Stromal androgen receptor roles in the development of normal prostate, benign prostate hyperplasia, and prostate cancer

Abstract

The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa.

Figure 1

Stromal androgen receptor (AR) plays critical roles in the development of prostate. Recombination experiments and AR knockout animal models reveal that androgen through AR in embryonic stromal cells, but not AR in epithelial cells, directs the development of the prostate via mesenchymal-epithelial interactions. Some other growth factors, such as keratinocyte growth factor (KGF), fibroblast growth factors (FGFs), insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor β (VEGF-β), and transforming growth factor (TGF), are involved in this process.

Figure 2

Stromal androgen receptor (AR) promotes the progression of benign prostate hyperplasia (BPH). Stromal AR can affect the progression of BPH via promoting prostate epithelial cell growth, prostate stromal cell growth, epithelial-mesenchymal transition (EMT) progress, and the recruitment of macrophage. CCL, chemokine ligand; FGF, fibroblast growth factor; GMCSF, granulocyte colony stimulating factor; TGF, transforming growth factor.

Figure 3

Stromal androgen receptor (AR) promotes the progression of prostate cancer (PCa). Evidence from in vitro cell line studies, recombination experiments, and AR knockout animal models demonstrates that stromal AR can promote PCa growth, metastasis, and tumorigenesis. FGF, fibroblast growth factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; MIP, macrophage inflammatory protein; SDF, stromal derived factor; TGF, transforming growth factor.