BACKGROUND: The classic cadherins, E-, P-, N and R- represent a family of transmembrane glycoproteins involved in calcium-dependent cell-cell adhesion, cell signaling, motility and invasion. The roles of E-cadherin and N-cadherin in bladder cancer have been investigated and are linked to the suppression or promotion of invasive potential, respectively. The expression of R-cadherin has not been reported in transitional cell carcinomas (TCC) although it has been shown to be involved in promoting the migration of cancer cells. In contrast, P-cadherin has been reported localized to the basal cell compartment of normal bladder mucosa, however, any potential role in bladder tumorigenesis has not been investigated. The goal of this study was to investigate the expression profile of P-cadherin in TCC and its correlation with clinical variables in order to define a potential role in bladder tumorigenesis.
METHODS: A total of 536 surgically resected bladder tumor specimens from 409 patients (269 superficial, 238 invasive and 29 Tx) were assembled in tissue microarrays (TMAs) and analyzed using immunohistochemistry. The intensity of P-cadherin staining was scored on a scale of 0-3. Cellular localization was recorded as membranous or cytoplasmic. Tissue localization of P-cadherin in each core was recorded as basal or unrestricted, the latter representing P-cadherin expression extending beyond the basal layer. Outcome analysis was performed using Pearson’s chi-square tests. Spearman’s correlation coefficient was used to compare P-cadherin with the expression of other cadherin/catenin elements. Overall and cancer-specific survival analysis was restricted to the cystectomy group and Kaplan-Meier/log rank test was performed.
RESULTS: The absence of P-cadherin staining was associated with muscle invasive disease, grade 3 classification (p<0.001) and nodal disease (p=0.009) but not lymphovascular invasion. Similar results were recorded when considering cytoplasmic and unrestricted localization of P-cadherin (p<0.001) with the exception of nodal involvement. A significant association was observed between cytoplasmic and unrestricted localization (R=0.266, p<0.001). Also, there was a significant correlation between loss of expression, cytoplasmic and unrestricted localization of P-cadherin with low expression and cytoplasmic localization of the cadherin complex components, plakoglobin, E-cadherin, β-catenin and p120^ctn. No correlation was recorded between the intensity of staining and the mesenchymal markers N-cadherin and vimentin, however, novel expression of vimentin correlated with cytoplasmic and unrestricted localization of P-cadherin. In survival analysis, the group with cytoplasmic localization of P-cadherin showed a shorter cancer-specific survival when compared to the group displaying membrane localization of P-cadherin (p=0.03). No difference was recorded between these groups in overall survival analysis.
CONCLUSIONS: In this study we have demonstrated that the loss of expression, the cytoplasmic relocation or the unrestricted tissue localization of P-cadherin, are associated with poor clinical outcome and prognosis in bladder cancer. The correlation between these parameters and the expression of other members of the cadherin-catenin complex in tumorigenesis identify a role for P-cadherin in bladder cancer.