Prostate-Specific Deletion of Cdh1 Induces Murine Prostatic Inflammation and Bladder Overactivity

Abstract

Benign Prostatic Hyperplasia (BPH) is an age-related debilitating prostatic disease that is frequently associated with prostatic inflammation and bothersome lower urinary tract symptoms (LUTS). Animal models have shown that formalin- and bacterial-induced prostatic inflammation can induce bladder dysfunction; however, the underlying mechanisms contributing to prostatic inflammation in BPH and bladder dysfunction are not clear. We previously reported that E-cadherin expression in BPH is down-regulated in hyperplastic nodules compared to expression in adjacent normal tissues. Here, we explored the potential consequences of prostatic E-cadherin down-regulation on the prostate and bladder in vivo using an inducible murine model of prostate luminal epithelial-specific deletion of Cdh1. The PSA-CreER T2 transgenic mouse strain expressing tamoxifen-inducible CreER T2 recombinase driven by a 6-kb human PSA promoter/enhancer was crossed with the B6.129-Cdh1 tm2Kem/J mouse to generate bigenic PSA-CreER T2/Cdh1 -/- mice. Deletion of E-cadherin was induced by transient administration of tamoxifen when mice reached sexual maturity (7 weeks of age). At 21-23 weeks of age, the prostate, bladder, and prostatic urethra were examined histologically, and bladder function was assessed using Void Spot Assays and cystometry. Mice with Cdh1 deletion had increased prostatic inflammation, prostatic epithelial hyperplasia and stromal changes at 21-23 weeks of age, as well as changes in bladder voiding function compared to age-matched controls. Thus, loss of E-cadherin in the murine prostate could result in prostatic defects that are characteristic of BPH and lower urinary tract symptoms, suggesting that E-cadherin down-regulation could be a driving force in human BPH development and progression.

E-cadherin deficiency promotes prostate macrophage inflammation and bladder overactivity in aged male mice

“…Similar to the pattern of E-cadherin immunostaining observed in prostate specimens from BPH patients, mice at 24 months of age displayed cell membrane E-cadherin expression in the epithelial layer of both Control and Cdh1 +/- mice, with a diffuse decreased expression in prostate glands of Cdh1 +/- mice in all lobes of the prostate (blue arrows, Figure 1D , center panel, Supplementary Figure 1 ). Cdh1 +/- mice also displayed glands with the mosaic pattern of E-cadherin negative cells surrounded by E-cadherin positive cells (black arrows, Figure 1D , right panel), similar to the pattern observed in Cdh1 -/- mice at 6 months of age [ 13 ].…”

“…E-cadherin immunostaining of the epithelial layer in normal adjacent prostate to BPH and BPH glands was uniformly distributed and most intense along the cell membrane, with decreased staining observed in BPH glands as evidenced by a reduction of clearly demarked E-cadherin positive cell borders in BPH glands ( Figure 1B ) [ 6 ]. This diffuse reduction in E-cadherin staining was not observed in mice with a homozygous deletion of the E-cadherin gene in luminal epithelial cells [ 13 ] ( Figure 1C ). While these Cdh1 -/- mice contain many prostate epithelial cells lacking E-cadherin staining, they are often found surrounded by E-cadherin positive luminal epithelial cells in a mosaic pattern [ 13 ] ( Figure 1C ).…”

“…This diffuse reduction in E-cadherin staining was not observed in mice with a homozygous deletion of the E-cadherin gene in luminal epithelial cells [ 13 ] ( Figure 1C ). While these Cdh1 -/- mice contain many prostate epithelial cells lacking E-cadherin staining, they are often found surrounded by E-cadherin positive luminal epithelial cells in a mosaic pattern [ 13 ] ( Figure 1C ). This is likely the result of replenishment of luminal epithelial cells from a basal progenitor that was not ablated of the E-cadherin gene [ 19 ].…”

“…We recently generated a murine model with homozygous deletion of the E-cadherin gene in prostatic luminal epithelial cells to determine functional consequences of E-cadherin ablation in BPH pathogenesis [ 13 ]. While these mice developed prostatic inflammation and overactive bladder at 6 months of age [ 13 ], this does not match strong aging-dependent development of LUTS in humans. This may be related to the findings that E-cadherin is only partially reduced in BPH luminal cells [ 14 – 16 ] and aging alone may induce changes in prostate and bladder [ 11 , 12 ].…”

Male Lower Urinary Tract Dysfunction: An Underrepresented Endpoint in Toxicology Research

“…A recent mouse model of prostate inflammation is based off observations that prostate secretory proteins are leaked into prostate stroma of some men with LUTD and accompanied with patchy loss of the adherens junction protein e-cadherin, suggesting a loss of prostate barrier function [226]. Genetic depletion of e-cadherin in mouse prostate epithelium increases prostate mass and cell proliferation, thickens prostate stroma, and increases voiding frequency while reducing voided urine volume, and increases spontaneous bladder contractions [227].…”