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Stromal Transforming Growth Factor-β Signaling Mediates Prostatic Response to Androgen Ablation by Paracrine Wnt Activity

Departments of ¹ Cancer Biology, ² Urologic Surgery, and ³ Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee and ⁴ Department of Medicine and Genetics and Development, Columbia University Medical Center, New York, New York

Requests for reprints: Neil A. Bhowmick, Department of Urologic Surgery, A-1302 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232. Phone: 615-343-7140; Fax: 615-322-5869; E-mail: neil.bhowmick{at}vanderbilt.edu.

Key Words: paracrine • TGF-β • Wnt

Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. Transient elevation of transforming growth factor-β (TGF-β) occurs after androgen ablation. To determine the role of TGF-β on prostate response to androgen ablation, conditional TGF-β type II receptor knockout mouse models of the epithelia (Tgfbr2^NKX3.1KO) and stromal fibroblasts (Tgfbr2^fspKO) were used. After castration, the prostates of Tgfbr2^NKX3.1KO mice had apoptosis levels similar to those expected for control Tgfbr2^{floxE2/floxE2} mice. Prostates of Tgfbr2^fspKO mice, however, had reduced regression and high levels of proliferation associated with canonical Wnt activity throughout the glandular epithelia regardless of androgen status. In contrast, Tgfbr2^{floxE2/floxE2} prostates had epithelial canonical Wnt activity only in the surviving proximal ducts after castration. In vitro studies showed that androgen antagonist, bicalutamide, transiently elevated both Tgfbr2^{floxE2/floxE2} and Tgfbr2^fspKO stromal expression of Wnt-2, Wnt-3a, and Wnt-5a. The neutralization of Wnt signaling by the expression of secreted frizzled related protein-2 (SFRP-2) resulted in decreased LNCaP prostate epithelial cell proliferation in stromal conditioned media transfer experiments. In vivo tissue recombination studies using Tgfbr2^fspKO prostatic stromal cells in combination with wild-type or SV40 large T antigen expressing epithelia resulted in prostates that were refractile to androgen ablation. The expression of SFRP-2 restored the Tgfbr2^fspKO-associated prostate responsiveness to androgen ablation. These studies reveal a novel TGF-β, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts after androgen ablation while supporting proximal duct survival. [Cancer Res 2008;68(12):4709–18]

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