Stroma Of Benign Prostatic Hyperplasia Research Articles

Spatial transcriptomics identifies candidate stromal drivers of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is the nodular proliferation of the prostate transition zone in older men, leading to urinary storage and voiding problems that can be recalcitrant to therapy. Decades ago, John McNeal proposed that BPH originates with the "reawakening" of embryonic inductive activity by adult prostate stroma, which spurs new ductal proliferation and branching morphogenesis. Here, by laser microdissection and transcriptional profiling of the BPH stroma adjacent to hyperplastic branching ducts, we identified secreted factors likely mediating stromal induction of prostate glandular epithelium and coinciding processes. The top stromal factors were insulin-like growth factor 1 (IGF1) and CXC chemokine ligand 13 (CXCL13), which we verified by RNA in situ hybridization to be coexpressed in BPH fibroblasts, along with their cognate receptors (IGF1R and CXCR5) on adjacent epithelium. In contrast, IGF1 but not CXCL13 was expressed in human embryonic prostate stroma. Finally, we demonstrated that IGF1 is necessary for the generation of BPH-1 cell spheroids and patient-derived BPH cell organoids in 3D culture. Our findings partially support historic speculations on the etiology of BPH and provide what we believe to be new molecular targets for rational therapies directed against the underlying processes driving BPH.

RNA sequencing and integrative analysis reveal pathways and hub genes associated with TGFβ1 stimulation on prostatic stromal cells.

Objective: Benign prostatic hyperplasia (BPH) is the most common urological disease in elderly men. The transforming growth factor beta 1 (TGFβ1) plays an important role in the proliferation and differentiation of BPH stroma. However, it is not clear yet which important pathways and key genes are the downstream of TGFβ1 acting on prostatic stromal cells. Methods: GSE132714 is currently the newer, available, and best high-throughput sequencing data set for BPH disease and includes the largest number of BPH cases. We examined the TGFβ1 expression level in BPH and normal prostate (NP) by analyzing the GSE132714 data set as well as carrying out immunohistochemistry of 15 BPH and 15 NP samples. Primary prostatic stromal cells (PrSCs) were isolated from five fresh BPH tissues. RNA sequencing and bioinformatics analysis were used to reveal important pathways and hub genes associated with TGFβ1 stimulation on PrSCs. Results: TGFβ1 was upregulated in BPH stroma compared to NP stroma. A total of 497 genes (244 upregulated and 253 downregulated) were differentially expressed in PrSCs with and without TGFβ1 stimulation. The Gene Ontology revealed that differentially expressed genes (DEGs) were mainly enriched in progesterone secretion, interleukin-7 receptor binding, and CSF1-CSF1R complex. The Wnt signaling pathway, PI3K−Akt signaling pathway, JAK−STAT signaling pathway, and Hippo signaling pathway were screened based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. FN1, SMAD3, CXCL12, VCAM1, and ICAM1 were selected as hub genes according to the degree of connection from the protein–protein interaction (PPI) network. Conclusion: This study sheds some new insights into the role of TGFβ1 in BPH stroma and provides some clues for the identification of potential downstream mechanisms and targets.

Roles of NF-κB activation in benign prostatic hyperplasia and association between NF-κB and HIF-1α

ObjectiveThe aim of this study was to elucidate the role of NF-κB activation in benign prostatic hyperplasia (BPH) using immunohistochemistry. MethodsImmunohistochemical staining for NF-κB was performed and evaluated, dividing into glands and stroma in 101 human BPH tissues. To evaluate the impacts of NF-κB activation on BPH progression, correlations between NF-κB expression and clinical findings, hormone receptors, and HIF-1α were evaluated. ResultsNF-κB expression was found in 37.6% and 30.7% in glands and stroma of BPH, respectively. Total and T-zone volumes in transrectal ultrasonography were significantly higher in patients with NF-κB activation than those without NF-κB activation in the stroma. However, NF-κB activation of stroma was not correlated with HIF-1α expression and microvessel density. In subgroup analysis based on NF-κB activation, androgen and progesterone receptors of stroma were highly expressed in HIF-1α negative cases than in HIF-1α positive cases. In cases without NF-κB activation, patients with HIF-1α positivity showed a high frequency of diffuse fibrosis than those with HIF-1α negativity (P = 0.001). ConclusionTaken together, our result showed that NF-κB activation of stroma was significantly correlated with low total and T-zone volumes in transrectal ultrasonography. Diffuse fibrosis was frequently found in patients with NF-κB inactivation and HIF-1α positivity.

Amide Proton Transfer Could Provide More Accurate Lesion Characterization in the Transition Zone of the Prostate.

There is an overlap comparing transition zone prostate cancer (TZ PCa) and benign prostatic hyperplasia (BPH) on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), creating additional challenges for assessment of TZ tumors on MRI. To evaluate whether amide proton transfer-weighted (APTw) imaging provides new diagnostic ideas for TZ PCa. Prospective. A total of 51 TZ PCa patients (age, 49-89), 44 stromal BPH (age, 57-92), and 45 glandular BPH patients (age, 56-92). A 3 T; T2WI turbo spin echo (TSE), quantitative T2*-weighted imaging, DWI echo planar imaging, 3D APTw TSE. Differences in APTw, apparent diffusion coefficient (ADC), and T2* among three lesions were compared by one-way analysis of variance (ANOVA). Regions of interest were drawn by two radiologists (X.Q.Z. and X.Y.Q., with 21 and 15 years of experience, respectively). Multivariable logistic regression analyses; ANOVA with post hoc testing; receiver operator characteristic curve analysis; Delong test. Significance level: P < 0.05. APTw among TZ PCa, stromal BPH, and glandular BPH (3.48% ± 0.83% vs. 2.76% ± 0.49% vs. 2.72% ± 0.45%, respectively) were significantly different except between stromal BPH and glandular BPH (P >0.99). Significant differences were found in ADC (TZ PCa 0.76 ± 0.16 × 10-3 mm2 /sec vs. stromal BPH 0.91 ± 0.14 × 10-3 mm2 /sec vs. glandular BPH 1.08 ± 0.18 × 10-3 mm2 /sec) among three lesions. APTw (OR=12.18, 11.80, respectively) and 1/ADC (OR=703.87, 181.11, respectively) were independent predictors of TZ PCa from BPH and stromal BPH. The combination of APTw and ADC had better diagnostic performance in the identification of TZ PCa from BPH and stromal BPH. APTw imaging has the potential to be of added value to ADC in differentiating TZ PCa from BPH and stromal BPH. 2 TECHNICAL EFFICACY: Stage 2.

E‐cadherin is downregulated in benign prostatic hyperplasia and required for tight junction formation and permeability barrier in the prostatic epithelial cell monolayer

We previously reported the presence of prostate-specific antigen (PSA) in the stromal compartment of benign prostatic hyperplasia (BPH). Since PSA is expressed exclusively by prostatic luminal epithelial cells, PSA in the BPH stroma suggests increased tissue permeability and the compromise of epithelial barrier integrity. E-cadherin, an important adherens junction component and tight junction regulator, is known to exhibit downregulation in BPH. These observations suggest that the prostate epithelial barrier is disrupted in BPH and E-cadherin downregulation may increase epithelial barrier permeability. The ultra-structure of cellular junctions in BPH specimens was observed using transmission electron microscopy (TEM) and E-cadherin immunostaining analysis was performed on BPH and normal adjacent specimens from BPH patients. In vitro cell line studies using benign prostatic epithelial cell lines were performed to determine the impact of small interfering RNA knockdown of E-cadherin on transepithelial electrical resistance and diffusion of fluorescein isothiocyanate (FITC)-dextran in transwell assays. The number of kiss points in tight junctions was reduced in BPH epithelial cells as compared with the normal adjacent prostate. Immunostaining confirmed E-cadherin downregulation and revealed a discontinuous E-cadherin staining pattern in BPH specimens. E-cadherin knockdown increased monolayer permeability and disrupted tight junction formation without affecting cell density. Our results indicate that tight junctions are compromised in BPH and loss of E-cadherin is potentially an important underlying mechanism, suggesting targeting E-cadherin loss could be a potential approach to prevent or treat BPH.

Revisiting quantitative multi-parametric MRI of benign prostatic hyperplasia and its differentiation from transition zone cancer.

This study investigates the multiparametric MRI (mpMRI) appearance of different types of benign prostatic hyperplasia (BPH) and whether quantitative mpMRI is effective in differentiating between prostate cancer (PCa) and BPH. Patients (n = 60) with confirmed PCa underwent preoperative 3T MRI. T2-weighted, multi-echo T2-weighted, diffusion weighted and dynamic contrast enhanced images (DCE) were obtained prior to undergoing prostatectomy. PCa and BPH (cystic, glandular or stromal) were identified in the transition zone and matched with MRI. Quantitative mpMRI metrics: T2, ADC and DCE-MRI parameters using an empirical mathematical model were measured. ADC values were significantly lower (p < 0.001) in PCa compared to all BPH types and can differentiate between PCa and BPH with high accuracy (AUC = 0.87, p < 0.001). T2 values were significantly lower (p < 0.001) in PCa compared to cystic BPH only, while glandular (p = 0.27) and stromal BPH (p = 0.99) showed no significant difference from PCa. BPH mimics PCa in the transition zone on DCE-MRI evidenced by no significant difference between them. mpMRI values of glandular (ADC = 1.31 ± 0.22µm2/ms, T2 = 115.7 ± 37.3ms) and cystic BPH (ADC = 1.92 ± 0.43µm2/ms, T2 = 242.8 ± 117.9ms) are significantly different. There was no significant difference in ADC (p = 0.72) and T2 (p = 0.46) between glandular and stromal BPH. Multiparametric MRI and specifically quantitative ADC values can be used for differentiating PCa and BPH, improving PCa diagnosis in the transition zone. However, DCE-MRI metrics are not effective in distinguishing PCa and BPH. Glandular BPH are not hyperintense on ADC and T2 as previously thought and have similar quantitative mpMRI measurements to stromal BPH. Glandular and cystic BPH appear differently on mpMRI and are histologically different.

Transition zone prostate cancer: Logistic regression and machine‐learning models of quantitative ADC, shape and texture features are highly accurate for diagnosis

The limitation of diagnosis of transition zone (TZ) prostate cancer (PCa) using subjective assessment of multiparametric (mp) MRI with PI-RADS v2 is related to overlapping features between cancers and stromal benign prostatic hyperplasia (BPH) nodules, particularly in small lesions. To evaluate modeling of quantitative apparent diffusion coefficient (ADC), texture, and shape features using logistic regression (LR) and support vector machine (SVM) models for the diagnosis of transition zone PCa. Retrospective. Ninety patients; 44 consecutive TZ PCa were compared with 61 consecutive BPH nodules (26 glandular/35 stromal). 3 T/T2 -weighted (T2 W) fast spin-echo, diffusion weighted imaging. A radiologist manually segmented lesions on axial images for quantitative ADC (mean, 10th , 25th -centile-ADC), T2 W-shape (circularity, convexity) and T2 W-texture (kurtosis, skewness, entropy, run-length nonuniformity [RLNU], gray-level nonuniformity [GLNU]) analysis. A second radiologist segmented one-fifth of randomly selected lesions to determine the reproducibility of measurements. The reference standard was histopathology for all lesions. Quantitative features were selected a priori and were compared using univariate and multivariate analysis. LR and SVM models of statistically significant features were constructed and evaluated using receiver operator characteristic (ROC) analysis. Subgroup analysis of TZ PCa vs. only stromal BPH and in lesions measuring <15 mm was performed. Agreement in measurements was assessed using the Dice similarity coefficient (DSC). Mean, 25th and 10th -centile ADC, circularity, and texture (entropy, RLNU, GLNU) features differed between groups (P < 0.0001-0.0058); however, at multivariate analysis only circularity and ADC metrics (P < 0.001) remained significant. LR and SVM models were highly accurate for the diagnosis of TZ PCa (sensitivity/specificity/AUC): 93.2%/98.4%/0.989 and 93.2%/96.7%/0.949, respectively, with no significance difference between the LR and SVM models (P = 0.2271). Reproducibility of segmentation was excellent (DSC 0.84 tumors and 0.87 BPH). Subgroup analyses of TZ PCa vs. stromal BPH (AUC = 0.976) and in <15 mm lesions (AUC = 0.990) remained highly accurate. LR and SVM models incorporating previously described quantitative ADC, shape and texture analysis features are highly accurate for the diagnosis of TZ PCa and remained accurate when comparing TZ PCa with stromal BPH and in smaller lesions. 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:940-950.

IMUNOMARCAÇÃO DE TGF-β EM PRÓSTATAS CANINAS NORMAIS E COM LESÕES PROLIFERATIVAS

Resumo O fator de crescimento transformador-β (TGF-β), um mediador do crescimento prostático, induz a angiogênese e inibe a proliferação celular. Neste estudo, esse marcador foi utilizado com o objetivo de avaliar sua imunomarcação no tecido normal e com lesões proliferativas benignas, pré-neoplásicas e neoplásicas da próstata canina. Para isso, foram selecionadas 54 glândulas com histomorfologia normal, hiperplasia prostática benigna (HPB) epitelial, HPB estromal, atrofia inflamatória proliferativa (PIA), neoplasia intraepitelial prostática (PIN) e carcinoma, utilizadas para a confecção de um bloco de microarranjo tecidual (Tissue Microarray - TMA). As lâminas de TMA foram submetidas à técnica de imunoistoquímica com o anticorpo anti-TGF-β, sendo avaliada a intensidade de imunomarcação nas células epiteliais e estromais. Houve imunomarcação de TGF-β no tecido normal e naqueles com lesões proliferativas. Maior imunomarcação de TGF-β foi constatada nas células do tecido prostático normal e com HPB, enquanto as células prostáticas com PIA, PIN e carcinoma exibiram menor imunomarcação dessa citocina, o que sugere a ação do TGF-β na manutenção da homeostase do tecido normal e com lesão proliferativa benigna e na progressão das lesões proliferativas pré-malignas e malignas da próstata canina.

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cell-conditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment.

TRAF6 regulates proliferation of stromal cells in the transition and peripheral zones of benign prostatic hyperplasia via Akt/mTOR signaling.

Increased prostatic smooth muscle tone and hyperplastic growth contribute to urethral obstruction and voiding symptoms in benign prostatic hyperplasia (BPH). It has been suggested that different proliferative potential of stromal cells between transition zone (TZ) and adjoining regions of the prostate plays a significant role in the development of BPH. However, the molecular mechanisms of this hyperplastic process remain unclear. We found tumor necrosis factor receptor-associated factor 6 (TRAF6) highly expressed in TZ stromal cells compared to peripheral zone (PZ) stromal cells by gene array analyzes. Therefore, we aim to study the potential mechanisms of stromal TRAF6 in promoting BPH progression. Stromal cells obtained from BPH-derived primary cultures. The TRAF6-siRNA vector were constructed and transfected into cultured human BPH primary TZ stromal cells, and TRAF6-overexpressing vector were constructed and transfected into cultured human BPH primary PZ stromal cells. Stromal cells were recombined with BPH-1 cells then subcutaneously inoculated into the kidney capsule of male nude mice. Cell proliferation was evaluated by CCK-8 assay. Multiple proteins in the Akt/mTOR pathway were assessed using western blot. TRAF6 levels were increased in TZ stroma compared with PZ stroma of BPH. The in vitro cell culture and in vivo cell recombination revealed that selective downregulation of TRAF6 in TZ stromal cells led to suppression of the proliferation, while upregulation of TRAF6 in PZ stromal cells enhanced the proliferation. We found that the Phosphorylation and Ubiquitination of Akt as well as the Phosphorylation of mTOR, P70S6K were decreased when TRAF6 was downregulated in primary cultured TZ stromal cells of BPH. TRAF6 can promote the proliferation of stromal cells of BPH via Akt/mTOR signaling. Our results may make stromal TRAF6 responsible for zonal characteristic of BPH and as a promising therapeutic strategy for BPH treatment.

Intraepithelial lymphocytes in relation to NIH category IV prostatitis in autopsy prostate.

Quantitative analysis of the number, normal and pathologic ratios between lymphocytes and epithelial cells (ECs), and the significance of intraepithelial lymphocytes (IELs) in normal prostatic epithelium, benign prostatic hyperplasia (BPH), and high grade prostatic intraepithelial neoplasia (PIN) in relation to NIH category IV prostatitis (histologic prostatitis: HP) was studied in autopsy prostate. IELs were analysed in 59 autopsy prostates, which was routinely embedded in paraffin and immunohistochemically stained for CD3. An average of 300-500 ECs were counted per case. The number of IELs was calculated as the mean/100 ECs. Category IV prostatitis was evaluated using NIH consensus grading system in terms of anatomical localization and grade. In healthy individuals the mean number of IELs/100 ECs was 0.61 ± 0.34% or ≤1 lymphocyte/100 ECs, which is considered as the normal basal level of prostate IELs. In category IV prostatitis, the mean number of IELs/100 ECs was 8.53 ± 3.25% or 5-11 lymphocytes/100 ECs. The number of IELs in both around and inside inflammation areas correlated to the grade and location of HP (P < 0.0001 and P < 0.0003), the presence of acute glandular inflammation (P < 0.0001), the scattered stromal lymphocytes (P = 0.029), and BPH and PIN associated prostatic inflammation (P < 0.0001). The study presents the first attempt to examine and score the basic quantitative values of prostatic IELs in normal prostate and in relation to category IV prostatitis. The detected normal upper limit of CD3+ IELs is 1 lymphocyte/100 ECs in the normal prostate epithelium. This is considered as an organ specific characteristic of the prostate-associated lymphoid tissue (PALT). Values >5 IELs/100 ECs indicate the presence of category IV prostatitis. The severity of inflammation correlates to the number of IELs. There is an intimate link between the quantity of the IELs, the degree of the severity and the localization of category IV prostatitis. HP is a chronic and dynamic inflammatory process affecting the whole prostate gland. The increased number of IELs suggests the immune or autoimmune character of category IV prostatitis, BPH and inflammatory preneoplastic (PIN) lesions in the prostatic tumor environment.

Proteomic analysis of patient tissue reveals PSA protein in the stroma of benign prostatic hyperplasia

Benign prostatic hyperplasia (BPH) is an age-related disease frequently associated with lower urinary tract symptoms (LUTS) that involves hyperplasia of both epithelial and stromal cells. Stromal fibrosis is a distinctive feature of BPH, but the exact mechanisms underlying this phenomenon are poorly understood. In the current study, proteomics analyses were utilized to identify proteins altered in the BPH stromal compartment from patients with symptomatic BPH. Stromal cells were isolated from histological nodules of BPH by laser capture microdissection (LCM) and subjected to liquid chromatography/mass spectrometry. Proteins identified included several stromal-specific proteins involved in extracellular matrix (ECM) remodeling, focal adhesion, and cellular junctions. Additionally, the proteomics array identified the presence of luminal epithelial secretory protein PSA. Immunostaining, ELISA, and in situ hybridization analyses of BPH tissues verified the presence of PSA protein but absence of PSA mRNA in the stromal compartment. E-cadherin was down-regulated in BPH epithelial cells compared to normal adjacent tissues, suggesting that alteration of cellular junctions could contribute to the presence of luminal epithelial secreted proteins PSA and KLK2 in the stromal compartment. The above findings suggest that the presence of secreted proteins PSA and KLK2 from prostate luminal epithelial cells in BPH stroma is a hallmark of BPH nodules, which could in part be due to alterations in cellular junction proteins and/or increased epithelial barrier permeability. Elucidating the cause and consequence of these secreted proteins in the stromal compartment of BPH may lead to new understanding of BPH pathogenesis as well as approaches to prevent and/or treat this common disease.

Transition Zone Prostate Cancer: Incremental Value of Diffusion-weighted Endorectal MR Imaging in Tumor Detection and Assessment of Aggressiveness

To evaluate the incremental value of using diffusion-weighted magnetic resonance (MR) imaging in addition to T2-weighted imaging for the detection of prostate cancer in the transition zone and the assessment of tumor aggressiveness. This retrospective HIPAA-compliant institutional review board-approved study included 156 consecutive patients (median age, 59.2 years) who underwent MR imaging before radical prostatectomy. Two readers who were blinded to patient data independently recorded their levels of suspicion on a five-point scale of the presence of transition zone tumors on the basis of T2-weighted imaging alone and then, 4 weeks later, diffusion-weighted imaging and T2-weighted imaging together. Apparent diffusion coefficients (ADCs) were measured in transition zone cancers and glandular and stromal benign prostatic hyperplasia. Areas under the receiver operating characteristic curves were used to evaluate detection accuracy, and generalized linear models were used to test ADC differences between benign and malignant prostate regions. Whole-mount step-section histopathologic examination was the reference standard. In overall tumor detection, addition of diffusion-weighted imaging to T2-weighted imaging improved the areas under the receiver operating characteristic curves for readers 1 and 2 from 0.60 and 0.60 to 0.75 and 0.71, respectively, at the patient level (P = .004 for reader 1 and P = .027 for reader 2) and from 0.64 and 0.63 to 0.73 and 0.68, respectively, at the sextant level (P = .001 for reader 1 and P = .100 for reader 2). Least squares mean ADCs (× 10(-3) mm(2)/sec) in glandular and stromal benign prostatic hyperplasia were 1.44 and 1.09, respectively. Mean ADCs were inversely associated with tumor Gleason scores (1.10, 0.98, 0.87, and 0.75 for Gleason scores of 3 + 3, 3 + 4, 4 + 3, and ≥ 4 + 4, respectively). Use of diffusion-weighted imaging in addition to T2-weighted imaging improved detection of prostate cancer in the transition zone, and tumor ADCs were inversely associated with tumor Gleason scores in the transition zone.

Diffusion kurtosis imaging study of prostate cancer: preliminary findings.

To evaluate the differences in parameters of diffusion kurtosis imaging (DKI) between prostate cancer, benign prostatic hyperplasia (BPH), and benign peripheral zone (PZ). Twenty-four foci of prostate cancer, 41 BPH nodules (14 stromal and 27 nonstromal hyperplasia), and 20 benign PZ from 20 patients who underwent radical prostatectomy were investigated. Diffusion-weighted imaging (DWI) was performed using 11 b-values (0-1500 s/mm(2) ). DKI model relates DWI signal decay to parameters that reflect non-Gaussian diffusion coefficient (D) and deviations from normal distribution (K). A mixed model analysis of variance and receiver operating characteristic (ROC) analyses were performed to assess the statistical significance of the metrics of DKI and apparent diffusion coefficient (ADC). K was significantly higher in prostate cancer and stromal BPH than in benign PZ (1.19 ± 0.24 and 0.99 ± 0.28 versus 0.63 ± 0.23, P < 0.001 and P < 0.001, respectively). K showed a trend toward higher levels in prostate cancer than in stromal BPH (1.19 ± 0.24 versus 0.99 ± 0.28, P = 0.051). On the ROC analyses, a significant difference in area under the curve was not observed between K and ADC, however, K showed the highest sensitivity among three parameters. DKI may contribute to the imaging diagnosis of prostate cancer, especially in the differential diagnosis of prostate cancer and BPH.

Transition Zone Prostate Cancer: Incremental Value of Diffusion-weighted Endorectal MR Imaging in Tumor Detection and Assessment of Aggressiveness

To evaluate the incremental value of using diffusion-weighted magnetic resonance (MR) imaging in addition to T2-weighted imaging for the detection of prostate cancer in the transition zone and the assessment of tumor aggressiveness. This retrospective HIPAA-compliant institutional review board-approved study included 156 consecutive patients (median age, 59.2 years) who underwent MR imaging before radical prostatectomy. Two readers who were blinded to patient data independently recorded their levels of suspicion on a five-point scale of the presence of transition zone tumors on the basis of T2-weighted imaging alone and then, 4 weeks later, diffusion-weighted imaging and T2-weighted imaging together. Apparent diffusion coefficients (ADCs) were measured in transition zone cancers and glandular and stromal benign prostatic hyperplasia. Areas under the receiver operating characteristic curves were used to evaluate detection accuracy, and generalized linear models were used to test ADC differences between benign and malignant prostate regions. Whole-mount step-section histopathologic examination was the reference standard. In overall tumor detection, addition of diffusion-weighted imaging to T2-weighted imaging improved the areas under the receiver operating characteristic curves for readers 1 and 2 from 0.60 and 0.60 to 0.75 and 0.71, respectively, at the patient level (P = .004 for reader 1 and P = .027 for reader 2) and from 0.64 and 0.63 to 0.73 and 0.68, respectively, at the sextant level (P = .001 for reader 1 and P = .100 for reader 2). Least squares mean ADCs (× 10(-3) mm(2)/sec) in glandular and stromal benign prostatic hyperplasia were 1.44 and 1.09, respectively. Mean ADCs were inversely associated with tumor Gleason scores (1.10, 0.98, 0.87, and 0.75 for Gleason scores of 3 + 3, 3 + 4, 4 + 3, and ≥ 4 + 4, respectively). Use of diffusion-weighted imaging in addition to T2-weighted imaging improved detection of prostate cancer in the transition zone, and tumor ADCs were inversely associated with tumor Gleason scores in the transition zone.

Down-Regulation of the Large-Conductance Ca&lt;sup&gt;2+&lt;/sup&gt;-Activated K&lt;sup&gt;+&lt;/sup&gt; Channel, K&lt;sub&gt;Ca&lt;/sub&gt;1.1 in the Prostatic Stromal Cells of Benign Prostate Hyperplasia

Large-conductance Ca(2+)-activated K(+) (BK(Ca)) channel encoded by K(Ca)1.1 plays an important role in the control of smooth muscle tone by modulating membrane potential and intracellular Ca(2+) mobilization. BK(Ca) channel is functionally expressed in prostatic smooth muscle cells, and is activated by α(1)-adrenoceptor agonists. The main objective of this study was to elucidate the pathophysiological significance of changes in prostatic K(Ca)1.1 expressions in benign prostatic hyperplasia (BPH). Our previous study has shown that K(Ca)3.1 encoding intermediate-conductance K(Ca) (IK(Ca)) channel is up-regulated in stromal cells of implanted urogenital sinuses (UGSs) of stromal hyperplasia BPH model rats and in those of prostatic tissues from BPH patients. In the present study, the results from real-time polymerase chain reaction (PCR), Western blot, and immunohistochemical analyses showed significant down-regulation of K(Ca)1.1 transcripts and proteins and negative correlation between K(Ca)1.1 and K(Ca)3.1 transcript expressions in prostatic stromal cells of both BPH model rats and BPH patients. Corresponding to down-regulation of K(Ca)1.1 expression in stromal cells of implanted UGSs, membrane depolarization by application of the BK(Ca) channel blocker was disappeared. Down-regulation of K(Ca)1.1 may be involved in the phenotype switch from contractile profile to proliferative one in prostatic stromal cells of BPH patients.

Intermediate-Conductance Ca2+-Activated K+ Channel, KCa3.1, as a Novel Therapeutic Target for Benign Prostatic Hyperplasia

Recently, a new experimental stromal hyperplasia animal model corresponding to clinical benign prostatic hyperplasia (BPH) was established. The main objective of this study was to elucidate the roles of the intermediate-conductance Ca(2+)-activated K(+) channel (K(Ca)3.1) in the implanted urogenital sinus (UGS) of stromal hyperplasia BPH model rats. Using DNA microarray, real-time polymerase chain reaction, Western blot, and/or immunohistochemical analyses, we identified the expression of K(Ca)3.1 and its transcriptional regulators in implanted UGS of BPH model rats and prostate needle-biopsy samples and surgical prostate specimens of BPH patients. We also examined the in vivo effects of a K(Ca)3.1 blocker, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), on the proliferation index of implanted UGS by measurement of UGS weights and proliferating cell nuclear antigen immunostaining. K(Ca)3.1 genes and proteins were highly expressed in implanted UGS rather than in the normal host prostate. In the implanted UGS, the gene expressions of two transcriptional regulators of K(Ca)3.1, repressor element 1-silencing transcription factor and c-Jun, were significantly down- and up-regulated, and the regulations were correlated negatively or positively with K(Ca)3.1 expression, respectively. Positive signals of K(Ca)3.1 proteins were detected exclusively in stromal cells, whereas they were scarcely immunolocalized to basal cells of the epithelium in implanted UGS. In vivo treatment with TRAM-34 significantly suppressed the increase in implanted UGS weights compared with the decrease in stromal cell components. Moreover, significant levels of K(Ca)3.1 expression were observed in human BPH samples. K(Ca)3.1 blockers may be a novel treatment option for patients suffering from BPH.

Expression of proteinase‐activated receptor‐2 (PAR2) is androgen‐dependent in stromal cell line (hPCPs) from benign prostatic hyperplasia

Growth properties of the prostate are regulated by a variety of hormones and growth factors. Benign prostatic hyperplasia (BPH) is characterized by abnormal epithelial and stromal proliferation. Varying androgen hormone levels in elderly men are correlated with abnormal proliferations of the prostate. Proteinase-activated receptor-2 (PAR2), a subtype of G-protein-coupled receptors, is known to induce multiple biological processes. It could also play a key role in the proliferation and metastasis of prostate cancer, but its effect on BPH pathogenesis is to a great extent unknown. Localization of PAR2 was determined both in pathologically altered and in normal prostate tissues by using immunohistochemical techniques. PAR2 activity was assessed by measuring changes in intracellular calcium [Ca(2+)](i) following stimulation of cultured stromal cells with a PAR2 agonist (trypsin) and a synthetic PAR2-activating peptide (AP). DHT-dependence of PAR2 expression in prostate cancer and prostatic stromal cell lines was examined with semi-quantitative and quantitative PCR. Cultured stromal cells (hPCPs) were stimulated with PAR2 AP and cell proliferation was determined through [(3)H]-thymidine incorporation. In comparison to normal prostate, PAR2 expression was increased in BPH stroma. DHT induced a higher expression of PAR2 when sub-physiological DHT-levels were used. Higher levels of DHT produced reduced PAR2 expression. A mitogenic effect was induced by applying PAR2 AP to hPCPs-cells. In conclusion, we found that PAR2 expression is hormone-dependent in prostatic stromal cells with a negative correlation and we consider it to be an important factor in mitogenesis in BPH.

Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor-beta (ERbeta) in BPH and PCa. ERbeta agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFalpha knock-out mice fail to respond to ERbeta agonist, demonstrating the requirement for TNFalpha signaling. In human tissues, ERbeta agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133(+) enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERbeta causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERbeta agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERbeta agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

Proton magnetic resonance spectroscopy of the central, transition and peripheral zones of the prostate: assignments and correlation with histopathology

Proton magnetic resonance spectroscopy (MRS) is used to compare the chemistry of the transition, central and peripheral zones of the prostate. The assignments are made using two-dimensional correlated spectroscopy and the results compared with histopathology. The chemistry associated with benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and malignant biopsy tissues are described. There are distinct MR spectral patterns for glandular and stromal BPH, PIN and adenocarcinoma. Importantly, there are also different spectral patterns from BPH in the transitional and central zones when compared to BPH in the peripheral zone. A pattern recognition method is used to analyze the MR spectra from the biopsy specimens. The resultant mathematical classifiers generated a high level of accuracy (sensitivity and specificity of 100 and 97%). It was found that for this accuracy to be achieved, the classifiers need to be developed by comparing the spectra with specialist serial sectioned histopathology. With serial sectioned pathology the pattern recognition method was capable of identifying less than 5% of adenocarcinoma in a given piece of tissue. Many of the chemicals identified in the biopsy specimens are available for inspection from the prostate, in vivo, at 3 T.