Polygenic risk score predicting susceptibility and outcome of benign prostatic hyperplasia in the Han Chinese.

BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.

Aberrant activation of TGF-ß/ROCK1 enhances stemness during prostatic stromal hyperplasia.

Benign prostatic hyperplasia (BPH) is a multifactorial disease in which abnormal growth factor activation and embryonic reawakening are considered important factors. Here we demonstrated that the aberrant activation of transforming growth factor ß (TGF-ß)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. When TGF-ß/ROCK1 is abnormally activated, MSCs are recruited and differentiate into fibroblasts/myofibroblasts, leading to prostate stromal hyperplasia. Further research showed that inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation. Collectively, our findings suggest that abnormal activation of TGF-ß/ROCK1 regulates stem cell lineage specificity, and the small molecule inhibitor GSK269962A could target ROCK1 and may be a potential treatment for BPH.

CYP7B1 as a Biomarker for Prostate Cancer Risk and Progression: Metabolic and Oncogenic Signatures (Diagnostic Immunohistochemistry Analysis by Tissue Microarray in Prostate Cancer Patients-Diamond Study).

We aimed to analyze the association between CYP7B1 and prostate cancer, along with its association with proteins involved in cancer and metabolic processes. A retrospective analysis was performed on 390 patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH). We investigated the interactions between CYP7B1 expression and proteins associated with PC and metabolic processes, followed by an analysis of the risk of biochemical recurrence based on CYP7B1 expression. Of the 139 patients with elevated CYP7B1 expression, 92.8% had prostate cancer. Overall, no increased risk of biochemical recurrence was associated with CYP7B1 expression. However, in a non-diabetic subgroup analysis, higher CYP7B1 expression indicated a higher risk of biochemical recurrence, with an HR of 1.78 (CI: 1.0-3.2, p = 0.05). PC is associated with elevated CYP7B1 expression. In a subgroup analysis of non-diabetic patients, elevated CYP7B1 expression was associated with an increased risk of biochemical recurrence, suggesting increased cancer aggressiveness.

Potential role of oxidative stress in pathogenesis of benign prostatic hyperplasia in male dogs.

The pathogenesis of benign prostatic hyperplasia (BPH) in dogs is still not fully understood. Some studies suggest that oxidative stress may have a potential role in the pathogenesis of BPH in dogs. Age-related hormonal changes may activate a chronic inflammatory response in the prostate. This causes the generation of reactive oxygen species (ROS) and results in oxidative stress. Excessive production of ROS results in DNA damage and hyperplastic transformation of prostatic cells. The use of antioxidants for improvement of treatment outcomes for canine PBH has been discussed. Further research is needed on the importance of oxidative stress in the development of BPH in dogs and the usefulness of antioxidants in the supportive treatment of this condition.

The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats.

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset of benign prostatic hyperplasia, prostatitis, and prostate cancer. In this study, we used 14 aged male Sprague Dawley rats, which were allocated into two groups, at the age of 18 months old. One group was fed ad libitum (a normal diet (ND)), and the other group followed a caloric restriction diet with a 60% decrease in intake. The rats were sacrificed at the age of 24 months. By immunohistochemical (IHC) and Western blot (WB) analyses, we studied the variations between the two groups in immune inflammation and fibrosis-related markers in aged prostate tissues. Morphological examinations showed lower levels of prostatic hyperplasia and fibrosis in the CR rats vs. the ND rats. The IHC results revealed that the prostates of the CR rats exhibited a lower immune proinflammatory infiltrate level and a reduced expression of the NLRP3 inflammasome pathway, together with significantly reduced expressions of mesenchymal markers and the profibrotic factor TGFß1. Finally, by WB analysis, we observed a reduced expression of ERα, which is notoriously implicated in prostate stromal proliferation, and increased expressions of SOD1 and Hsp70, both exerting protective effects against oxidative stress. Overall, these data suggest that CR brings potential benefits to prostatic tissues as it reduces the physiological immune-inflammatory processes and the tissue remodeling caused by aging.

Effect of methanol extract of Plectranthus esculentus N.E.Br tuber and its fractions on indices of benign prostatic hyperplasia in Wistar rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Many ethnopharmacological properties (anti-tumor, etc.) have been credited to Plectranthus esculentus tuber but the scientific basis has not been established. AIM OF THE STUDY: To evaluate the effect of methanol extract of P. esculentus tuber (MEPET) (phase 1) and its fractions (phase 2) on benign prostatic hyperplasia (BPH) in rats. MATERIALS AND METHODS: The study was conducted in two phases. Phase 1, thirty-five male albino rats (6 weeks old) were divided into seven groups of five rats each: normal control (NC) received olive oil (subcutaneously) and water (orally); disease control (DC) received testosterone propionate (TP) (3 mg/kg) and water; test groups (1,2,3 and 4) received TP + MEPET at 100, 200, 400, 600 mg/kg respectively; positive control, received TP + finasteride (5 mg/70 kg). After 28 days, their relative prostate weights (RPW) and prostate specific antigen (PSA) were determined. Phase 2, thirty rats were divided into 6 groups of 5 rats each: NC received olive oil (subcutaneously daily) and dimethyl sulfoxide (DMSO) (orally); DC received TP (3 mg/kg), and DMSO; test group 1 received TP and aqueous fraction of MEPET (400 mg/kg); test group 2 received TP and methanol fraction of MEPET (400 mg/kg); test group 3 received TP, and ethyl acetate fraction of MEPET (400 mg/kg); positive control received TP and finasteride (5 mg/70 kg). After 28 days, their erythrocyte sedimentation rates, RPW, prostate levels of PSA, DHT, inflammatory, apoptotic markers and prostate histology were determined. RESULTS: Ethyl acetate fraction of MEPET modulated most of the parameters of BPH in the rats in a manner akin to finasteride as corroborated by prostate histology. CONCLUSIONS: EFPET could be useful in the treatment of BPH.

Prostatic stromal tumor of uncertain malignant potential: a case report and literature review.

Prostatic stromal tumors, encompassing prostatic sarcoma and stromal tumors of uncertain malignant potential (STUMP), represent an exceedingly rare category of prostatic diseases, with a prevalence of less than 1%. We present a rare case involving a man in his early 40s diagnosed with STUMP. Despite presenting with normal prostate-specific antigen (PSA) concentrations, the patient experienced persistent dysuria and gross hematuria for >7 months, leading to an initial misdiagnosis of benign prostatic hyperplasia. Persistent symptoms prompted further investigation, with magnetic resonance imaging (MRI) revealing a suspicious lesion on the left side of the prostate, initially thought to be malignant. Transrectal prostatic biopsy subsequently confirmed the presence of mucinous liposarcoma, with no medical history of diabetes, coronary heart disease, or hypertension. The treatment approach comprised robot-assisted laparoscopic radical prostatectomy, culminating in a postoperative pathological definitive diagnosis of STUMP. This case underscores the indispensable role of early MRI in the diagnostic process, highlighting the necessity of detailed pathological examination for a conclusive diagnosis. Our report aims to illuminate the diagnostic challenges and potential treatment pathways for STUMP, emphasizing its consideration in the differential diagnosis of prostatic tumors to advance clinical outcomes in this rare but important condition.

Activation of the cGMP/PKG/ERK signaling pathway associated with PDE5Is inhibits fibroblast activation by downregulating autophagy in early progressive benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia (BPH) is one of the most prevalent diseases affecting aging males. However, approximately, 8% of the BPH patients under 50-year-old experience remarkably early progression, for reasons that remain elusive. Among the various factors implicated in promoting BPH advancement, the activation of fibroblasts and autophagy hold particular importance. Our research endeavors to explore the mechanisms behind the accelerated progression in these patients. METHODS: Immunohistochemistry and immunofluorescence were performed to detect the expression levels of LC3, p62, PDE5, and α-SMA in diverse BPH tissues and prostate stromal cells. The autophagy activator rapamycin, the autophagy suppressor chloroquine, and siRNA transfection were used to identify the impact of autophagy on fibroblast activation. RESULTS: Prostatic stromal fibroblasts in early progressive BPH tissues displayed activation of autophagy with an upregulation of LC3 and a concurrent downregulation of p62. After starvation or rapamycin treatment to a heightened level of autophagy, fibroblasts exhibited activation. Conversely, chloroquine treatment and ATG-7-knockdown effectively suppressed the level of autophagy and fibroblast activation. High expression of PDE5 was found in early progressive BPH stromal cells. The administration of PDE5 inhibitors (PDE5Is) hindered fibroblast activation through suppressing autophagy by inhibiting the ERK signaling pathway. CONCLUSION: Our findings suggest that autophagy plays a pivotal role in promoting BPH progression through fibroblast activation, while PDE5Is effectively suppress autophagy and fibroblast activation via the ERK signaling pathway. Nevertheless, further investigations are warranted to comprehensively elucidate the role of autophagy in BPH progression.

Effects of Taraxaci Herba (Dandelion) on Testosterone Propionate-Induced Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.

Integrating spatial transcriptomics and single-cell RNA-sequencing reveals the alterations in epithelial cells during nodular formation in benign prostatic hyperplasia.

OBJECTIVE: Proliferative nodular formation represents a characteristic pathological feature of benign prostatic hyperplasia (BPH) and serves as the primary cause for prostate volume enlargement and consequent lower urinary tract symptoms (LUTS). Its specific mechanism is largely unknown, although several cellular processes have been reported to be involved in BPH initiation and development and highlighted the crucial role of epithelial cells in proliferative nodular formation. However, the technological limitations hinder the in vivo investigation of BPH patients. METHODS: The robust cell type decomposition (RCTD) method was employed to integrate spatial transcriptomics and single cell RNA sequencing profiles, enabling the elucidation of epithelial cell alterations during nodular formation. Immunofluorescent and immunohistochemical staining was performed for verification. RESULTS: The alterations of epithelial cells during the formation of nodules in BPH was observed, and a distinct subgroup of basal epithelial (BE) cells, referred to as BE5, was identified to play a crucial role in driving this progression through the hypoxia-induced epithelial-mesenchymal transition (EMT) signaling pathway. BE5 served as both the initiating cell during nodular formation and the transitional cell during the transformation from luminal epithelial (LE) to BE cells. A distinguishing characteristic of the BE5 cell subgroup in patients with BPH was its heightened hypoxia and upregulated expression of FOS. Histological verification results confirmed a significant association between c-Fos expression and key biological processes such as hypoxia and cell proliferation, as well as the close relationship between hypoxia and EMT in BPH tissues. Furthermore, a strong link between c-Fos expression and the progression of BPH was also been validated. Additionally, notable functional differences were observed in glandular and stromal nodules regarding BE5 cells, with BE5 in glandular nodules exhibiting enhanced capacities for EMT and cell proliferation characterized by club-like cell markers. CONCLUSIONS: This study elucidated the comprehensive landscape of epithelial cells during in vivo nodular formation in patients, thereby offering novel insights into the initiation and progression of BPH.

A prospective analysis of thulium laser enucleation in benign prostatic hyperplasia comparing low- and high-power approaches for prostates exceeding 80 g.

INTRODUCTION AND OBJECTIVES: To compare the perioperative and functional outcomes of low-power and high-power thulium:YAG VapoEnucleation (ThuVEP) of the prostate for the treatment of large-volume benign prostatic hyperplasia (BPH) (> 80 ml). PATIENTS AND METHODS: A prospective analysis of 80 patients with symptomatic BPO and prostatic enlargement (more than 80 ml) was conducted. They were divided randomly into two groups (40 patients in each group). One group was treated with low-power ThuVEP, and the other group was treated with high-power ThuVEP. All patients were assessed preoperatively and early postoperatively, and 12-month follow-up data were analyzed. The complications were noted and classified according to the modified Clavien classification system. RESULTS: The mean age at surgery was 68 (± 6.1) years, and the mean prostate volume was 112 (± 20.1) cc, and there were no differences between the groups (p = 0.457). The mean operative time was 88.4 ± 11.79 min for group A and 93.4 ± 16.34 min for group B, while the mean enucleation time was 59.68 ± 7.24 min for group A and 63.13 ± 10.75 min for group B. There were no significant differences between the groups regarding catheterization time and postoperative stay. The quality of life (QoL), International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), postvoiding residual urine (PVR), and prostate volume improved significantly after treatment and were not significantly different between those treated with the different energies. The incidence of complications was low and did not differ between both the groups. CONCLUSION: Low-power ThuVEP is feasible, safe, and effective with comparable results with high-power ThuVEP in the treatment of BPO.

Untargeted metabolomics reveals that declined PE and PC in obesity may be associated with prostate hyperplasia.

BACKGROUND: Recent studies have shown that obesity may contribute to the pathogenesis of benign prostatic hyperplasia (BPH). However, the mechanism of this pathogenesis is not fully understood. METHODS: A prospective case-control study was conducted with 30 obese and 30 nonobese patients with BPH. Prostate tissues were collected and analyzed using ultra performance liquid chromatography ion mobility coupled with quadrupole time-of-flight mass spectrometry (UPLC-IMS-Q-TOF). RESULTS: A total of 17 differential metabolites (3 upregulated and 14 downregulated) were identified between the obese and nonobese patients with BPH. Topological pathway analysis indicated that glycerophospholipid (GP) metabolism was the most important metabolic pathway involved in BPH pathogenesis. Seven metabolites were enriched in the GP metabolic pathway. lysoPC (P16:0/0:0), PE (20:0/20:0), PE (24:1(15Z)/18:0), PC (24:1(15Z)/14:0), PC (15:0/24:0), PE (24:0/18:0), and PC (16:0/18:3(9Z,12Z,15Z)) were all significantly downregulated in the obesity group, and the area under the curve (AUC) of LysoPC (P-16:0/0/0:0) was 0.9922. The inclusion of the seven differential metabolites in a joint prediction model had an AUC of 0.9956. Thus, both LysoPC (P-16:0/0/0:0) alone and the joint prediction model demonstrated good predictive ability for obesity-induced BPH mechanisms. CONCLUSIONS: In conclusion, obese patients with BPH had a unique metabolic profile, and alterations in PE and PC in these patients be associated with the development and progression of BPH.

Identification and functional activity of Nik related kinase (NRK) in benign hyperplastic prostate.

OBJECTIVE: Benign prostatic hyperplasia (BPH) is common in elder men. The current study aims to identify differentially expressed genes (DEGs) in hyperplastic prostate and to explore the role of Nik related kinase (NRK) in BPH. METHODS: Four datasets including three bulk and one single cell RNA-seq (scRNA-seq) were obtained to perform integrated bioinformatics. Cell clusters and specific metabolism pathways were analyzed. The localization, expression and functional activity of NRK was investigated via RT-PCR, western-blot, immunohistochemical staining, flow cytometry, wound healing assay, transwell assay and CCK-8 assay. RESULTS: A total of 17 DEGs were identified by merging three bulk RNA-seq datasets. The findings of integrated single-cell analysis showed that NRK remarkably upregulated in fibroblasts and SM cells of hyperplasia prostate. Meanwhile, NRK was upregulated in BPH samples and localized almost in stroma. The expression level of NRK was significantly correlated with IPSS and Qmax of BPH patients. Silencing of NRK inhibited stromal cell proliferation, migration, fibrosis and EMT process, promoted apoptosis and induced cell cycle arrest, while overexpression of NRK in prostate epithelial cells showed opposite results. Meanwhile, induced fibrosis and EMT process were rescued by knockdown of NRK. Furthermore, expression level of NRK was positively correlated with that of α-SMA, collagen-I and N-cadherin, negatively correlated with that of E-cadherin. CONCLUSION: Our novel data identified NRK was upregulated in hyperplastic prostate and associated with prostatic stromal cell proliferation, apoptosis, cell cycle, migration, fibrosis and EMT process. NRK may play important roles in the development of BPH and may be a promising therapeutic target for BPH/LUTS.

Metabolic profiling in tissues and urine of patients with prostatic lesions and the diagnostic value of urine extracellular vesicles metabolites in prostate cancer.

BACKGROUND: Prostate cancer (PCa) lacks convenient and highly specific diagnostic markers. Although the value of extracellular vesicles (EV) in oncology is widely recognized, the diagnostic value of EV metabolites requires further exploration. This study aimed to explore the diagnostic value of urine EV (u-EV) metabolomics in PCa. METHODS: We first detected metabolites in paired tissues cells (cells), tissue EV (t-EVs), u-EVs, and urine samples in cohort 1 (8 PCa vs. 5 benign prostatic hypertrophy, BPH) to prob the feasibility of EV metabolites as diagnostic markers. We then analyzed the value of u-EVs as markers for PCa diagnosis and typing in the expanded sample cohort (60 PCa vs. 40 BPH). RESULTS: U-EV metabolites were more consistent with those in tissue-derived samples (cells and t-EVs) than those in urine, and more differential metabolites between BPH and PCa were identified in u-EV. Subsequently, we used a random forest model to construct a panel of six metabolites for PCa, which showed an area under the curve (AUC) of 0.833 in training cohort and 0.844 in validation cohort. We also found significantly differentially expressed metabolites between PCa subtypes (Gleason ≤ 7 vs. Gleason > 7 and localized vs. metastasis), demonstrating the value of EV metabolites in PCa typing and prognostic assessment. CONCLUSION: Metabolomic analysis of u-EVs is a promising source of noninvasive markers for PCa diagnosis.

Microbiome analysis reveals the inducing effect of Pseudomonas on prostatic hyperplasia via activating NF-κB signalling.

Benign prostatic hyperplasia (BPH) is a prevalent disease among middle-aged and elderly males, but its pathogenesis remains unclear. Dysbiosis of the microbiome is increasingly recognized as a significant factor in various human diseases. Prostate tissue also contains a unique microbiome, and its dysbiosis has been proposed to contribute to prostate diseases. Here, we obtained prostate tissues and preoperative catheterized urine from 24 BPH individuals, and 8 normal prostate samples as controls, which followed strict aseptic measures. Using metagenomic next-generation sequencing (mNGS), we found the disparities in the microbiome composition between normal and BPH tissues, with Pseudomonas significantly enriched in BPH tissues, as confirmed by fluorescence in situ hybridization (FISH). Additionally, we showed that the prostate microbiome differed from the urine microbiome. In vitro experiments revealed that lipopolysaccharide (LPS) of Pseudomonas activated NF-κB signalling, leading to inflammation, proliferation, and EMT processes, while inhibiting apoptosis in prostatic cells. Overall, our research determines the presence of microbiome dysbiosis in BPH, and suggests that Pseudomonas, as the dominant microflora, may promote the progression of BPH through LPS activation of NF-κB signalling.

Whole-exome sequencing of Nigerian benign prostatic hyperplasia reveals increased alterations in apoptotic pathways.

BACKGROUND: Through whole-exome sequencing of 60 formalin-fixed paraffin-embedded Nigerian (NGRn) benign prostatic hyperplasia (BPH) samples, we identified germline and somatic alterations in apoptotic pathways impacting BPH development and progression. Prostate enlargement is a common occurrence in male aging; however, this enlargement can lead to lower urinary tract symptoms that negatively impact quality of life. This impact is disproportionately present in men of African ancestry. BPH pathophysiology is poorly understood and studies examining non-European populations are lacking. METHODS: In this study, NGRn BPH, normal prostate, and prostate cancer (PCa) tumor samples were sequenced and compared to characterize genetic alterations in NGRn BPH. RESULTS: Two hundred and two nonbenign, ClinVar-annotated germline variants were present in NGRn BPH samples. Six genes [BRCA1 (92%), HSD3B1 (85%), TP53 (37%), PMS2 (23%), BARD1 (20%), and BRCA2 (17%)] were altered in at least 10% of samples; however, compared to NGRn normal and tumor, the frequency of alterations in BPH samples showed no significant differences at the gene or variant level. BRCA2_rs11571831 and TP53_rs1042522 germline alterations had a statistically significant co-occurrence interaction in BPH samples. In at least two BPH samples, 173 genes harbored somatic variants known to be clinically actionable. Three genes (COL18A1, KIF16B, and LRP1) showed a statistically significant (p < 0.05) higher frequency in BPH. NGRn BPH also had five gene pairs (PKD1/KIAA0100, PKHD1/PKD1, DNAH9/LRP1B, NWD1/DCHS2, and TCERG1/LMTK2) with statistically significant co-occurring interactions. Two hundred and seventy-nine genes contained novel somatic variants in NGRn BPH. Three genes (CABP1, FKBP1C, and RP11-595B24.2) had a statistically significant (p < 0.05) higher alteration frequency in NGRn BPH and three were significantly higher in NGRn tumor (CACNA1A, DMKN, and CACNA2D2). Pairwise Fisher's exact tests showed 14 gene pairs with statistically significant (p < 0.05) interactions and four interactions approaching significance (p < 0.10). Mutational patterns in NGRn BPH were similar to COSMIC (Catalog of Somatic Mutations in Cancer) signatures associated with aging and dysfunctional DNA damage repair. CONCLUSIONS: NGRn BPH contained significant germline alteration interactions (BRCA2_rs11571831 and TP53_rs1042522) and increased somatic alteration frequencies (LMTK2, LRP1, COL18A1, CABP1, and FKBP1C) that impact apoptosis. Normal prostate development is maintained by balancing apoptotic and proliferative activity. Dysfunction in either mechanism can lead to abnormal prostate growth. This work is the first to examine genomic sequencing in NGRn BPH and provides data that fill known gaps in the understanding BPH and how it impacts men of African ancestry.

Spatial architectures of somatic mutations in normal prostate, benign prostatic hyperplasia and coexisting prostate cancer.

This study aimed to identify somatic mutations in nontumor cells (NSMs) in normal prostate and benign prostatic hyperplasia (BPH) and to determine their relatedness to prostate cancer (PCA). From 22 PCA patients, two prostates were sampled for 3-dimensional mapping (50 normal, 46 BPH and 1 PCA samples), and 20 prostates were trio-sampled (two normal or BPH samples and one PCA sample) and analyzed by whole-genome sequencing. Normal and BPH tissues harbored several driver NSMs and copy number alterations (CNAs), including in FOXA1, but the variations exhibited low incidence, rare recurrence, and rare overlap with PCAs. CNAs, structural variants, and mutation signatures were similar between normal and BPH samples, while BPHs harbored a higher mutation burden, shorter telomere length, larger clone size, and more private NSMs than normal prostates. We identified peripheral-zonal dominance and right-side asymmetry in NSMs, but the asymmetry was heterogeneous between samples. In one normal prostate, private oncogenic RAS-signaling NSMs were detected, suggesting convergence in clonal maintenance. Early embryonic mutations exhibited two distinct distributions, characterized as layered and mixed patterns. Our study identified that the BPH genome differed from the normal prostate genome but was still closer to the normal genome than to the PCA genome, suggesting that BPH might be more related to aging or environmental stress than to tumorigenic processes.

An AFM-Based Model-Fitting-Free Viscoelasticity Characterization Method for Accurate Grading of Primary Prostate Tumor.

Viscoelasticity is a crucial property of cells, which plays an important role in label-free cell characterization. This paper reports a model-fitting-free viscoelasticity calculation method, correcting the effects of frequency, surface adhesion and liquid resistance on AFM force-distance (FD) curves. As demonstrated by quantifying the viscosity and elastic modulus of PC-3 cells, this method shows high self-consistency and little dependence on experimental parameters such as loading frequency, and loading mode (Force-volume vs. PeakForce Tapping). The rapid calculating speed of less than 1ms per curve without the need for a model fitting process is another advantage. Furthermore, this method was utilized to characterize the viscoelastic properties of primary clinical prostate cells from 38 patients. The results demonstrate that the reported characterization method a comparable performance with the Gleason Score system in grading prostate cancer cells, This method achieves a high average accuracy of 97.6% in distinguishing low-risk prostate tumors (BPH and GS6) from higher-risk (GS7-GS10) prostate tumors and a high average accuracy of 93.3% in distinguishing BPH from prostate cancer.

The role of autophagy in prostate cancer and prostatic diseases: a new therapeutic strategy.

BACKGROUND: Autophagy is a well-conserved catabolic process that plays a key role in cell homeostasis. In the prostate, defective autophagy has been implicated in the genesis and progression of several pathological conditions. AIM: The present review explored the autophagy pathway in prostate-related dysfunctions, focusing on prostate cancer (PCa), benign prostatic hyperplasia (BPH) and prostatitis. RESULTS: Impaired autophagy activity has been shown in animal models of BPH and prostatitis. Moreover, autophagy activation by specific and non-specific drugs improved both conditions in pre-clinical studies. Conversely, the efficacy of autophagy inducers in PCa remains controversial, depending on intrinsic PCa characteristics and stage of progression. Intriguingly, autophagy inhibitors have shown beneficial effects in PCa suppression or even to overcome chemotherapy resistance. However, there are still open questions regarding the upstream mechanisms by which autophagy is deregulated in the prostate and the exact role of autophagy in PCa. The lack of specificity and increased toxicity associated with the currently autophagy inhibitors limits its use clinically, reflecting in reduced number of clinical data. CONCLUSION: New therapeutic strategies to treat prostatic diseases involving new autophagy modulators, combination therapy and new drug formulations should be explored. Understanding the autophagy signaling in each prostatic disease is crucial to determine the best pharmacological approach.

Transcriptomic analysis of benign prostatic hyperplasia identifies critical pathways in prostatic overgrowth and 5-alpha reductase inhibitor resistance.

BACKGROUND: The medical therapy of prostatic symptoms (MTOPS) trial randomized men with symptoms of benign prostatic hyperplasia (BPH) and followed response of treatment with a 5α-reductase inhibitor (5ARI), an alpha-adrenergic receptor antagonist (α-blocker), the combination of 5ARI and α-blocker or no medical therapy (none). Medical therapy reduced risk of clinical progression by 66% but the reasons for nonresponse or loss of therapeutic response in some patients remains unresolved. Our previous work showed that prostatic glucocorticoid levels are increased in 5ARI-treated patients and that glucocorticoids can increased branching of prostate epithelia in vitro. To understand the transcriptomic changes associated with 5ARI treatment, we performed bulk RNA sequencing of BPH and control samples from patients who received 5ARI versus those that did not. Deconvolution analysis was performed to estimate cellular composition. Bulk RNA sequencing was also performed on control versus glucocorticoid-treated prostate epithelia in 3D culture to determine underlying transcriptomic changes associated with branching morphogenesis. METHOD: Surgical BPH (S-BPH) tissue was defined as benign prostatic tissue collected from the transition zone (TZ) of patients who failed medical therapy while control tissue termed Incidental BPH (I-BPH) was obtained from the TZ of men undergoing radical prostatectomy for low-volume/grade prostatic adenocarcinoma confined to the peripheral zone. S-BPH patients were divided into four subgroups: men on no medical therapy (none: n = 7), α-blocker alone (n = 10), 5ARI alone (n = 6) or combination therapy (α-blocker and 5ARI: n = 7). Control I-BPH tissue was from men on no medical therapy (none: n = 8) or on α-blocker (n = 6). A human prostatic cell line in 3D culture that buds and branches was used to identify genes involved in early prostatic growth. Snap-frozen prostatic tissue taken at the time of surgery and 3D organoids were used for RNA-seq analysis. Bulk RNAseq data were deconvoluted using CIBERSORTx. Differentially expressed genes (DEG) that were statistically significant among S-BPH, I-BPH, and during budding and branching of organoids were used for pathway analysis. RESULTS: Transcriptomic analysis between S-BPH (n = 30) and I-BPH (n = 14) using a twofold cutoff (p < 0.05) identified 377 DEG (termed BPH377) and a cutoff < 0.05 identified 3377 DEG (termed BPH3377). Within the S-BPH, the subgroups none and α-blocker were compared to patients on 5ARI to reveal 361 DEG (termed 5ARI361) that were significantly changed. Deconvolution analysis of bulk RNA seq data with a human prostate single cell data set demonstrated increased levels of mast cells, NK cells, interstitial fibroblasts, and prostate luminal cells in S-BPH versus I-BPH. Glucocorticoid (GC)-induced budding and branching of benign prostatic cells in 3D culture was compared to control organoids to identify early events in prostatic morphogenesis. GC induced 369 DEG (termed GC359) in 3D culture. STRING analysis divided the large datasets into 20-80 genes centered around a hub. In general, biological processes induced in BPH supported growth and differentiation such as chromatin modification and DNA repair, transcription, cytoskeleton, mitochondrial electron transport, ubiquitination, protein folding, and cholesterol synthesis. Identified signaling pathways were pooled to create a list of DEG that fell into seven hubs/clusters. The hub gene centrality was used to name the network including AP-1, interleukin (IL)-6, NOTCH1 and NOTCH3, NEO1, IL-13, and HDAC/KDM. All hubs showed connections to inflammation, chromatin structure, and development. The same approach was applied to 5ARI361 giving multiple networks, but the EGF and sonic hedgehog (SHH) hub was of particular interest as a developmental pathway. The BPH3377, 5ARI363, and GC359 lists were compared and 67 significantly changed DEG were identified. Common genes to the 3D culture included an IL-6 hub that connected to genes identified in BPH hubs that defined AP1, IL-6, NOTCH, NEO1, IL-13, and HDAC/KDM. CONCLUSIONS: Reduction analysis of BPH and 3D organoid culture uncovered networks previously identified in prostatic development as being reinitiated in BPH. Identification of these pathways provides insight into the failure of medical therapy for BPH and new therapeutic targets for BPH/LUTS.