TGF Beta1 Expression Correlates with Survival and Tumor Aggressiveness of Prostate Cancer.

ABSTRACT

BACKGROUND: Although biopsy Gleason score and clinical stage can be used to inform treatment decisions for prostate cancer, identifying molecular markers of tumor aggressiveness could lead to a more tailored approaches to therapy. In the present study, we investigated the association of transforming growth factor (TGF)-ß1 levels and various markers of tumor aggressiveness and explore some potential mechanisms underlying the associations. METHODS: We used human and murine prostate cancer cell lines and their respective hormone resistance sub-lines, in vitro and in vivo to examine the changes in tumor aggressiveness, as well as the pathway responsible for these changes. Furthermore, 105 prostate cancer biopsy specimens were analyzed to correlate the level of TGF-ß1 with the clinical characteristics of patients. RESULTS: Our data revealed that activated TGF-ß1 signaling resulted in more aggressive tumor growth and augmented the epithelial-mesenchymal transition. Activated IL-6 signaling was associated with TGF-ß1 levels and the aggressive tumor features noted in TGF-ß1-positive prostate cancers in vitro and in vivo. Furthermore, the TGF-ß1 levels significantly correlated with Tregs accumulation in vivo. The clinical data indicated that TGF-ß1 immunoreactivity had a moderate positive correlation with IL-6 staining, advanced clinical stage, higher Gleason score, and pretreatment PSA in patients with prostate cancer. CONCLUSIONS: TGF-ß1 levels are significantly associated with aggressive prostate features. In vitro and in vivo alternations of TGF-ß1 expression impacts tumor invasiveness, tumor growth rate and recruitment of immunosuppressive Treg cells in the tumor microenvironment. TGF-ß1 expression may represent a clinical useful biomarker to guide prostate cancer treatment decisions.