Expression profile of Rho kinases in urinary bladder cancer.

PURPOSE: To investigate the expression of RhoA, RhoB, RhoC, Rac1 and Cdc42 kinases in urothelial cell carcinoma (UCC) of the urinary bladder and determine the expression profile of 107 Rho-associated genes, including GTPases, GDIs, GAPs and GEFs. METHODS: Rho expression was investigated using microarrays, qPCR and Western blotting in 77 UCC specimens with paired normal urothelium. Computational analysis was also performed on Gene Expression Omnibus datasets. Further microarray analysis was carried out for the expression profiling of the Rho-associated genes. RESULTS: RhoB mRNA and protein levels were significantly lower in UCC, suggesting a tumour-suppressor role. On the contrary, mRNA of RhoC and protein levels of RhoA, RhoC and Cdc42, respectively, were significantly higher in UCC vs. normal tissue. High Cdc42 mRNA levels correlated with worse overall survival (p=0.027), whereas high RhoB mRNA levels correlated both with better overall (p=0.0258) and cancer-specific (p=0.0272) survival. Computational analysis verified the expression profile of Rho kinases among superficial UCCs, muscle-invasive UCCs and normal tissues. CONCLUSION: The majority of the Rho-related genes showed over-expression in UCC vs. normal tissue. Alterations in RhoA, RhoB, RhoC, Rac1 and Cdc42 expression play a significant role in the genesis and progression of UCC of the urinary bladder.

Molecular mechanisms in urinary bladder carcinogenesis.

Urinary bladder cancer accounts for approximately 5% of all newly diagnosed malignancies in the developed world. Smoking, occupational exposure and dietary factors constitute the most important exogenous risk factors for bladder carcinogenesis. Yet, individuals with seemingly equal exposure to environmental carcinogens develop bladder cancer in an unpredictable manner. This is probably attributed to the fact that DNA repair capacity varies in human populations, pointing the role of genetic susceptibility in human cancer. Numerous studies demonstrated that certain genetic and epigenetic alterations are fairly constant. Loss of heterozygosity (LOH) at chromosome 9 is an aberration found in urothelial cell carcinoma (UCC) of all stages and grades as well as in dysplastic urothelium, possibly representing an early event in urinary bladder carcinogenesis. On the contrary, gains of 3p can only be found in tumors demonstrating highly malignant behavior. Microsatellite instability (MSI) is another frequent finding in urinary bladder cancer. This has led many investigator groups to employ the analysis for MSI for early diagnosis of UCC with promising results. The silencing of certain genes such as p16(INK4A) and DAPK by aberrant methylation of their promoter region also represents an important mechanism in carcinogenesis. Similarly, alterations in certain tumor suppressor genes and proto-oncogenes result in uncontrolled cell proliferation, reduced apoptosis and have been associated with more aggressive UCC phenotypes. Undoubtedly, the application of these observations in clinical practice will make a breakthrough in the management of bladder cancer.

Pheochromocytoma of the urinary bladder: report of 2 cases and review of literature.

Pheochromocytoma of the urinary bladder is a rare neoplasm of the chromaffin tissue of the sympathetic nervous system within the layers of the bladder wall. Approximately 220 cases have been reported in literature. It accounts for less than 0.06% of all urinary bladder tumors and less than 1% of all pheochromocytomas. Females are affected more frequently and it is more common between the second to fourth decades of life. The diagnosis is strongly based on the clinical symptoms related to catecholamine hypersecretion. In some cases however, the tumor is hormonally inactive and may go undetected for years. The cytologic features of benign and malignant tumors overlap and thus there are no reliable features of malignancy. Nevertheless the prognosis seems to be better for patients with superficial tumors comparing to patients with invasive tumors, found in 5-10% of cases. In the majority of cases the treatment of choice is surgical resection. For metastatic tumors, chemotherapy and radiotherapy seem to be effective. The authors present two new cases of pheochromocytoma of the urinary bladder. The presenting symptom was painless hematuria. Both patients had well-controlled blood pressure and none of the characteristic symptoms of pheochromocytoma. The authors discuss the difficulties in diagnosis and treatment and briefly review literature.