Stromal TGF-β signaling induces AR activation in prostate cancer

// Feng Yang 1 , Yizhen Chen 1 , Tao Shen 1 , Dan Guo 1 , Olga Dakhova 2 , Michael M. Ittmann 2 , Chad J. Creighton 3 , Yiqun Zhang 3 , Truong D. Dang 1 , David R. Rowley 1 1 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 2 Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030 3 Department of Medicine, Baylor College of Medicine, Houston, TX 77030 Correspondence to: Feng Yang, e-mail: fyang@bcm.edu David Rowley, e-mail: drowley@bcm.edu Keywords: TGF-β, AR, tumor microenvironment, prostate stroma, prostate cancer, co-culture Received: April 24, 2014      Accepted: September 27, 2014      Published: November 06, 2014 ABSTRACT AR signaling is essential for the growth and survival of prostate cancer (PCa), including most of the lethal castration-resistant PCa (CRPC). We previously reported that TGF-β signaling in prostate stroma promotes prostate tumor angiogenesis and growth. By using a PCa/stroma co-culture model, here we show that stromal TGF-β signaling induces comprehensive morphology changes of PCa LNCaP cells. Furthermore, it induces AR activation in LNCaP cells in the absence of significant levels of androgen, as evidenced by induction of several AR target genes including PSA, TMPRSS2, and KLK4. SD-208, a TGF-β receptor 1 specific inhibitor, blocks this TGF-β induced biology. Importantly, stromal TGF-β signaling together with DHT induce robust activation of AR. MDV3100 effectively blocks DHT-induced, but not stromal TGF-β signaling induced AR activation in LNCaP cells, indicating that stromal TGF-β signaling induces both ligand-dependent and ligand-independent AR activation in PCa. TGF-β induces the expression of several growth factors and cytokines in prostate stromal cells, including IL-6, and BMP-6. Interestingly, BMP-6 and IL-6 together induces robust AR activation in these co-cultures, and neutralizing antibodies against BMP-6 and IL-6 attenuate this action. Altogether, our study strongly suggests tumor stromal microenvironment induced AR activation as a direct mechanism of CRPC.