Expression of the endothelin axis in noninvasive and superficially invasive bladder cancer: relation to clinicopathologic and molecular prognostic parameters.

Abstract

The endothelin (ET) axis plays a role in cancer biology and plays a potential role as a target for molecular therapy in urogenital tumours. Alterations of several proteins of the ET axis were detected in invasive bladder cancer. To examine the potential role of the expression of ET axis proteins compared to other prognostic parameters (kinase inhibitor 67 [Ki-67], tumour protein 53 [TP53], and fibroblast growth factor receptor 3 gene [FGFR3] mutations) in noninvasive and invasive bladder cancer. Tissue microarrays from 154 consecutive patients with pTa-pT2 urothelial bladder cancer were immunohistochemically stained for endothelin 1 (ET-1), endothelin A and B receptors (ET(A)R, ET(B)R), TP53, and Ki-67. FGFR3 mutations were detected by SNaPshot analysis. The results were correlated with clinicopathologic parameters and disease-specific survival, overall survival, and recurrence-free survival. Proteins of the ET axis were frequently expressed in bladder cancer (ET-1 in 62% of tumours, ET(A)R in 93% of tumours, and ET(B)R in 84% of tumours). ET-1 expression was strongly correlated with tumour stage (p=0.015), histologic grade (p=0.008), and low proliferation status (p=0.003). ET(A)R immunostaining was only associated with low proliferation status (p=0.015). Kaplan-Meier survival analysis showed a significantly longer overall survival for patients with ET-1-expressing tumours (p=0.007). A significantly longer disease-free survival was found in patients with ET(A)R-expressing tumours (p=0.040), whereas ET(B)R expression was significantly correlated to a longer disease-free survival only in subgroups of patients with multifocal tumours (p=0.031), low proliferation index (Ki-67 ≤10; p=0.050), low TP53 expression (≤10; p=0.018), and tumours with an FGFR3 mutation (p=0.026). In the global model for recurrence-free survival, only high-grade (p=0.048) and negative ET(A)R immunoreactivity (p=0.048) were correlated with poor prognosis. In addition to other factors, particularly age at diagnosis and growth pattern, lack of ET-1 expression may be an independent negative prognostic factor for the overall-survival probability of bladder cancer patients. Lack of ET(A)R expression may be an independent negative marker for recurrence-free survival.