Pathogenesis Of Urothelial Carcinoma Research Articles

Canine urothelial carcinoma: genomically aberrant and comparatively relevant.

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 customAgilent SureFISH probes, was performedto 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 key to urothelial neoplasia, warranting investigation for diagnostic, prognostic, and therapeutic applications.

FGFR3 overexpression is prognostic of adverse outcome for muscle-invasive bladder carcinoma treated with adjuvant chemotherapy

BackgroundAlterations in fibroblast growth factor receptor 3 (FGFR3) have been implicated in the pathogenesis of urothelial carcinoma. However, its clinicopathological significance has not been clearly established, especially in muscle-invasive bladder cancer (MIBC). ObjectivesThe aim of our study was to investigate the mutation and overexpression of FGFR3 in MIBC cases from radical cystectomy and to analyze the prognostic and predictive significance in the groups with or without adjuvant chemotherapy. Methods and materialsStudy cohorts included 72 cases of MIBC including 42 patients who were treated with adjuvant chemotherapy. The mutation status of FGFR3 exons 7, 10, and 15 was investigated and protein expression was evaluated. The findings were analyzed for the association with relevant clinicopathological findings. ResultsFGFR3 mutations were found in 7 patients (9.7%) and were correlated with a pattern of papillary growth, moderate histologic grade (G2 vs. G3), and moderately advanced TNM stage (II–III vs. IV). FGFR3 protein overexpression was detected in 33 cases (45.8%) but was not associated with the relevant clinicopathological parameters. In patients treated with adjuvant chemotherapy, FGFR3 overexpression was correlated with shorter disease-free survival (P = 0.067, 95% confidence interval: 14.8–29.6, marginal significance) and overall survival (P = 0.035), remaining as a significant independent prognostic factor for disease-free survival and overall survival in multivariate analysis using Cox proportional hazards model. In patients without adjuvant chemotherapy, FGFR3 mutation or overexpression did not have prognostic significance in multivariate analysis. ConclusionWe report the FGFR3 alterations in MIBCs, and discuss their biological implication in subsets of patients. FGFR3 overexpression was predictive of adverse outcome in patients with adjuvant cisplatin-based chemotherapy after radical cystectomy. The utility of FGFR3 as a therapeutic target is suggested.

Correlation of Wnt5a expression with histopathological grade/stage in urothelial carcinoma of the bladder

BackgroundBladder cancer, including urothelial carcinoma (UC), is the most common malignancy of the urinary tract and the fourth most frequent cancer overall in men. Wnt5a, a member of the Wnt family of proteins, has been shown to have contradictory roles in the pathogenesis of many cancers, acting either as tumor suppressor or tumor promoter. The objective of this study was to investigate the expression and role of Wnt5a in the pathogenesis of UC and suggest possible clinical applications for diagnosis, prognosis and treatment.MethodsWe characterized the expression of Wnt5a in 33 human UC samples using immunohistochemistry. The samples were obtained via transurethral resection, immediately fixed in formalin and then embedded in paraffin. The correlation between Wnt5a immunoreactivity, histological grade, and pathological stage of the tumor was analyzed. The expression of Wnt5a mRNA as well as the effect of Wnt5a on cell migration was also evaluated in two UC cell lines, T24 and J82, and a normal urothelial cell line.ResultsOur immunohistochemical results revealed that Wnt5a staining intensity correlated positively with the histological grade and pathological stage of the UC. Wnt5a mRNA expression differed widely in the three urothelial cell lines, with high levels in one carcinoma cell line and low levels in the other cell line in comparison to the normal urothelial cell line. Migration increased in both UC cell lines in response to Wnt5a treatment.ConclusionsOur results show that the Wnt5a pathway may play a role in the pathogenesis of UC and suggest that Wnt5a may serve as an additional, complementary diagnostic/prognostic marker for UC.Virtual slidehttp://www.diagnosticpathology.diagnomx.eu/vs/1952312091979566

Loss of Sh3gl2/Endophilin A1 Is a Common Event in Urothelial Carcinoma that Promotes Malignant Behavior

Urothelial carcinoma (UC) causes substantial morbidity and mortality worldwide. However, the molecular mechanisms underlying urothelial cancer development and tumor progression are still largely unknown. Using informatics analysis, we identified Sh3gl2 (endophilin A1) as a bladder urothelium-enriched transcript. The gene encoding Sh3gl2 is located on chromosome 9p, a region frequently altered in UC. Sh3gl2 is known to regulate endocytosis of receptor tyrosine kinases implicated in oncogenesis, such as the epidermal growth factor receptor (EGFR) and c-Met. However, its role in UC pathogenesis is unknown. Informatics analysis of expression profiles as well as immunohistochemical staining of tissue microarrays revealed Sh3gl2 expression to be decreased in UC specimens compared to nontumor tissues. Loss of Sh3gl2 was associated with increasing tumor grade and with muscle invasion, which is a reliable predictor of metastatic disease and cancer-derived mortality. Sh3gl2 expression was undetectable in 19 of 20 human UC cell lines but preserved in the low-grade cell line RT4. Stable silencing of Sh3gl2 in RT4 cells by RNA interference 1) enhanced proliferation and colony formation in vitro, 2) inhibited EGF-induced EGFR internalization and increased EGFR activation, 3) stimulated phosphorylation of Src family kinases and STAT3, and 4) promoted growth of RT4 xenografts in subrenal capsule tissue recombination experiments. Conversely, forced re-expression of Sh3gl2 in T24 cells and silenced RT4 clones attenuated oncogenic behaviors, including growth and migration. Together, these findings identify loss of Sh3gl2 as a frequent event in UC development that promotes disease progression.

A phase II study of cabozantinib (XL184) in patients with advanced/metastatic urothelial carcinoma.

TPS4589 Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.

The Significance of Fragile Histidine Triad Protein as a Molecular Prognostic Marker of Bladder Urothelial Carcinoma

The role and clinical significance of fragile histidine triad (FHIT) gene in the pathogenesis of bladder urothelial carcinoma (UC) and the potential of Fhit protein as a prognostic biomarker for UC were investigated. FHIT expression was determined according to semiquantitative immunohistochemical staining for Fhit protein levels in normal bladder and bladder UC tissues. Associations between FHIT expression, clinicopathological features and survival were evaluated. This study evaluated 42 cases of normal bladder and 125 cases of bladder UC; bladder UC cases had a median follow-up of 53.5 months. Immuno histochemistry showed that 95.2% of normal cases and 47.2% of bladder UC cases, respectively, were positive for Fhit protein; this difference was statistically significant. There was a significant association between negative FHIT expression in bladder UC and advanced tumour stage, high pathological grade, large tumour size, tumour recurrence and reduced survival time, but no association with age, gender, tumour number or tumour shape. The FHIT gene may have an important role in the pathogenesis of bladder UC and was expressed at lower levels in bladder UC compared with normal bladder tissue. Using Fhit protein as a biomarker could provide important information about patient prognosis.

Newer developments in the therapeutics of the transitional cell carcinoma of renal pelvis

Many of the risk factors and pathogenesis of urothelial carcinoma of the renal pelvis are similar to the ones of the more common urothelial bladder cancer. In addition, two endemic nephropathies and two inherited syndromes have been linked with the development of upper urologic cancer. Multiple synchronous or metachronous lesions throughout urinary tract are rather common and should always be sought in the management of this entity. Surgical resection is the treatment of choice in early-stage tumors. The role of adjuvant radiation and chemoradiation for carcinoma of the renal pelvis remains to be redefined, given the advent of conformal approaches and intensity modulation. In non-surgical candidates, chemotherapy remains the mainstay. Metastatic urothelial renal pelvic cancer is usually treated with combination platinum-based chemotherapy. Definitive radiation therapy should be considered in persons with locally advanced/unresectable disease, multiple comorbidities, and/or severely compromised performance status. Recently, the antifolate agent pemetrexed has demonstrated an overall response rate of circa 30% in urothelial carcinoma. New targeted agents, alone or in combination with cytotoxic drugs, are currently being tested in clinical trials and may lead to new and exciting avenues for the therapy of this disease.

The effect of gender on response to bacillus Calmette‐Guérin therapy for patients with non‐muscle‐invasive urothelial carcinoma of the bladder

To determine the influence of gender on the outcome of patients with high-risk non-muscle-invasive bladder cancer treated with intravesical bacille Calmette-Guérin (BCG) therapy, as the role of hormone status in the pathogenesis of urothelial carcinoma and the response to treatment remains subject to debate. We reviewed 1021 consecutive patients (756 men and 265 women) who were treated with induction BCG between 1978 and 2006 for multiple or recurrent high-grade Ta, T1, and/or carcinoma in situ (CIS) bladder cancer. All patients had > or = 5 years of follow-up. The endpoints of initial response to BCG and the time to disease recurrence and progression were correlated with gender using Kaplan-Meier methods and multivariate Cox regression models. Men were significantly more likely to present with high grade (P = 0.003) tumours and with CIS (P < 0.001), while age and clinical stage at presentation were similar between men and women. There was no significant difference in the initial response to BCG by gender, as 593/756 (78.4%) men and 219/265 (82.6%) women had no evidence of disease at 6 months after BCG treatment (P = 0.14). The median time to recurrence after BCG therapy was also similar for men and women (20 vs 21 months, P = 0.51). Likewise, there was no evidence of a significant association between gender and the risk of disease progression after BCG therapy, such that the 5-year estimated freedom from progression was 77% and 82%, respectively, for men and women (P = 0.08). Moreover, on a multivariate analysis controlling for patient age and tumour stage, grade and CIS, gender was not associated with the risk of recurrence (hazard ratio 0.94, 95% confidence interval 0.79-1.11; P = 0.44) or progression (1.18, 0.85-1.63; P = 0.33) after BCG. When the outcomes for women treated with BCG were stratified by age <50 years (the median age of menopause in the USA) vs > or = 50 years, again there were no differences in the risk of tumour recurrence (P = 0.95) or progression (P = 0.35). These data suggest that the outcomes of men and women with high risk non-muscle-invasive urothelial carcinoma treated with BCG are similar. As such, further studies are required to determine the clinical relevance of preclinical evidence that has suggested a potential role for sex steroids in the pathophysiology of bladder cancer.

Non-muscle invasive bladder cancer with concomitant vaginal urothelial carcinoma: a case report and review of the literature

A 74-year-old female was referred to our hospital for non-muscle invasive bladder tumors initially treated at another hospital. Preoperatively, computed tomography and magnetic resonance imaging demonstrated non-muscle invasive bladder tumors and a vaginal tumor. A second transurethral resection of the bladder tumors, transvaginal tumor resection, and systemic chemotherapy were performed. The histopathological appearances of both tumors were very similar and the diagnoses were urothelial carcinoma (UC). The pathogenesis of the vaginal UC was considered to be the primary UC or metastasis from the bladder UC. Vaginal UC is extremely rare and this is only the 15th report in the literature.

Management of Bladder Cancer

Cancer of the urinary bladder is the fifth most prevalent solid tumour in the US. Urothelial carcinoma is the most common form of bladder cancer, accounting for about 90% of cases. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. Urothelial carcinoma is a chemo-sensitive disease, with a high overall and complete response rate to combination chemotherapy. In the setting of muscle-invasive urothelial carcinoma, use of neoadjuvant chemotherapy is associated with overall survival benefit. The role of adjuvant chemotherapy in this setting is yet to be validated. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients. Currently, there is no standard second-line therapy for patients in whom first-line chemotherapy for metastatic disease has failed. Many newer chemotherapeutic agents have shown modest activity in urothelial carcinoma. Improved understanding of molecular biology and pathogenesis of urothelial carcinoma has opened avenues for the use of molecularly targeted therapies, several of which are being tested in clinical trials. Currently, several novel drugs seem particularly promising including inhibitors of the epidermal growth factor receptor pathway, such as cetuximab, and inhibitors of tumour angiogenesis, such as bevacizumab and sunitinib. Development of reliable molecular predictive markers is expected to improve treatment decisions, therapy development and outcomes in urothelial carcinoma. Funding of and participation in clinical trials are key to advancing the care of urothelial cancer patients. Current and emerging strategies in the medical management of urothelial carcinoma are reviewed.

The Role of Genetic Instability in the Pathogenesis and Progression of Urothelial Carcinoma

Cancer appears to arise as a series of rate limiting steps, each of which represents the attainment of one cellular capability necessary for uncontrolled growth and invasion. As alterations in gene number or sequence can lead to the development of these cellular capabilities, the regulation of DNA fidelity is a vital homeostatic process. Mechanisms that disrupt DNA regulation lead to genomic instability and occur on two levels affecting either chromosomes (CIN; chromosomal instability) or individual DNA nucleotides (MSI; microsatellite instability). We conducted a search of the current literature to evaluate the evidence for the genomic instability in urothelial carcinoma (UC), and discuss the clinical role of the molecular pathways. Whilst CIN occurs more frequently in UC than MSI, the MSI molecular pathway is better understood. Distinct patterns of MSI occur in upper and lower urinary tract UC and produce tumours with a distinctive phenotype. Investigations into the mechanism of MSI in UC have revealed insights into the global pathogenesis of UC, similarities with other anatomically distant cancers and novel therapeutic strategies. The molecular mechanisms of CIN remain elusive.