Stromal TGF-ß signaling mediates prostatic response to androgen ablation by paracrine Wnt activity

Mechanisms of androgen dependence of the prostate are critical to understanding prostate cancer progression to androgen independence associated with disease mortality. A transient elevation of transforming growth factor-beta (TGF-ß) expression after androgen ablation suggested cooperation of the pathways in prostate regression. To determine the role of TGF-ß on prostate response to androgen ablation, conditional TGF-ß type II receptor knockout mouse models of the epithelia (Tgfbr2 NKX3.1KO ) and stromal fibroblasts (Tgfbr2 fspKO ) were used. Following 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 through out the glandular epithelia regardless of androgen status. In contrast, Tgfbr2 FloxE2/FloxE2 prostates had epithelial canonical Wnt activity only in the surviving proximal ducts following 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 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. The studies reveal a novel TGF-ß, androgen, and Wnt paracrine signaling axis that enables prostatic regression of the distal ducts following androgen ablation while supporting proximal duct survival.