Expression of the Endothelin Axis in Noninvasive and Superficially Invasive Bladder Cancer: Relation to Clinicopathologic and Molecular Prognostic Parameters

Background: 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. Objectives: 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. Design, setting, and participants: 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 (ETAR, ETBR), TP53, and Ki-67. FGFR3 mutations were detected by SNaPshot analysis. Measurements: The results were correlated with clinicopathologic parameters and disease-specific survival, overall survival, and recurrence-free survival. Results and limitations: Proteins of the ET axis were frequently expressed in bladder cancer (ET-1 in 62% of tumours, ETAR in 93% of tumours, and ETBR 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). ETAR 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 ETAR-expressing tumours (p = 0.040), whereas ETBR 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 ETAR immunoreactivity (p = 0.048) were correlated with poor prognosis. Conclusions: 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 ETAR expression may be an independent negative marker for recurrence-free survival.

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