Prognostic Impact of Canonical TGF-β Signaling in Urothelial Bladder Cancer.

: Dysregulation of TGF-β signaling plays multiple roles in cancer development and progression. In the canonical TGF-β pathway, TGF-β regulates the expression of hundreds of target genes via interaction with Smads, signal transducers and transcriptional modulators. We evaluated the association of TGF-β1, Smad2, and Smad4, the key components of canonical TGFβ pathway, with clinicopathologic characteristics of urothelial bladder cancer, and assessed their prognostic value in prediction of patients' outcome. : Immunohistochemical analysis of TGF-β1, Smad2, and Smad4 expression was performed on 404 urothelial bladder cancer samples, incorporated in tissue microarrays. Expression status was correlated with clinicopathological and follow-up data. The median follow-up was 61 months. : High expression of TGF-β1, Smad2, and Smad4 was detected in 68.1%, 31.7% and 45.2% of the tumors, respectively. TGF-β1 overexpression was significantly associated with high tumor grade, and advanced pathologic stage ( < 0.001, respectively). Conversely, high Smad2 and Smad4 expression was linked to low tumor grade ( = 0,003, = 0.048, respectively), and low tumor stage ( < 0.001, = 0.003, respectively). Smad2 showed an inverse correlation with variant morphology and divergent differentiation of urothelial tumors ( = 0.014). High TGF-β1 correlated directly, while Smad2 and Smad4 correlated inversely to cancer-specific death ( = 0.043, = 0.003, and = 0.022, respectively). There was a strong relationship between Smad2 and Smad4 expression ( < 0.001). Survival analyses showed that high Smad2 and Smad4 expression was associated with longer overall survival ( = 0.003, = 0.034, respectively), while in multivariate regression analysis TGF-β1 manifested as an independent predictor of poor outcome. : Unraveling the complex roles and significance of TGF-β signaling in urothelial bladder cancer might have important implications for therapy of this disease. Assessment of TGF-β pathway status in patients with urothelial bladder cancer may provide useful prognostic information, and identify patients that could have the most benefit from therapy targeting TGF-β signaling cascade.