-weeks. The goal of these studies was to characterize the early cellular response that mediates this regenerative phenomenon, which is unique among mammalian organ systems. STC was performed on eighteen 12-week-old female Fischer F344 rats. At 1, 3, 5 and 7-days post-STC, the bladder was harvested 2-hours after intraperitoneal injection of bromodeoxyuridine (BrdU. Fluorescent BrdU labeling was quantified in cells within the urothelium, lamina propria (LP, muscularis propria (MP and serosa. Cell location was confirmed with fluorescently co-labeled cytokeratin, vimentin or smooth muscle actin (SMA, to identify urothelial, interstitial and smooth muscle cells, respectively. Expression of sonic hedgehog (Shh, Gli-1 and bone morphogenic factor-4 (BMP-4 were evaluated with immunochemistry. Three non-operated rats injected with BrdU served as controls. Less than 1% of cells in the bladder wall were labeled with BrdU in control bladders, but this percentage significantly increased by 5-8-fold at all time points post-STC. The spatiotemporal characteristics of the proliferative response were defined by a significantly higher percentage of BrdU-labeled cells within the urothelium at 1-day than in the MP and LP. A time-dependent shift at 3 and 5-days post-STC revealed significantly fewer BrdU-labeled cells in the MP than LP or urothelium. By 7-days the percentage of BrdU-labeled cells was similar among urothelium, LP and MP. STC also caused an increase in immunostaining for Shh, Gli-1 and BMP-4. In summary, the early stages of functional bladder regeneration are characterized by time-dependent changes in the location of the proliferating cell population, and expression of several evolutionarily conserved developmental signaling proteins. This report extends

Adjuvant chemotherapy for locally advanced urothelial carcinoma: an overview of the USC experience.

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Dorff, Tanya B; Tsao-Wei, Denice; Miranda, Gus; Skinner, Donald G; Stein, John P; Quinn, David I

2009-02-01

To describe the tolerability of two chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for adjuvant treatment of patients with locally advanced urothelial cancer after radical cystectomy. The USC Department of Urology bladder cancer database was searched for subjects who received adjuvant chemotherapy following cystectomy for transitional cell carcinoma with extravesical and/or lymph node involvement, yielding 187 cases. Clinical details regarding toxicity, number of cycles administered, and cancer outcome were analyzed. The majority of subjects had lymph node involvement (70%). Sixty-eight percent of subjects received MVAC and 32% received GC, the latter regimen was predominant after 2000. Fifty-six percent of subjects received all four planned cycles (51% GC and 58% MVAC). With a median follow-up of 11.2 years (range 1.9-19.6), 96 patients (51%) have suffered a relapse, with no significant difference between chemotherapy regimens. Median time to recurrence for the population was 3.7 years and median overall survival is 4.6 years (3.0-9.3). The median time from recurrence to death was 6.7 months and was not significantly different between MVAC and GC. Both MVAC and GC are tolerated after cystectomy for advanced urothelial carcinoma. A significant proportion of high-risk patients survive, free of disease, beyond 10 years. At recurrence, patients previously treated with adjuvant chemotherapy have a survival that appears much shorter than patients who develop metastases in the absence of this exposure, suggesting resistance to salvage chemotherapy.

Delayed Ureterectomy after Incomplete Nephroureterectomy for Upper Tract Urothelial Carcinoma: Pathologic Findings and Outcomes

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E. Jason Abel

2013-12-01

Full Text Available Objectives To evaluate the pathologic findings and outcomes after distal ureterectomy for a retained ureteral segment following incomplete nephroureterectomy for urothelial carcinoma of the renal pelvis or ureter. Materials and Methods After IRB approval, an institutional database identified patients who underwent distal ureterectomy for a retained ureteral segment after assumed complete nephroureterectomy for urothelial carcinoma of the upper ureter or renal pelvis. Clinical and pathologic variables were analyzed. Results From January 1993 to July 2007, 12 patients were identified with median age at the time of ureterectomy of 60.5 years (41-85 years. Initial approach to surgery was open in 9 patients and laparoscopic in 3 patients. The median time from nephroureterectomy to distal ureterectomy was 23.5 months (range 2-66. At the time of initial surgery, pathologic stage was Ta, T1, T2, and T3 in 3,4,1, and 4 patients respectively. Initial pathology was urothelial carcinoma; grade 2 in 6 patients and grade 3 in six patients. Pathology from the subsequent surgery demonstrated urothelial carcinoma in the retained ureteral segment in 8 patients, dysplasia or atypia in 3 patients, and 1 patient with chronic inflammation. Local recurrence in 2 patients was present in a segment of ureter discontinuous with the bladder after laparoscopic nephroureterectomy. Three patients (25%, all with initial grade 3 renal pelvis lesions, developed metastatic disease. Conclusions Tumor recurrence in a retained ureteral segment after incomplete nephroureterectomy is a significant problem and may contribute to intravesical recurrence or metastatic disease. Complete, en bloc resection is imperative to minimize these risks.

Pathologic Response Rates of Gemcitabine/Cisplatin versus Methotrexate/Vinblastine/Adriamycin/Cisplatin Neoadjuvant Chemotherapy for Muscle Invasive Urothelial Bladder Cancer

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Franklin C. Lee

2013-01-01

Full Text Available Objectives. To compare pathologic outcomes after treatment with gemcitabine and cisplatin (GC versus methotrexate, vinblastine, adriamycin, and cisplatin (MVAC in the neoadjuvant setting. Methods. Data was retrospectively collected on 178 patients with T2-T4 bladder cancer who underwent radical cystectomy between 2003 and 2011. Outcomes of interest included those with complete response (pT0 and any response (≤pT1. Odds ratios were calculated using multivariate logistic regression. Results. Compared to those who did not receive neoadjuvant chemotherapy, there were more patients with complete response (28% versus 9%, OR 3.11 (95% CI: 1.45–6.64, P=0.03 and any response (52% versus 25%, OR 3.23 (95% CI: 1.21–8.64, P=0.01. Seventy-two patients received GC (n=41 or MVAC (n=31. CR was achieved in 29% and 22% of GC and MVAC patients, respectively (multivariate OR 0.39, 95% CI 0.10–1.58. Any response (≤pT1 was achieved in 56% of GC and 45% of MVAC patients (multivariate OR 0.45, 95% CI 0.12–1.71. Conclusions. We observed similar pathologic response rates for GC and MVAC neoadjuvant chemotherapy in this cohort of patients with muscle invasive urothelial cancer (MIBC. Our findings support the use of GC as an alternative regimen in the neoadjuvant setting.

Quantitative Analysis of Differential Proteome Expression in Bladder Cancer vs. Normal Bladder Cells Using SILAC Method.

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Ganglong Yang

Full Text Available The best way to increase patient survival rate is to identify patients who are likely to progress to muscle-invasive or metastatic disease upfront and treat them more aggressively. The human cell lines HCV29 (normal bladder epithelia, KK47 (low grade nonmuscle invasive bladder cancer, NMIBC, and YTS1 (metastatic bladder cancer have been widely used in studies of molecular mechanisms and cell signaling during bladder cancer (BC progression. However, little attention has been paid to global quantitative proteome analysis of these three cell lines. We labeled HCV29, KK47, and YTS1 cells by the SILAC method using three stable isotopes each of arginine and lysine. Labeled proteins were analyzed by 2D ultrahigh-resolution liquid chromatography LTQ Orbitrap mass spectrometry. Among 3721 unique identified and annotated proteins in KK47 and YTS1 cells, 36 were significantly upregulated and 74 were significantly downregulated with >95% confidence. Differential expression of these proteins was confirmed by western blotting, quantitative RT-PCR, and cell staining with specific antibodies. Gene ontology (GO term and pathway analysis indicated that the differentially regulated proteins were involved in DNA replication and molecular transport, cell growth and proliferation, cellular movement, immune cell trafficking, and cell death and survival. These proteins and the advanced proteome techniques described here will be useful for further elucidation of molecular mechanisms in BC and other types of cancer.

[Transitional tumours of urinary bladder (author's transl)].

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Laumonier, R

1979-01-01

An overall survey of the transitional epithelium of the bladder and its carcinomas. This study is based upon the recent literature, in particular the considerable contribution of scanner electron microscopy. a) The transitional epithelium has the reputation of having a simple structure and even behaviour. In fact, it is complex with highly specialised surface cells. It has marked powers of regeneration after aggressions of various types. b) Tumours of the transitional epithelium are defined in relation to rupture of the basal lamina. Invasive carcinomas are classified according to their histological stage of penetration, their pure or partially metaplasic type and their degree defined according to the criteria of Broders. There exists a correlation between these three types of evaluation. Non-invasive carcinomas are either papillary--putting into question the reality of benign bladder papilloma--or flat mucosal and then often associated closely or at a distance with an invasive carcinoma. c) Abnormal regeneration, dysplasia or hyperplasia as a result of aggressions of different types or developing in isolation represent a high risk histologically, implying the need for careful follow-up and surveillance. d) Histopathological study of urothelial or transitional tumours is simple in operative specimens but difficult in biopsies. It requires close cooperation between surgeons and pathologists to ensure correct orientation of the fragments.

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial

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Crabb, Simon; Caddy, Joshua; Dunkley, Denise; Rajaram, Jessica; Ellis, Deborah; Hill, Stephanie; Whitehead, Amy; Huddart, Robert; Griffiths, Gareth; Kalevras, Michail

2018-01-01

Background: urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder...

Anti-PD-L1/TGFβR2 (M7824) fusion protein induces immunogenic modulation of human urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis.

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Grenga, Italia; Donahue, Renee N; Gargulak, Morgan L; Lepone, Lauren M; Roselli, Mario; Bilusic, Marijo; Schlom, Jeffrey

2018-03-01

Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and urothelial carcinoma. M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGFβ) receptor 2, which functions as a TGFβ "trap." Advanced urothelial tumors have been shown to express TGFβ, which possesses immunosuppressive properties that promote cancer progression and metastasis. The rationale for a combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and immune cell infiltrate and simultaneously reduce or eliminate TGFβ from the tumor microenvironment. In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines. Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1 (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL, antigen-specific cytotoxic T lymphocytes and natural killer cells. M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-L1. However, compared to anti-PD-L1, M7824 increases (A) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B) TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8 + T-cell-mediated lysis of tumor cells. These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune-mediated lysis. Compared to anti-PD-L1 or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune

Prostanoid-dependent bladder pain caused by proteinase-activated receptor-2 activation in mice: Involvement of TRPV1 and T-type Ca2+ channels

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Maho Tsubota

2018-01-01

Full Text Available We studied the pronociceptive role of proteinase-activated receptor-2 (PAR2 in mouse bladder. In female mice, intravesical infusion of the PAR2-activating peptide, SLIGRL-amide (SL, caused delayed mechanical hypersensitivity in the lower abdomen, namely ‘referred hyperalgesia’, 6–24 h after the administration. The PAR2-triggered referred hyperalgesia was prevented by indomethacin or a selective TRPV1 blocker, and restored by a T-type Ca2+ channel blocker. In human urothelial T24 cells, SL caused delayed prostaglandin E2 production and COX-2 upregulation. Our data suggest that luminal PAR2 stimulation in the bladder causes prostanoid-dependent referred hyperalgesia in mice, which involves the activation of TRPV1 and T-type Ca2+ channels.

Pulsating electromagnetic field stimulation of urothelial cells induces apoptosis and diminishes necrosis: new insight to magnetic therapy in urology.

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Juszczak, K; Kaszuba-Zwoinska, J; Thor, P J

2012-08-01

The evidence of electromagnetic therapy (EMT) efficacy in stress and/or urge urinary incontinence, as well as in detrusor overactivity is generally lacking in the literature. The potential EMT action of neuromuscular tissue depolarization has been described. Because there is no data on the influence of pulsating electromagnetic fields (PEMF) on the urothelium, we evaluated the effect of PEMF stimulation on rat urothelial cultured cells (RUCC). In our study 15 Wistar rats were used for RUCC preparation. RUCC were exposed to PEMF (50 Hz, 45±5 mT) three times for 4 hours each with 24-hour intervals. The unexposed RUCC was in the same incubator, but in a distance of 35 cm from the PEMF generator. Annexin V-APC (AnV+) labelled was used to determine the percentage of apoptotic cells and propidium iodide (PI+), as standard flow cytometric viability probe to distinguish necrotic cells from viable ones. The results are presented in percentage values. The flow cytometric analysis was carried out on a FACS calibur flow cytometer using Cell-Quest software. In PEMF-unstimulated RUCC, the percentage of AnV+, PI+, and AnV+PI+ positive cells were 1.24±0.34%, 11.03±1.55%, and 12.43±1.96%, respectively. The percentages of AnV+, PI+, and AnV+PI+ positive cells obtained after PEMF stimulation were 1.45±0.16% (p=0.027), 7.03±1.76% (p<0.001), and 9.48±3.40% (p=0.003), respectively. The PEMF stimulation of RUCC induces apoptosis (increase of AnV+ cells) and inhibits necrosis (decrease of PI+ cells) of urothelial cells. This leads us to the conclusion that a low-frequency pulsating electromagnetic field stimulation induces apoptosis and diminishes necrosis of rat urothelial cells in culture.

Evaluation of the depth of infiltration of urothelial carcinoma in the vesical wall obtained by transurethral intravesical echotomography

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Milošević Radovan

2007-01-01

Full Text Available Background/Aim. Transitional cell carcinoma (TCC is the most frequent tumor of the bladder and represents 95−98% of blader neoplasams and 2−3% of all carcinomas in the body. In urogenital oncology more frequent is only prostatic cancer. Evaluation of the depth of infiltration of urothelial carcinoma in the vesical wall represents the clinical base in treatment planning and prognosis. Clinical investigation and convential radiological procedures have a low level of accuracy in estimating the local growth of the tumor. The aims of our investigation were to determine the depth of infiltration of urothelial carcinoma in the vesical wall in the investigated group of patients by transurethral intravesical echotomography (TIE and computerised tomography (CT scan and to compare results obtained by both methods with pathohistological (PH results, and, based on the difference of the results determine which method was more accurate in the evaluation of the depth of infiltration of urothelial carcinoma in the vesical wall. Methods. Thirty patients with TCC of the bladder both genders, aged 51−81 years were involved in our investigation. In all of these patients, radical cystectomy (RC was performed. This was neccessary to provide the defintive PH result. Transurethral intravesical echotomography was performed by ultrasound scanner type 1846 Bruel and Kjaer, sond type 1850, and the CT scan was perfomed by Pace plus, General Electric, U.S.A. The specimen for the definitive PH result obtained by RC includes all standards of the TNM classification. Results. Using CT scan, the most frequent was T1 stage (17 patients or 56.68%. Using TIE, the most frequent was T2 stage (22 patients or 73.33%. After RC the most frequent was T2 stage (21 patients or 70%. The Kolmogorov-Smirnov test, showed a high significant difference between the results obtained using CT and definitive PH results after RC. The same test showed no statistically significant difference between

PDT-induced apoptosis in bladder carcinoma cells

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Bachor, Ruediger; Reich, Ella D.; Kleinschmidt, Klaus; Repassy, Denes; Hautmann, Richard E.

1999-02-01

Photodynamic therapy (PDT) is a highly efficient inducer of apoptosis in EY-28 bladder carcinoma cells, resulting in extensive DNA fragmentation. Bladder carcinoma cells EY-28 (Tumorbank Heidelberg, Germany) were incubated for 1 h with 1 (mu) g AamTPPn/ml or 2 (mu) g AamTPPn/ml. After incubation cells were refed with complete medium and irradiated with 0.75 J/cm2. To identify apoptotic cells, a in situ cell death detection kit POD (Boehringer Mannheim, Germany) was used. The chromatin condensation characteristic to apoptotic cells was detected by transmission electron microscopy. Using 1 (mu) g AamTPPn/ml and 2 (mu) g AamTPPn/ml (9-Acetamido-2,7,12,17- tetra-n-Porpylporphycene), respectively, and irradiation at 0.75 J/cm2, a percentage of 36.9% and 54.7%, respectively, of apoptotic cells was detected.

Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis

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F. Aura Kullmann

2018-04-01

Full Text Available Interstitial cystitis/bladder pain syndrome (IC/BPS is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunn’s nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons, in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a “sensory network” and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans

Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γ Agonists

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Martin B. Oleksiewicz

2008-01-01

Full Text Available Despite clinical promise, dual-acting activators of PPARα and γ (here termed PPARα+γ agonists have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARα is invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγ can in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARα as well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γ agonists may be caused by receptor-mediated effects (exaggerated pharmacology. Based on previously published mode of action data for the PPARα+γ agonist ragaglitazar, and the available literature about the role of PPARα and γ in rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γ agonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

Expression of selected pathway-marker genes in human urothelial cells exposed chronically to a non-cytotoxic concentration of monomethylarsonous acid

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Matthew Medeiros

2014-01-01

Full Text Available Bladder cancer has been associated with chronic arsenic exposure. Monomethylarsonous acid [MMA(III] is a metabolite of inorganic arsenic and has been shown to transform an immortalized urothelial cell line (UROtsa at concentrations 20-fold less than arsenite. MMA(III was used as a model arsenical to examine the mechanisms of arsenical-induced transformation of urothelium. A previous microarray analysis revealed only minor changes in gene expression at 1 and 2 months of chronic exposure to MMA(III, contrasting with substantial changes observed at 3 months of exposure. To address the lack of information between 2 and 3 months of exposure (the critical period of transformation, the expression of select pathway marker genes was measured by PCR array analysis on a weekly basis. Cell proliferation rate, anchorage-independent growth, and tumorigenicity in SCID mice were also assessed to determine the early, persistent phenotypic changes and their association with the changes in expression of these selected marker genes. A very similar pattern of alterations in these genes was observed when compared to the microarray results, and suggested that early perturbations in cell signaling cascades, immunological pathways, cytokine expression, and MAPK pathway are particularly important in driving malignant transformation. These results showed a strong association between the acquired phenotypic changes that occurred as early as 1–2 months of chronic MMA(III exposure, and the observed gene expression pattern that is indicative of the earliest stages in carcinogenesis.

Tumor, serum and urine carcinoembryonic antigen (CEA) in upper urinary tract urothelial cancer

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Stefanovic, V.; Ignjatovic, M.

1987-01-01

The aim of this investigation was to study the possible diagnostic value of a CEA test in cancer of the renal pelvis and ureter. Thirty-eight patients with upper urinary tract cancer, 15 patients with transitional cell carcinoma of the bladder, 6 kidney carcinoma patients and 25 healthy adults were studied. CEA was determined in tumor tissue, serum and urine, by using a monoclonal radioimmunoassay. Increased serum CEA level was found in 7 out of 27 patients (26%) with active cancer of the renal pelvis and ureter. None of 11 patients with inactive cancer had an increased serum CEA level. No significant correlation was found between the serum CEA level and the histological grading. The tumor CEA content varied markedly, from values obtainted in normal urothelium up to 840 ng/g wet weight. CEA content of tumor tissue did not correlate with the serum level. Our data suggest that serum and urine CEA have not diagnostic accuracy for clinical diagnosis of upper tract urothelial cancer. (orig.) [de

Expression of MDM2 mRNA, MDM2, P53 and P16 Proteins in Urothelial Lesions in the View of the WHO 4th Edition Guidelines as A Molecular Insight towards Personalized Medicine

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Olfat Hammam

2017-08-01

Full Text Available AIM: Here we imposed a multimarker molecular panel composed of P53, MDM2 protein & mRNA & P16 with the identification of sensitive and specific cut offs among the Egyptian urothelial carcinomas bilharzial or not emphasize the pathological and molecular classifications, pathways and prognosis as a privilege for adjuvant therapy. METHODS: Three hundred and ten urothelial lesions were pathologically evaluated and grouped as follows: 50 chronic cystitis as benign, 240 urothelial carcinomas and 20 normal bladder tissue as a control. Immunohistochemistry for MDM Protein, P16 & p53 and In Situ Hybridization for MDM2mRNA were done. RESULTS: MDM2mRNA overexpression correlated with low grade low stage non invasive tumors, while P53 > 40% & p16 40% & P16 10% from high grade, high stage invasive urothelial carcinomas (with p53 > 40, p16 40 & p16 < 10%, together with the histopathological features can distinguish in situ urothelial lesions from dysplastic and atypical lesions.

HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

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Angeline S Andrew

Full Text Available Bladder cancer is the 4(th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62. This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63. The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25 than females (OR 1.56 95%CI 0.83-2.95, (SNP-gender interaction P = 0.048. We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003. The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

Gamma-Klotho exhibits multiple roles in tumor growth of human bladder cancer.

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Hori, Shunta; Miyake, Makito; Tatsumi, Yoshihiro; Morizawa, Yosuke; Nakai, Yasushi; Onishi, Sayuri; Onishi, Kenta; Iida, Kota; Gotoh, Daisuke; Tanaka, Nobumichi; Fujimoto, Kiyohide

2018-04-13

Alpha-Klotho (KLα) and beta-Klotho (KLβ) have recently been reported to correlate with cancer prognosis in some malignancies and we previously reported the association between KLα, KLβ, and urothelial carcinoma of the bladder (UCB), indicating that KLβ acts as a tumor promoter. However, the association between gamma-Klotho (KLγ) and cancer prognosis remains unclear. In the present study, we evaluated the association between KLγ and UCB. To evaluate the effect of KLγ on human bladder cancer cell lines in vitro assays were performed. Exogenous KLγ increased the ability of human bladder cancer cells to proliferate, migrate, invade, form colonies, and provide anchorage-independent growth potential. In in vivo assays, eighteen mice bearing xenografts inoculated using UM-UC-3, were randomly divided into three groups and treated with a small interfering RNA (siRNA) by intratumoral administration once a week for four weeks. Knockdown of KLγ with siRNA led to a dramatic change in tumor growth and suggested that KLγ had effects on tumor growth, including promotion of cell proliferation, inhibition of apoptosis, and enhancement of the epithelial-mesenchymal transition. To confirm the study, human tissue samples were used and patients were divided into two groups according to KLγ expression level. High expression of KLγ was significantly associated with higher stage and grade cancer and the presence of lymphovascular invasion compared to patients with lower expression of KLγ. Our results suggest that KLγ plays an important role in tumor invasion and progression and these results may lead to the development of new therapies and diagnostic methods for UCB.

Polymeric film of 6-arm-poly(ethylene glycol) amine graphene oxide with poly (ε-caprolactone): Adherence and growth of adipose derived mesenchymal stromal cells culture on rat bladder

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Durán, Marcela; Durán, Nelson; Luzo, Angela C. M.; Duarte, Adriana S. S.; Volpe, Bruno B.; Ceragioli, Helder J.; Andrade, Patricia F.; De Souza, Joel G.; Fávaro, Wagner J.

2017-06-01

Nanotechnology has been more present in different fields related to health. The need to find a durable material, of easy use, and which does not interfere significantly in the growth and differentiation of stem cells for the construction of a scaffold for use in urologic surgery, with the purpose of reducing infections, regeneration times and even graft rejection during reconstitution in patients with urethral stricture was conducted a broad survey of information about this and came to the consensus of this project: using graphene oxide, a widely studied nanomaterials which has been presenting numerous beneficial results when in contact with the adipose-derived stem cells. Advanced techniques for the growth, differentiation and proliferation of adipose-derived stem cells were used, as well as the characterization of graphene oxide sheets. For this study, it was prepared the graphene oxide/6 ARM-Poly (ethylene glycol) amine films with poly (ε-caprolactone). The graphene suspension in organic solvent was prepared by using an ultrasonicator bath and subsequently, the film was formed by solvent evaporation. Total characterization of graphene oxide/6 ARM-PEG-amine/ poly (ε-caprolactone) film was carried out. It was tested growth and adhesion of adipose-derived stem cells on the film, as well as, were verified the histopathological effects of this scaffold when implanted in the urinary bladder to repair the lesion. Our results demonstrated that this scaffold with adipose-derived stem cells enhanced the repair in rat urinary bladder defect model, resulting in a regular bladder. Improved organized muscle bundles and urothelial layer were observed in animals treated with this scaffold with adipose-derived stem cells compared with those treated only suture thread or scaffold. Thus, our biomaterial could be suitable for tissue engineered urinary tract reconstruction.

Polymeric film of 6-arm-poly(ethylene glycol) amine graphene oxide with poly (ε-caprolactone): Adherence and growth of adipose derived mesenchymal stromal cells culture on rat bladder

International Nuclear Information System (INIS)

Durán, Marcela; Durán, Nelson; Fávaro, Wagner J.; Luzo, Angela C.M.; Duarte, Adriana S. S.; Volpe, Bruno B.; Ceragioli, Helder J.; Andrade, Patricia F.; De Souza, Joel G.

2017-01-01

Nanotechnology has been more present in different fields related to health. The need to find a durable material, of easy use, and which does not interfere significantly in the growth and differentiation of stem cells for the construction of a scaffold for use in urologic surgery, with the purpose of reducing infections, regeneration times and even graft rejection during reconstitution in patients with urethral stricture was conducted a broad survey of information about this and came to the consensus of this project: using graphene oxide, a widely studied nanomaterials which has been presenting numerous beneficial results when in contact with the adipose-derived stem cells. Advanced techniques for the growth, differentiation and proliferation of adipose-derived stem cells were used, as well as the characterization of graphene oxide sheets. For this study, it was prepared the graphene oxide/6 ARM-Poly (ethylene glycol) amine films with poly (ε-caprolactone). The graphene suspension in organic solvent was prepared by using an ultrasonicator bath and subsequently, the film was formed by solvent evaporation. Total characterization of graphene oxide/6 ARM-PEG-amine/ poly (ε-caprolactone) film was carried out. It was tested growth and adhesion of adipose-derived stem cells on the film, as well as, were verified the histopathological effects of this scaffold when implanted in the urinary bladder to repair the lesion. Our results demonstrated that this scaffold with adipose-derived stem cells enhanced the repair in rat urinary bladder defect model, resulting in a regular bladder. Improved organized muscle bundles and urothelial layer were observed in animals treated with this scaffold with adipose-derived stem cells compared with those treated only suture thread or scaffold. Thus, our biomaterial could be suitable for tissue engineered urinary tract reconstruction. (paper)

Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma.

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Chuang, Ai-Ying; DeMarzo, Angelo M; Veltri, Robert W; Sharma, Rajni B; Bieberich, Charles J; Epstein, Jonathan I

2007-08-01

The histologic distinction between high-grade prostate cancer and infiltrating high-grade urothelial cancer may be difficult, and has significant implications because each disease may be treated very differently (ie, hormone therapy for prostate cancer and chemotherapy for urothelial cancer). Immunohistochemistry of novel and established prostatic and urothelial markers using tissue microarrays (TMAs) were studied. Prostatic markers studied included: prostate-specific antigen (PSA), prostein (P501s), prostate-specific membrane antigen (PSMA), NKX3.1 (an androgen-related tumor suppressor gene), and proPSA (pPSA) (precursor form of PSA). "Urothelial markers" included high molecular weight cytokeratin (HMWCK), p63, thrombomodulin, and S100P (placental S100). TMAs contained 38 poorly differentiated prostate cancers [Gleason score 8 (n=2), Gleason score 9 (n=18), Gleason score 10 (n=18)] and 35 high-grade invasive urothelial carcinomas from radical prostatectomy and cystectomy specimens, respectively. Each case had 2 to 8 tissue spots (0.6-mm diameter). If all spots for a case showed negative staining, the case was called negative. The sensitivities for labeling prostate cancers were PSA (97.4%), P501S (100%), PSMA (92.1%), NKX3.1 (94.7%), and pPSA (94.7%). Because of PSA's high sensitivity on the TMA, we chose 41 additional poorly differentiated primary (N=36) and metastatic (N=5) prostate carcinomas which showed variable PSA staining at the time of diagnosis and performed immunohistochemistry on routine tissue sections. Compared to PSA, which on average showed 18.8% of cells with moderate to strong positivity, cases stained for P501S, PSMA, and NKX3.1 had on average 42.5%, 53.7%, 52.9% immunoreactivity, respectively. All prostatic markers showed excellent specificity. HMWCK, p63, thrombomodulin, and S100P showed lower sensitivities in labeling high-grade invasive urothelial cancer in the TMAs with 91.4%, 82.9%, 68.6%, and 71.4% staining, respectively. These urothelial

Long non-coding RNA ANRIL is up-regulated in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic pathway

International Nuclear Information System (INIS)

Zhu, Hongxue; Li, Xuechao; Song, Yarong; Zhang, Peng; Xiao, Yajun; Xing, Yifei

2015-01-01

Antisense non-coding RNA in the INK4 locus (ANRIL) is a member of long non-coding RNAs and has been reported to be dysregulated in several human cancers. However, the role of ANRIL in bladder cancer remains unclear. This present study aimed to investigate whether and how ANRIL involved in bladder cancer. Our results showed up-regulation of ANRIL in bladder cancer tissues versus the corresponding adjacent non-tumor tissues. To explore the specific mechanisms, ANRIL was silenced by small interfering RNA or short hairpin RNA transfection in human bladder cancer T24 and EJ cells. Knockdown of ANRIL repressed cell proliferation and increased cell apoptosis, along with decreased expression of Bcl-2 and increased expressions of Bax, cytoplasmic cytochrome c and Smac and cleaved caspase-9, caspase-3 and PARP. However, no change of cleaved caspase-8 level was observed. Furthermore, in vivo experiment confirmed that knockdown of ANRIL inhibited tumorigenic ability of EJ cells in nude mice. Meanwhile, in accordance with in vitro study, knockdown of ANRIL inhibited expression of Bcl-2 and up-regulated expressions of Bax and cleaved caspase-9, but did not affect cleaved caspase-8 level. In conclusion, we first report that ANRIL possibly serves as an oncogene in bladder cancer and regulates bladder cancer cell proliferation and apoptosis through the intrinsic apoptosis pathway. - Highlights: • We first report the role of ANRIL in bladder cancer. • ANRIL is obviously up-regulated in bladder cancer tissues. • ANRIL regulates bladder cancer cell proliferation and cell apoptosis through the intrinsic pathway.

Putrescine importer PlaP contributes to swarming motility and urothelial cell invasion in Proteus mirabilis.

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Kurihara, Shin; Sakai, Yumi; Suzuki, Hideyuki; Muth, Aaron; Phanstiel, Otto; Rather, Philip N

2013-05-31

Previously, we reported that the speA gene, encoding arginine decarboxylase, is required for swarming in the urinary tract pathogen Proteus mirabilis. In addition, this previous study suggested that putrescine may act as a cell-to-cell signaling molecule (Sturgill, G., and Rather, P. N. (2004) Mol. Microbiol. 51, 437-446). In this new study, PlaP, a putative putrescine importer, was characterized in P. mirabilis. In a wild-type background, a plaP null mutation resulted in a modest swarming defect and slightly decreased levels of intracellular putrescine. In a P. mirabilis speA mutant with greatly reduced levels of intracellular putrescine, plaP was required for the putrescine-dependent rescue of swarming motility. When a speA/plaP double mutant was grown in the presence of extracellular putrescine, the intracellular levels of putrescine were greatly reduced compared with the speA mutant alone, indicating that PlaP functioned as the primary putrescine importer. In urothelial cell invasion assays, a speA mutant exhibited a 50% reduction in invasion when compared with wild type, and this defect could be restored by putrescine in a PlaP-dependent manner. The putrescine analog Triamide-44 partially inhibited the uptake of putrescine by PlaP and decreased both putrescine stimulated swarming and urothelial cell invasion in a speA mutant.

[Glandular squamous cell carcinoma of the urinary bladder].

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Kovylina, M V; Pushkar', D Iu; Zaĭrat'iants, O V; Rasner, P I

2006-01-01

The paper gives a clinical observation of a 52 year-old male with a rare histological urinary bladder tumor primary grandular-squamous-cell carcinoma (pT3N IM0). The tumor is represented by two components large acinic-cell adenocarcinoma and squamous-cell carcinoma with keratinization, which smoothly pass one into another; the tumor has grown through all layers of the urinary bladder wall but it has failed to grow into the peritoneum. A microscopic study has indicated that the urachus is intact. Metastases were found in 3 of 8 lymph nodes: one showed high-grade adenocarcinoma and two others displayed average-grade squamous-cell carcinoma.

Primary Diffuse Large Cell Lymphoma of the Bladder: Case Report and Literature Review

OpenAIRE

Mansour Ansari; Hamid Nasrollahi; Majdaddin Rajaei; Maral Mokhtari; Seyed Hasan Hamedi; Mohammad Mohammadianpanah; Shapour Omidvari; Ahmad Mosalaei; Niloofar Ahmadloo

2017-01-01

Most bladder tumors are epithelial in origin. Nonepithelial cancers are rarely located in the bladder. Sarcomas are the most common malignancies among nonepithelial cancers. Primary bladder lymphoma is rare and mostly low grade. Here, we have reported a case of diffuse large cell lymphoma of the bladder. The patient, a 64-year-old man, had urinary frequency for 18 months. Abdominal sonography indicated a thick bladder wall and transurethral biopsy showed diffuse large cell lymp...

Primary Diffuse Large Cell Lymphoma of the Bladder: Case Report and Literature Review

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Mansour Ansari

2017-01-01

Full Text Available Most bladder tumors are epithelial in origin. Nonepithelial cancers are rarely located in the bladder. Sarcomas are the most common malignancies among nonepithelial cancers. Primary bladder lymphoma is rare and mostly low grade. Here, we have reported a case of diffuse large cell lymphoma of the bladder. The patient, a 64-year-old man, had urinary frequency for 18 months. Abdominal sonography indicated a thick bladder wall and transurethral biopsy showed diffuse large cell lymphoma. Immunohistochemistry (IHC results showed that the tumor was positive for CD20, CD45, and Pax-5 and negative for BCL-2, cytokeratin, and S100. He had a normal bone marrow biopsy, abdominal, pelvic and chest CT scans. He had no B symptoms. The patient received 6 cycles of R-CHOP followed by radiotherapy (36 Gy to the pelvis. Six months after treatment, the patient is well and has returned to work. We have searched PubMed for primary diffuse large cell lymphoma. Primary diffuse large cell lymphoma of the bladder is best treated according to treatment for diffuse large cell lymphoma of other sites, which includes chemotherapy and radiotherapy. As seen in our review, primary diffuse large cell lymphoma of the bladder has a similar clinical course to diffuse large cell lymphoma of other sites.

Sperm associated antigen 9 plays an important role in bladder transitional cell carcinoma.

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Deepika Kanojia

Full Text Available BACKGROUND: Majority of bladder cancer deaths are caused due to transitional cell carcinoma (TCC which is the most prevalent and chemoresistant malignancy of urinary bladder. Therefore, we analyzed the role of Sperm associated antigen 9 (SPAG9 in bladder TCC. METHODOLOGY AND FINDINGS: We examined SPAG9 expression and humoral response in 125 bladder TCC patients. Four bladder cancer cell lines were assessed for SPAG9 expression. In addition, we investigated the effect of SPAG9 ablation on cellular proliferation, cell cycle, migration and invasion in UM-UC-3 bladder cancer cells by employing gene silencing approach. Our SPAG9 gene and protein expression analysis revealed SPAG9 expression in 81% of bladder TCC tissue specimens. High SPAG9 expression (>60% SPAG9 positive cells was found to be significantly associated with superficial non-muscle invasive stage (P = 0.042 and low grade tumors (P = 0.002 suggesting SPAG9 putative role in early spread and tumorigenesis. Humoral response against SPAG9 was observed in 95% of patients found positive for SPAG9 expression. All four bladder cancer cell lines revealed SPAG9 expression. In addition, SPAG9 gene silencing in UM-UC-3 cells resulted in induction of G0-G1 arrest characterized by up-regulation of p16 and p21 and consequent down-regulation of cyclin E, cyclin D and cyclin B, CDK4 and CDK1. Further, SPAG9 gene silencing also resulted in reduction in cellular growth, and migration and invasion ability of cancer cells in vitro. CONCLUSIONS: Collectively, our data in clinical specimens indicated that SPAG9 is potential biomarker and therapeutic target for bladder TCC.

Disulfide high mobility group box-1 causes bladder pain through bladder Toll-like receptor 4.

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Ma, Fei; Kouzoukas, Dimitrios E; Meyer-Siegler, Katherine L; Westlund, Karin N; Hunt, David E; Vera, Pedro L

2017-05-25

Bladder pain is a prominent symptom in several urological conditions (e.g. infection, painful bladder syndrome/interstitial cystitis, cancer). Understanding the mechanism of bladder pain is important, particularly when the pain is not accompanied by bladder pathology. Stimulation of protease activated receptor 4 (PAR4) in the urothelium results in bladder pain through release of urothelial high mobility group box-1 (HMGB1). HGMB1 has two functionally active redox states (disulfide and all-thiol) and it is not known which form elicits bladder pain. Therefore, we investigated whether intravesical administration of specific HMGB1 redox forms caused abdominal mechanical hypersensitivity, micturition changes, and bladder inflammation in female C57BL/6 mice 24 hours post-administration. Moreover, we determined which of the specific HMGB1 receptors, Toll-like receptor 4 (TLR4) or receptor for advanced glycation end products (RAGE), mediate HMGB1-induced changes. Disulfide HMGB1 elicited abdominal mechanical hypersensitivity 24 hours after intravesical (5, 10, 20 μg/150 μl) instillation. In contrast, all-thiol HMGB1 did not produce abdominal mechanical hypersensitivity in any of the doses tested (1, 2, 5, 10, 20 μg/150 μl). Both HMGB1 redox forms caused micturition changes only at the highest dose tested (20 μg/150 μl) while eliciting mild bladder edema and reactive changes at all doses. We subsequently tested whether the effects of intravesical disulfide HMGB1 (10 μg/150 μl; a dose that did not produce inflammation) were prevented by systemic (i.p.) or local (intravesical) administration of either a TLR4 antagonist (TAK-242) or a RAGE antagonist (FPS-ZM1). Systemic administration of either TAK-242 (3 mg/kg) or FPS-ZM1 (10 mg/kg) prevented HMGB1 induced abdominal mechanical hypersensitivity while only intravesical TLR4 antagonist pretreatment (1.5 mg/ml; not RAGE) had this effect. The disulfide form of HMGB1 mediates bladder pain directly (not

Micropapillary bladder cancer: current treatment patterns and review of the literature.

Science.gov (United States)

Willis, Daniel L; Flaig, Thomas W; Hansel, Donna E; Milowsky, Matthew I; Grubb, Robert L; Al-Ahmadie, Hikmat A; Plimack, Elizabeth R; Koppie, Theresa M; McConkey, David J; Dinney, Colin P; Hoffman, Vanessa A; Droller, Michael J; Messing, Edward; Kamat, Ashish M

2014-08-01

No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature. A survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network-sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review. Most survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease. The management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of seven chemicals on DNA damage in the rat urinary bladder: a comet assay study.

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Wada, Kunio; Yoshida, Toshinori; Takahashi, Naofumi; Matsumoto, Kyomu

2014-07-15

The in vivo comet assay has been used for the evaluation of DNA damage and repair in various tissues of rodents. However, it can give false-positive results due to non-specific DNA damage associated with cell death. In this study, we examined whether the in vivo comet assay can distinguish between genotoxic and non-genotoxic DNA damage in urinary bladder cells, by using the following seven chemicals related to urinary bladder carcinogenesis in rodents: N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), glycidol, 2,2-bis(bromomethyl)-1,3-propanediol (BMP), 2-nitroanisole (2-NA), benzyl isothiocyanate (BITC), uracil, and melamine. BBN, glycidol, BMP, and 2-NA are known to be Ames test-positive and they are expected to produce DNA damage in the absence of cytotoxicity. BITC, uracil, and melamine are Ames test-negative with metabolic activation but have the potential to induce non-specific DNA damage due to cytotoxicity. The test chemicals were administered orally to male Sprague-Dawley rats (five per group) for each of two consecutive days. Urinary bladders were sampled 3h after the second administration and urothelial cells were analyzed by the comet assay and subjected to histopathological examination to evaluate cytotoxicity. In the urinary bladders of rats treated with BBN, glycidol, and BMP, DNA damage was detected. In contrast, 2-NA induced neither DNA damage nor cytotoxicity. The non-genotoxic chemicals (BITC, uracil, and melamine) did not induce DNA damage in the urinary bladders under conditions where some histopathological changes were observed. The results indicate that the comet assay could distinguish between genotoxic and non-genotoxic chemicals and that no false-positive responses were obtained. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of arsenite on cell cycle progression in a human bladder cancer cell line

International Nuclear Information System (INIS)

Hernandez-Zavala, A.; Cordova, E.; Razo, L.M. del; Cebrian, M.E.; Garrido, E.

2005-01-01

Bladder cancer is one of the most important diseases associated with arsenic (As) exposure in view of its high prevalence and mortality rate. Experimental studies have shown that As exposure induces cell proliferation in the bladder of sodium arsenite (iAsIII) subchronically treated mice. However, there is little available information on its effects on the cell cycle of bladder cells. Thus, our purpose was to evaluate the effects of iAsIII on cell cycle progression and the response of p53 and p21 on the human-derived epithelial bladder cell line HT1197. iAsIII treatment (1-10 μM) for 24 h induced a dose-dependent increase in the proportion of cells in S-phase, which reached 65% at the highest dose. A progressive reduction in cell proliferation was also observed. BrdU was incorporated to cellular DNA in an interrupted form, suggesting an incomplete DNA synthesis. The time-course of iAsIII effects (10 μM) showed an increase in p53 protein content and a transient increase in p21 protein levels accompanying the changes in S-phase. These effects were correlated with iAs concentrations inside the cells, which were not able to metabolize inorganic arsenic. Our findings suggest that p21 was not able to block CDK2-cyclin E complex activity and was therefore unable to arrest cells in G1 allowing their progression into the S-phase. Further studies are needed to ascertain the mechanisms underlying the effects of iAsIII on the G1 to S phase transition in bladder cells

Urothelial dysfunction and sensory protein expressions in patients with urological or systemic diseases and hypersensitive bladder

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Hueih-Ling Ong

2017-09-01

Conclusion: Patients with OAB or HSB showed increased urothelial inflammation and lower barrier protein expression. Increased M3/β3-AR or M2/β3-AR in the urothelium was associated with OAB, whereas decreased M3/β3-AR or M2/β3-AR was associated with poor voiding efficiency and large PVR in LUTD.

Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy.

Science.gov (United States)

Gonzalez-Roibon, Nilda; Kim, Jenny J; Faraj, Sheila F; Chaux, Alcides; Bezerra, Stephania M; Munari, Enrico; Ellis, Carla; Sharma, Rajni; Keizman, Daniel; Bivalacqua, Trinity J; Schoenberg, Mark; Eisenberger, Mario; Carducci, Michael; Netto, George J

2014-06-01

To assess the insulin-like growth factor-1 receptor (IGF1R) expression in urothelial carcinoma (UC) and its prognostic role in relation to clinicopathologic parameters. A total of 100 cases of invasive UC were evaluated using tissue microarrays. Membranous IGF1R staining was evaluated using immunohistochemistry. A scoring method analogous to that of HER2 expression in breast carcinoma was used, and the highest score was assigned in each tumor. IGF1R was considered overexpressed in cases with score≥1. We found IGF1R overexpression in 62% of invasive UC. IGF1R overexpression was associated with race (P=.04) and pT category (P=.03). Median follow-up was 29 months (range, 0.5-212). Progression rate was 60%, and overall mortality and cancer-specific mortality rates were 69% and 51%, respectively. In invasive UC, IGF1R overexpression was significantly associated with overall mortality and cancer-specific mortality (Mantel Cox P=.0002 and P=.006, respectively). IGF1R overexpression was associated with increased hazard ratios (HRs) for overall mortality (HR=2.63, P=.001) and cancer-specific mortality (HR=2.45, P=.01), independently and after adjusting for clinicopathologic features and treatment modalities. We found IGF1R overexpression in 62% of bladder UC. More importantly, IGF1R overexpression was a significant predictor of overall mortality and cancer-specific mortality, suggesting its potential role as a prognosticator in UC of bladder. Copyright © 2014 Elsevier Inc. All rights reserved.

Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

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Fischer, Nicolas, E-mail: simplissimus@gmx.de [Department of Urology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn (Germany); Goeke, Friederike, E-mail: Friederike.goeke@ukb.uni-bonn.de [Department of Pathology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn (Germany); Splittstoesser, Vera, E-mail: Veri.sp@web.de [Department of Urology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn (Germany); Lankat-Buttgereit, Brigitte, E-mail: Lankatbu@staff.uni-marburg.de [Department of Internal Medicine, Philipps-University of Marburg, Baldingerstrasse, 35043 Marburg (Germany); Mueller, Stefan C., E-mail: Stefan.mueller@ukb.uni-bonn.de [Department of Urology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn (Germany); Ellinger, Joerg, E-mail: Joerg.ellinger@ukb.uni-bonn.de [Department of Urology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn (Germany)

2012-01-06

Highlights: Black-Right-Pointing-Pointer The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. Black-Right-Pointing-Pointer We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. Black-Right-Pointing-Pointer We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2-T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

Expression of programmed cell death protein 4 (PDCD4) and miR-21 in urothelial carcinoma

International Nuclear Information System (INIS)

Fischer, Nicolas; Göke, Friederike; Splittstößer, Vera; Lankat-Buttgereit, Brigitte; Müller, Stefan C.; Ellinger, Jörg

2012-01-01

Highlights: ► The tumor suppressor gene PDCD4 is down-regulated in many tumorous entities. ► We investigate the impact of PDCD4 and its regulating factor miR-21 in urothelial carcinoma. ► We confirm PDCD4 as a tumor suppressor gene and it could be a diagnostic marker for this tumor. -- Abstract: Background: We investigated the role of the programmed cell death 4 (PDCD4) tumor suppressor gene in specimens of transitional cell carcinoma and of healthy individuals. Methods: PDCD4 immunohistochemical expression was investigated in 294 cases in histologically proven transitional cell carcinoma in different tumorous stages (28 controls, 122 non-muscle invasive urothelial carcinoma, stages Tis-T1, 119 invasive transitional cell carcinoma stages T2–T4 and 25 metastases). MiR-21 expression, an important PDCD4 regulator, was assessed with real-time PCR analysis and showed inverse correlation to tissue PDCD4 expression. Results: Nuclear and cytoplasmatic PDCD4 immunostaining decreased significantly with histopathological progression of the tumor (p < 0001). Controls showed strong nuclear and cytoplasmatic immunohistochemical staining. MiR-21 up regulation in tissue corresponded to PDCD4 suppression. Conclusions: These data support a decisive role for PDCD4 down regulation in transitional cell carcinoma and confirm miR-21 as a negative regulator for PDCD4. Additionally, PDCD4 immunohistochemical staining turns out to be a possible diagnostic marker for transitional cell carcinoma.

Immunohistochemical Investigation of HER/AKT/mTOR Pathway and Cellular Adhesion Molecules in Urothelial Carcinomas

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Nikolaos Koletsas

2017-01-01

Full Text Available Background. Several investigators have suggested the possibility that the expression of both EGFR and HER2 could be utilized for molecularly targeted therapy in urinary bladder cancer. We tried to evaluate the expression of HER2 and EGFR and activation of the AKT/PTEN/mTOR pathway in urothelial carcinomas and if there is any association between them and cellular adhesion molecules (CAMs. Materials and Methods. Forty-one paraffin-embedded urothelial cancer tissue blocks were collected. Immunostains for HER2, EGFR, MIB1, phospho-AKT, PTEN, phospho-mTOR, e-cadherin, p-cadherin, and b-catenin were performed on tissue microarrays sections. The immunohistochemical results were correlated with clinicopathological parameters. Results. The overexpression of HER2 was found in 19.6% of the cases and it was associated with high grade tumors with a high mitotic index and phosphorylation of AKT and mTOR. Muscle-invasive tumors presented both cytoplasmic and nuclear losses of PTEN expression. There was no association between HER/AKT/mTOR pathway activation and CAM expression. Although cadherins were often coexpressed, only p-cadherin immunoreactivity was associated with tumor grade and high proliferative index. Conclusions. HER2 overexpression is found in a respective proportion of urothelial carcinomas. P-cadherin expression is associated with high grade UCs but it is not affected by HER2 overexpression or by activation of HER/AKT/mTOR pathway.

Telomerase reverse transcriptase promoter mutations in bladder cancer

DEFF Research Database (Denmark)

Allory, Yves; Beukers, Willemien; Sagrera, Ana

2014-01-01

for detection of recurrences in urine in patients with urothelial bladder cancer (UBC). DESIGN, SETTING, AND PARTICIPANTS: A set of 111 UBCs of different stages was used to assess TERT promoter mutations by Sanger sequencing and TERT messenger RNA (mRNA) expression by reverse transcription...... surveillance after diagnosis of non-muscle-invasive UBC (n=194), was tested using a SNaPshot assay. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association of mutation status with age, sex, tobacco, stage, grade, fibroblast growth factor receptor 3 (FGFR3) mutation, progression-free survival, disease...... frequent among FGFR3 mutant tumors (p=0.0002). There was no association between TERT mutations and mRNA expression (p=0.3). Mutations were not associated with clinical outcome. In urine, TERT mutations had 90% specificity in subjects with hematuria but no bladder tumor, and 73% in recurrence-free UBC...

Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer.

Science.gov (United States)

Kauffman, Eric C; Robinson, Brian D; Downes, Martin J; Powell, Leagh G; Lee, Ming Ming; Scherr, Douglas S; Gudas, Lorraine J; Mongan, Nigel P

2011-12-01

Bladder cancer is approximately three times more common in men as compared to women. We and others have previously investigated the contribution of androgens and the androgen receptor (AR) to bladder cancer. JMJD2A and LSD1 are recently discovered AR coregulator proteins that mediate AR-dependent transcription via recently described histone lysine-demethylation (KDM) mechanisms. We used immunohistochemistry to examine JMJD2A, LSD1, and AR expression in 72 radical cystectomy specimens, resulting in evaluation of 129 tissue samples (59 urothelial carcinoma, 70 benign). We tested levels of these proteins for statistical association with clinicopathologic variables and patient survival. Expression of these markers was also assessed in human bladder cancer cell lines. The effects of pharmacological inhibition of LSD1 on the proliferation of these bladder cancer cells was determined. JMJD2A and AR levels were significantly lower in malignant versus benign urothelium, while increased LSD1 levels were observed in malignant urothelium relative to benign. A significant reduction in all three proteins occurred with cancer stage progression, including muscle invasion (JMJD2A/LSD1/AR), extravesical extension (JMJD2A/LSD1), and lymph node metastasis (JMJD2A/AR). Lower JMJD2A intensity correlated with additional poor prognostic features, including lymphovascular invasion, concomitant carcinoma in situ and tobacco usage, and predicted significantly worse overall survival. Pharmacological inhibition of LSD1 suppressed bladder cancer cell proliferation and androgen-induced transcription. Our results support a novel role for the AR-KDM complex in bladder cancer initiation and progression, identify JMJD2A as a promising prognostic biomarker, and demonstrate targeting of the KDM activity as an effective potential approach for bladder cancer growth inhibition. Copyright © 2011 Wiley Periodicals, Inc.

The dual effects of polar methanolic extract of Hypericum perforatum L. in bladder cancer cells

Science.gov (United States)

Nseyo, U. O.; Nseyo, O. U.; Shiverick, K. T.; Medrano, T.; Mejia, M.; Stavropoulos, N.; Tsimaris, I.; Skalkos, D.

2007-02-01

�g/ml) + light at 630nm induced DNA fragmentation in a light dose-dependent manner; in contrast, PMF or light alone did not induce DNA fragmentation. In separate experiments, PMF alone treatment produced a dose-dependent DNA synthesis with a 90% inhibition at a concentration of 25μg/ml (IC90 = 25μg/ml). Expression of p53 and p27 cell cycle regulatory proteins was not altered by PMF alone, however, a dose-dependent increase in p21 expression was observed that correlates with PMF concentrations. Cyclin A and cyclin B protein levels showed a clear decrease inverse to the concentration of PMF. In the absence of light treatment, flow cytometry analysis showed that PMF alone results in G 0/G I cell cycle arrest, with a 2-fold increase in G 0/G I cells concomitant with 50% decrease in cells in both S and G II/M phases. However, flow cytometry on PMF alone-treated cells did not show sub G 0/G I peak, further evidence of the lack of apoptosis as a mechanism of effect of PMF in the dark. Conclusions: With respect to light treatment, apoptosis appears to play a vital role in PDT-induced cytotoxicity. The flow cytometry and DNA laddering results revealed that T24 cells demonstrated apoptotic responses in PMF-mediated PDT. Experiments conducted with PMF alone showed a dose-dependent inhibition of DNA synthesis associated with G 0/G I cell cycle arrest and the extract is able to coordinate changes in key cell cycle regulatory proteins in human bladder cancer cells. Both experimental conditions suggest PMF as a potent and effect anti-proliferative agent in cancer chemoprevention and therapy of human urothelial carcinoma cells.

Downregulation of glutathione S-transferase M1 protein in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced mouse bladder carcinogenesis

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Chuang, Jing-Jing [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China); Dai, Yuan-Chang [Department of Pathology, Chiayi Christian Hospital, Chiayi, Taiwan (China); Lin, Yung-Lun; Chen, Yang-Yi; Lin, Wei-Han [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China); Chan, Hong-Lin [Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, Hsinchu, Taiwan (China); Liu, Yi-Wen, E-mail: ywlss@mail.ncyu.edu.tw [Department of Microbiology, Immunology and Biopharmaceuticals, College of Life Sciences, National Chiayi University, Chiayi, Taiwan (China)

2014-09-15

Bladder cancer is highly recurrent following specific transurethral resection and intravesical chemotherapy, which has prompted continuing efforts to develop novel therapeutic agents and early-stage diagnostic tools. Specific changes in protein expression can provide a diagnostic marker. In our present study, we investigated changes in protein expression during urothelial carcinogenesis. The carcinogen BBN was used to induce mouse bladder tumor formation. Mouse bladder mucosa proteins were collected and analyzed by 2D electrophoresis from 6 to 20 weeks after commencing continuous BBN treatment. By histological examination, the connective layer of the submucosa showed gradual thickening and the number of submucosal capillaries gradually increased after BBN treatment. At 12-weeks after the start of BBN treatment, the urothelia became moderately dysplastic and tumors arose after 20-weeks of treatment. These induced bladder lesions included carcinoma in situ and connective tissue invasive cancer. In protein 2D analysis, the sequentially downregulated proteins from 6 to 20 weeks included GSTM1, L-lactate dehydrogenase B chain, keratin 8, keratin 18 and major urinary proteins 2 and 11/8. In contrast, the sequentially upregulated proteins identified were GSTO1, keratin 15 and myosin light polypeptide 6. Western blotting confirmed that GSTM1 and NQO-1 were decreased, while GSTO1 and Sp1 were increased, after BBN treatment. In human bladder cancer cells, 5-aza-2′-deoxycytidine increased the GSTM1 mRNA and protein expression. These data suggest that the downregulation of GSTM1 in the urothelia is a biomarker of bladder carcinogenesis and that this may be mediated by DNA CpG methylation. - Highlights: • GSTM1 and NQO-1 proteins decreased in the mouse bladder mucosa after BBN treatment. • BBN induced GSTO1 and Sp1 protein expression in the mouse bladder mucosa. • 5-Aza-2′-deoxycytidine increased GSTM1 mRNA and protein in human bladder cancer cell. • GSTM1

Loss of MTUS1/ATIP expression is associated with adverse outcome in advanced bladder carcinomas: data from a retrospective study

International Nuclear Information System (INIS)

Rogler, Anja; Lehmann, Jan; Petsch, Sabrina; Hartmann, Arndt; Stoehr, Robert; Hoja, Sabine; Giedl, Johannes; Ekici, Arif B; Wach, Sven; Taubert, Helge; Goebell, Peter J; Wullich, Bernd; Stöckle, Michael

2014-01-01

Seventy percent of all bladder tumours tend to recur and need intensive surveillance, and a subset of tumours progress to muscle-invasive and metastatic disease. However, it is still difficult to find the adequate treatment for every individual patient as it is a very heterogeneous disease and reliable biomarkers are still missing. In our study we searched for new target genes in the critical chromosomal region 8p and investigated the potential tumour suppressor gene candidate MTUS1/ATIP in bladder cancer. MTUS1 was identified to be the most promising deleted target gene at 8p in aCGH analysis with 19 papillary bladder tumours. A correlation with bladder cancer was further validated using immunohistochemistry of 85 papillary and 236 advanced bladder tumours and in functional experiments. Kaplan-Meier analysis and multivariate Cox-regression addressed overall survival (OS) and disease-specific survival (DSS) as a function of MTUS1/ATIP expression. Bivariate correlations investigated associations between MTUS1/ATIP expression, patient characteristics and histopathology. MTUS1 expression was analysed in cell lines and overexpressed in RT112, where impact on viability, proliferation and migration was measured. MTUS1 protein expression was lost in almost 50% of all papillary and advanced bladder cancers. Survival, however, was only influenced in advanced carcinomas, where loss of MTUS1 was associated with adverse OS and DSS. In this cohort, there was also a significant correlation of MTUS1 expression and histological subtype: positive expression was detected in all micropapillary tumours and aberrant nuclear staining was detected in a subset of plasmocytoid urothelial carcinomas. MTUS1 was expressed in all investigated bladder cell lines and overexpression in RT112 led to significantly decreased viability. MTUS1 is a tumour suppressor gene in cultured bladder cancer cells and in advanced bladder tumours. It might represent one new target gene at chromosome 8p and can be

Imaging Features of Helical Computed Tomography Suggesting Advanced Urothelial Carcinoma Arising from the Pelvocalyceal System

International Nuclear Information System (INIS)

Kwak, Kyung Won; Park, Byung Kwan; Kim, Chan Kyo; Lee, Hyun Moo; Choi, Han Y ong

2008-01-01

Background: Urothelial carcinoma is the most common malignant tumor arising from the pelvocalyceal system. Helical computed tomography (CT) is probably the best preoperative-stage modality for the determination of treatment plan and prognosis. Purpose: To obtain helical CT imaging features suggesting advanced pelvocalyceal urothelial carcinoma. Material and Methods: Preoperative CT images in 44 patients with pelvocalyceal urothelial carcinoma were retrospectively reviewed and correlated with the pathological examination to determine imaging features suggesting stage III or IV of the disease. Results: Pathological stages revealed stage I in 16, stage II in three, stage III in 17, and stage IV in eight patients. Seven patients had metastatic lymph nodes. CT imaging showed that renal parenchymal invasion, sinus fat invasion, and lymph node metastasis were highly suggestive of advanced urothelial cell carcinoma (P<0.05). Helical CT sensitivity, specificity, and accuracy for advanced pelvocalyceal urothelial carcinoma were 76% (19/25), 84% (16/19), and 80% (35/44), respectively. Conclusion: Preoperative helical CT may suggest imaging features of advanced urothelial carcinoma, influencing treatment plan and patient prognosis, even though its accuracy is not so high

CXCL5 knockdown expression inhibits human bladder cancer T24 cells proliferation and migration

Energy Technology Data Exchange (ETDEWEB)

Zheng, Jiajia [Department of Laboratory Medicine, Peking University Third Hospital, Beijing (China); Zhu, Xi [Department of Urology, Beijing Friendship Hospital Affiliated to Capital Medical University, Beijing (China); Zhang, Jie, E-mail: zhangjiebjmu@163.com [Department of Laboratory Medicine, Peking University Third Hospital, Beijing (China)

2014-03-28

Highlights: • We first demonstrated CXCL5 is highly expressed in human bladder tumor tissues and cells. • CXCL5 knockdown inhibits proliferation, migration and promotes apoptosis in T24 cells. • CXCL5 knockdown inhibits Snail, PI3K-AKT and ERK1/2 signaling pathways in T24 cells. • CXCL5 is critical for bladder tumor growth and progression. - Abstract: CXCL5 (epithelial neutrophil activating peptide-78) which acts as a potent chemoattractant and activator of neutrophil function was reported to play a multifaceted role in tumorigenesis. To investigate the role of CXCL5 in bladder cancer progression, we examined the CXCL5 expression in bladder cancer tissues by real-time PCR and Western blot, additionally, we used shRNA-mediated silencing to generate stable CXCL5 silenced bladder cancer T24 cells and defined its biological functions. Our results demonstrated that mRNA and protein of CXCL5 is increased in human bladder tumor tissues and cell lines, down-regulation of CXCL5 in T24 cells resulted in significantly decreased cell proliferation, migration and increased cell apoptosis in vitro through Snail, PI3K-AKT and ERK1/2 signaling pathways. These data suggest that CXCL5 is critical for bladder tumor growth and progression, it may represent a potential application in cancer diagnosis and therapy.

CXCL5 knockdown expression inhibits human bladder cancer T24 cells proliferation and migration

International Nuclear Information System (INIS)

Zheng, Jiajia; Zhu, Xi; Zhang, Jie

2014-01-01

Highlights: • We first demonstrated CXCL5 is highly expressed in human bladder tumor tissues and cells. • CXCL5 knockdown inhibits proliferation, migration and promotes apoptosis in T24 cells. • CXCL5 knockdown inhibits Snail, PI3K-AKT and ERK1/2 signaling pathways in T24 cells. • CXCL5 is critical for bladder tumor growth and progression. - Abstract: CXCL5 (epithelial neutrophil activating peptide-78) which acts as a potent chemoattractant and activator of neutrophil function was reported to play a multifaceted role in tumorigenesis. To investigate the role of CXCL5 in bladder cancer progression, we examined the CXCL5 expression in bladder cancer tissues by real-time PCR and Western blot, additionally, we used shRNA-mediated silencing to generate stable CXCL5 silenced bladder cancer T24 cells and defined its biological functions. Our results demonstrated that mRNA and protein of CXCL5 is increased in human bladder tumor tissues and cell lines, down-regulation of CXCL5 in T24 cells resulted in significantly decreased cell proliferation, migration and increased cell apoptosis in vitro through Snail, PI3K-AKT and ERK1/2 signaling pathways. These data suggest that CXCL5 is critical for bladder tumor growth and progression, it may represent a potential application in cancer diagnosis and therapy

microRNA-495 promotes bladder cancer cell growth and invasion by targeting phosphatase and tensin homolog

International Nuclear Information System (INIS)

Tan, Mingyue; Mu, Xingyu; Liu, Zhihong; Tao, Le; Wang, Jun; Ge, Jifu; Qiu, Jianxin

2017-01-01

Accumulating evidence has linked deregulation of microRNA-495 (miR-495) to tumorigenesis; however, its function in tumor progression is controversial. This work was undertaken to explore the expression and biological roles of miR-495 in bladder cancer. The expression of miR-495 was examined in 67 pairs of bladder cancer and adjacent normal bladder tissues. The roles of miR-495 in bladder cancer cell proliferation and invasion in vitro and tumorigenesis in vivo were determined. Direct target gene(s) mediating the activity of miR-495 in bladder cancer cells was identified. It was found that miR-495 was expressed at greater levels in bladder tissues and cell lines. High expression of miR-495 was significantly associated with larger tumor size, advanced TNM stage, and lymph node metastasis. Overexpression of miR-495 significantly promoted bladder cancer cell proliferation and invasion, whereas inhibition of miR-495 suppressed cell proliferation and invasion. PTEN, a well-defined tumor suppressor was identified to be a target gene of miR-495. A significant inverse correlation between miR-495 and PTEN expression was noted in bladder cancer tissues (r = −0.3094, P = 0.0125). Overexpression of miR-495 led to reduction of PTEN expression in bladder cancer cells. Rescue experiments showed that enforced expression of PTEN impaired miR-495-mediated bladder cancer proliferation and invasion. In vivo mouse studies demonstrated that overexpression of miR-495 accelerated the growth of subcutaneous bladder cancer xenografts, which was associated with downregulation of PTEN. Overall, these findings indicate that miR-495 upregulation contributes to bladder cancer cell growth, invasion, and tumorigenesis by targeting PTEN and offer a potential therapeutic target for bladder cancer. - Highlights: • miR-495 upregulation induces aggressive phenotype in bladder cancer. • miR-495 is inversely correlated with PTEN in bladder cancer. • miR-495 promotes bladder cancer cell

The Role of Genetically Modified Mesenchymal Stem Cells in Urinary Bladder Regeneration.

Science.gov (United States)

Snow-Lisy, Devon C; Diaz, Edward C; Bury, Matthew I; Fuller, Natalie J; Hannick, Jessica H; Ahmad, Nida; Sharma, Arun K

2015-01-01

Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stem progenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration. Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2) and bladder smooth muscle content (~42% vs ~36%) in Cyr61OX (over-expressing) vs Cyr61KD (knock-down) groups. Muscle content decreased to ~25% at 10 weeks in Cyr61KD groups. Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/mm2 and ~51%, respectively) at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation. Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation of MSCs with CD34+ HSPCs and may be specifically targeted as an

G Protein-Coupled Receptor 87 (GPR87 Promotes Cell Proliferation in Human Bladder Cancer Cells

Directory of Open Access Journals (Sweden)

Xia Zhang

2015-10-01

Full Text Available G protein-coupled receptor 87 (GPR87 is a newly deorphanized member of the cell surface molecule G protein-coupled receptor family. GPR signaling was shown to play a role in promotion of cell growth and survival, metastasis, and drug resistance. The overexpression of GPR87 has also been reported in many malignant tumors including bladder cancer. The aim of the present study is to examine the effect of silencing GPR87 expression with a replication-deficient recombinant adenoviral vector expressing short hairpin RNA targeting GPR87 (Ad-shGPR87 and to explore the underlying molecular mechanisms in bladder cancer cells. Six GPR87-expressing human bladder cancer cells, HT1197, HT1376, J82, RT112, TCCSUP and UMUC3, were used. Infection with Ad-shGPR87 effectively downregulated the GPR87 expression, and significantly reduced the percentage of viable cells in 4 of 6 cell lines as detected by an MTT assay. Significant inhibition on cell proliferation with Ad-shGPR87 was observed in the wild-type p53 bladder cancer cell lines (HT1197, RT112, TCCSUP and UMUC3, but not in the mutant p53 cells (HT1376 and J82. As represented by a wild-type p53 RT112 cell, Ad-shGPR87 infection significantly enhanced p53 and p21 expression and caused caspase-dependent apoptosis. Furthermore, the treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-expressing RT112 xenografts. GPR87 appeared to be a promising target for gene therapy, and Ad-shGPR87 had strong antitumor effects, specifically anti-proliferative and pro-apoptotic effects, against GPR87-expressing human bladder cancer cells.