Increased CK5/CK8-Positive Intermediate Cells with Stromal Smooth Muscle Cell Atrophy in the Mice Lacking Prostate Epithelial Androgen Receptor

Yuanjie Niu,Chih-Rong Shyr,Chawnshang Chang,Zhiqun Shang,Shuyuan Yeh,Juan Wang,Shu-Pin Huang,Irina Agoulnik

doi:10.1371/journal.pone.0020202

Abstract

Results from tissue recombination experiments documented well that stromal androgen receptor (AR) plays essential roles in prostate development, but epithelial AR has little roles in prostate development. Using cell specific knockout AR strategy, we generated pes-ARKO mouse with knock out of AR only in the prostate epithelial cells and demonstrated that epithelial AR might also play important roles in the development of prostate gland. We found mice lacking the prostate epithelial AR have increased apoptosis in epithelial CK8-positive luminal cells and increased proliferation in epithelial CK5-positive basal cells. The consequences of these two contrasting results could then lead to the expansion of CK5/CK8-positive intermediate cells, accompanied by stromal atrophy and impaired ductal morphogenesis. Molecular mechanism dissection found AR target gene, TGF-β1, might play important roles in this epithelial AR-to-stromal morphogenesis modulation. Collectively, these results provided novel information relevant to epithelial AR functions in epithelial-stromal interactions during the development of normal prostate, and suggested AR could also function as suppressor in selective cells within prostate.

Highlights

The prostate arises from the endodermal epithelium of the urogenital sinus (UGS), which is surrounded by an embryonic connective tissue called the urogenital sinus mesenchyme (UGM)
It has become increasingly apparent that TGF-b intimately regulates the proliferation, growth arrest, and differentiation of human prostatic stromal cells, which is increased in benign prostatic hyperplasia (BPH) [5,6,7]
androgen receptor (AR) is gradually deleted in the prostatic epithelium of the ventral, dorsal-lateral lobes, but not significantly in the anterial lobes, which is in agreement with early report [17]

Summary

Introduction

The prostate arises from the endodermal epithelium of the urogenital sinus (UGS), which is surrounded by an embryonic connective tissue called the urogenital sinus mesenchyme (UGM). In response to testosterone secreted from the fetal testis, epithelial buds emerge from the wall of the UGS and grow into the surrounding UGM, and undergo branching morphogenesis in the perinatal period. TGF-b signals may play important roles in the differentiation of prostate stroma by stimulation of the mature of smooth muscle cells. It has become increasingly apparent that TGF-b intimately regulates the proliferation, growth arrest, and differentiation of human prostatic stromal cells, which is increased in benign prostatic hyperplasia (BPH) [5,6,7]. Previous studies reported that TGF-b is an important regulator of stromal cell growth and promote the differentiation of prostatic stromal cells towards smooth muscle cell phenotype [8,9,10]. How epithelial AR regulates the expression and secretion of epithelium TGF-b has not been reported

Methods

Results

Discussion

Conclusion