A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is usually described as a pathological proliferation of prostatic fibroblasts/myofibroblasts and epithelial cells. In the present study of BPH samples, we have made a morphological and immunohistochemical study of BPH prostatic sections using markers of proliferation, apoptosis, hormone receptors, and TGF-beta signaling. We found no evidence of proliferation in the stroma but in the epithelium of some ducts; 0.7% of the basal and 0.4% of luminal cells were positive for Ki67 and PCNA. Androgen receptor and estrogen receptor beta (ERbeta)1 and ERbetacx were abundant in both stromal and epithelial compartments but cells expressing ERalpha were very rare. What was very common in all BPH samples was the following: (i) regions of the ductal epithelium where the epithelial cells did not express E-cadherin, had lost their polarization, and become spindle shaped (the nuclei of these cells were strongly positive for pSmad 3 and Snail); and (ii) regions where the walls of the blood vessels were extremely thick and there was loss of endothelial layer. Loss of E-cadherin, increased pSmad 3, and high expression of Snail are all characteristic of epithelial-mesenchymal transition (EMT). We conclude that BPH is not a disease of prostatic stromal proliferation but rather of accumulation of mesenchymal-like cells derived from the prostatic epithelium and the endothelium. TGF-beta is thought to play a key role in EMT. Our data suggests that TGF-beta/Smad should be considered as targets for treatment of BPH.

Fig. 1.

Expression of ERβ1, ERα, AR, and ERβcx in the representative BPH tissue samples. Immunostaining of ERβ1 (A and B). ERβ1 is expressed both in the basal and luminal cells in the glandular epithelium. It is also present in the nuclei of some stromal cells. Both epithelium and stroma are almost negative for ERα (C and D). AR is consistently found in the nuclei of luminal cells, as well as stromal cells in high proportion (E and F). ERβcx is detected mostly in the epithelium of the ducts, both in basal and luminal cells (G) and less frequently in the stroma (H). (Scale bar, 100 μm.)

Fig. 2.

Proliferation and apoptosis in prostate samples from BPH patients. Index of proliferation was calculated by using the markers Ki67 and PCNA. (B and D) Shown is the lack of expression of proliferation in the stromal compartment. In the epithelium of some ducts, Ki67-positive (A) or PCNA-positive (C) were detected mostly in the basal layer. The antiapoptotic protein Bcl-2 was strongly detected in epithelium (E) and in some infiltrations of immune cells in the stroma (F). (Scale bar, 100 μm.)

Fig. 3.

Distribution of CK8, E-cadherin, and vimentin in BPH prostatic glandular epithelium. CK8 expression was detected by using LMW antibody. A down-regulation of this cytokeratin is observed in multilayer epithelium ducts (A and B) that are losing epithelium organization. E-cadherin is almost absent in BPH ducts as is shown in C and in more detail in D. An increase in vimentin expression is detected in hyperplastic glands and surrounding stroma (E and F). (Scale bar, 100 μm.)

Fig. 4.

Detection of EMT regulators in BPH tissue. The expression of the transcriptional factors pSmad 3 (A and B), Snail (C and D), and Slug (E and F) were analyzed in BPH samples. We observe a markedly nuclear staining of these factors in areas of epithelium remodeling where cells are getting an elongated appearance. (Scale bar, 50 μm.)