Prostatic Intraepithelial Neoplasia Research Articles

Sulfiredoxin as a Potential Therapeutic Target for Advanced and Metastatic Prostate Cancer.

The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.

Deletion of NKX3.1 via CRISPR/Cas9 Induces Prostatic Intraepithelial Neoplasia in C57BL/6 Mice.

Several techniques have been employed for deletion of the NKX3.1 gene, resulting in developmental defects of the prostate, including alterations in ductal branching morphogenesis and prostatic secretions as well as epithelial hyperplasia and dysplasia. To investigate whether the CRISPR/Cas9-mediated technique can be applied to study prostate carcinogenesis through exon I deletion of NKX3.1 gene, alterations in the prostatic intraepithelial neoplasia (PIN) and their regulatory mechanism were observed in the prostate of NKX3.1 knockout (KO) mice produced by the CRISPR/Cas9-mediated NKX3.1 mutant gene, at the ages of 16 and 24 weeks. The weight of dorsal-lateral prostate (DLP) and anterior prostate (AP) were observed to be increased in only the 24 weeks KO mice, although morphogenesis was constant in all groups. Obvious PIN 1 and 2 lesions were frequently detected in prostate of the 24 weeks KO mice, as compared with the same age wild type (WT) mice. Ki67, a key indicator for PIN, was densely stained in the epithelium of prostate in the 24 weeks KO mice, while the expression of p53 protein was suppressed in the same group. Also, both the 16 and 24 weeks KO mice reveal inhibition of the PI3K/AKT/mTOR pathway in the prostate. However, prostate specific antigen (PSA) levels and Bax/Bcl-2 expressions were decreased in the prostate of 16 weeks KO mice, and were increased in only the 24 weeks KO mice. Taken together, the results of the present study provide additional evidence that CRISPR/Cas9-mediated exon 1 deletion of the NKX3.1 gene successfully induces PIN lesions, along with significant alterations of Ki67 expression, EGFR signaling pathway, and cancer-regulated proteins.

Interobserver Variability in the Diagnosis of High-Grade Prostatic Intraepithelial Neoplasia in a Tertiary Hospital in Northern Jordan.

Prostate intraepithelial neoplasia is described as a precursor lesion to prostatic adenocarcinoma. High-grade prostate intraepithelial neoplasia (HGPIN) is classified as both grade 2 and 3 prostate intraepithelial neoplasia due to inconsistency between pathologists’ findings. In our study, we assessed the interobserver variability in the diagnosis of HGPIN among genitourinary and nongenitourinary pathologists. All cases with prostate adenocarcinoma diagnosis on needle core biopsy, radical prostatectomy, and transurethral resection of prostate (TURP) between the years 2005 and 2014 were included. In total, 191 prostate cancer cases were included: 109 needle core biopsies, 45 radical prostatectomies, and 37 TURP. All were independently reviewed by 2 urologic pathologists for the presence of HGPIN. High-grade prostate intraepithelial neoplasia was diagnosed in 65 cases (34%), among which the lesion was recognized by the reporting pathologists in 36 (55%) of the cases and was missed in 29 (45%) of the cases with a κ coefficient of 0.53. There was a moderate interobserver agreement in the diagnosis of HGPIN. Consultation with genitourinary pathologist can improve HGPIN diagnosis.

Utility of PIN4 cocktail antibody in the atypical foci of the Prostate

Aims: Diagnosis of prostatic carcinoma is based on histomorphological features. However, sometimes this can be challenging. In such situations immunohistochemistry can be a useful adjunct. This study is aimed to evaluate such suspicious or atypical cases by using PIN4 cocktail antibody (AMACR+p63+CK5/14). Materials and methods: The present study was prospectively conducted at Upgraded Department of Pathology, Osmania general hospital, Hyderabad, Telangana state, India from August 2013 to July 2016. All hematoxylin and Eosin slides of prostatic specimens received during this period were routinely analyzed and cases with suspicious foci were subjected to immunohistochemistry. Immunohistochemistry was performed to look for expression of AMACR/p63/CK5/14 by using PIN4 Cocktail antibody. Observation and results: Out of 306 prostatic specimens, 210 cases were Benign, 36 were malignant, 16 were PIN and 44 cases showed suspicious foci and these cases subjected to PIN4 cocktail antibody. Cases with p63+/CK5/14+/AMACR- were considered as benign, cases with p63-/CK5/14-/AMACR+ were considered as malignant, cases with p63+/CK5+/CK14+/AMACR+ were considered as Prostatic intraepithelial neoplasia (PIN)/Atypical adenomatous hyperplasia(AAH),cases with p63-/CK5/14-/AMACR- were considered as Atypical small acinar proliferation (ASAP). Conclusion: Immunohistochemistry can be useful adjunct to biopsy. It reduces the chance of overdiagnosis of benign lesions as malignant, and under diagnosis of malignancies as benign. Also reduces the chances of unnecessary re-biopsy.

Cordia lutea L. Flowers: A Promising Medicinal Plant as Chemopreventive in Induced Prostate Carcinogenesis in Rats.

The objective of this study was to evaluate the chemopreventive effect of the ethanolic extract of Cordia lutea flowers (EECL) on N-methyl-N-nitrosourea- (MNU), cyproterone-, and testosterone-induced prostate cancer in rats. 40 Holtzman male rats were used and assigned to 5 groups (n = 8). In Group I, rats received normal saline (10 mL/Kg); Group II: rats were induced for prostate cancer with cyproterone, testosterone, and NMU; Groups III, IV, and V: rats received EECL daily, at doses of 50, 250, and 500 mg/kg body weight, respectively. After the period of treatment, animals were sacrificed by an overdose of pentobarbital and blood samples were collected for determination of prostate-specific antigen (PSA). The prostate was dissected and weighed accurately. The ventral lobe of the prostate was processed for histopathology analysis. The somatic prostate index decreased with EECL at dependent dose, from 0.34 ± 0.04 to 0.23 ± 0.05 (P < 0.05). The PSA levels also decreased significantly at doses of 250 and 500 mg/kg. Histopathological analysis showed a decrease in the number of prostatic layers with high-grade prostatic intraepithelial neoplasia (HG-PIN) and low-grade prostatic intraepithelial neoplasia (LG-PIN) at the dose of 500 mg/kg. The ethanolic extract of Cordia lutea flowers had a chemopreventive effect on induced prostate cancer in rats.

Immunohistochemical study of Ki-67, p53 and Notch1 expressions in prostate cancer of different grades

To determine the prognostic value of the expression of Ki-67, p53, and Notch1 in the diagnosis of prostate cancer. Surgical and diagnostic materials obtained from patients with benign prostatic hyperplasia, prostate intraepithelial neoplasia, and prostate cancer of different grades underwent studies; a total of 98 patients were examined. Cell antigens were determined using rabbit anti-Ki-67 monoclonal antibodies (Clone SP6), mouse anti-p53 monoclonal antibodies (Clone Y5), and recombinant anti-Notch1 antibodies (Clone EP1238Y). Comparing Ki-67, p53, and Notch1 expression indices revealed statistically significant differences. There was a significant direct correlation between Ki-67 and p53 expression indices and prostate cancer grade groups based on the morphological Gleason grading system (rs=0.736; p<0.001; rs=0.682; p=0.035, respectively) and a strong inverse correlation between Notch1 expression and prostate cancer grade groups (rs= -0.425, p<0.001). Notch1 expression in conjunction with the low proliferative activity of cells and the absence of p53 (Y5) protein may suggest that the mechanism of apoptosis is preserved in tumor cells, which expands indications for medical treatment of prostate cancer.

Epidemiology and Diagnostics of Prostate Cancer During COVID-19 Pandemic

Background: Prostate cancer (PCa) is the second most common cancerin the male population and represents a major health problem, especially in developed countries, where older men are more prevalent in the general population. Analyzing recent data for European countries, the incidence is highest in Northern and Western Europe (>200 per 100,000), while the rate is lower in Eastern and Southern Europe, but shows a continuous increase. Globally, about 450,000 Europeans are diagnosed with prostate cancer each year, and prostate cancer was the second most common cause of cancer-related deaths in 2018, when it was the cause of death for 107,000 men in Europe. Global data for BiH indicate that PCa is the second most common cancer in the male population, or the third leading cause of death in men due to cancer. Objective: The aim of this study was to analyze (PCa) how PCa screening is the most controversial topic regarding statements described in the urological literature searching most important biomedical on-line databases. Methods: Authors used descriptive method for this systematic study based on the published literature, summarized through meta-analysis, to show that screening was associated with an increase in PCa diagnosis. Results and Discussion: Most of autghors written about this topic and concluded that the greater detection of localized and less advanced PCa disease, but without benefits in the field of PCa “specific survival” and “overall survival”, “overdiagnosis” and “overtreatment”, leading to recommendations against systematic population screening in all countries, including Europe. The main diagnostic tools for diagnosing PCa are digitorectal examination (DRE), serum specific antigen concentration (PSA), transrectal ultrasonography (TRUS) and mp MRI, and the definitive diagnosis is based on pathohistological verification of cancer in prostate biopsy specimens or operative specimen. The indication for biopsy should be determined based on PSA levels and/or suspected DRE, depending on age, potential comorbidities and therapeutic consequences, and the indication for repeated biopsy is an increase or persistently elevated PSA, suspected DRE, “atypical small acinar proliferation” (ASAP), extensive high grade “prostatic intraepithelial neoplasia” (PIN) and positive multiparametric MRI of the prostate (PI-RADS ≥3). Conclusion: PCa volume assessment is based on DRE and PSA with the addition of multiparametric MRI, bone scan and CT, although there are new imaging modalities, such as PET/CT scan and Diffusion-weighted whole-body MRI. However, the cost-effectiveness” of these new approaches needs to be further assessed. Given that COVID-19 has imposed other priorities on all health systems, we hope that the diagnosis of clinically significant prostate cancer and adequate treatment is not questionable at this time.

Icaritin reduces prostate cancer progression via inhibiting high-fat diet-induced serum adipokine in TRAMP mice model.

Objective: Obesity resulting from high-fat diets has a close relationship with the morbidity and mortality associated with Prostate cancer (PCa) in males. The anti-cancer role of Icaritin (ICT, a traditional Chinese herbal medicine) has been reported in several types of cancer including PCa. Adipokines are novel adipocyte-specific secretory protein, which plays a key role in the development of various diseases including obesity, diabetes, atherosclerosis, and cancer. However, the function of ICT and the molecular mechanisms underlying its role in PCa regression through modulation of adipokines have not been studied. Here, we assessed the anti-cancer properties of ICT under the influence of human epidermal growth factor receptor type 2 (HER2) pathway modulating adipokines in obese PCa models.Materials and Methods: In this study, we used transgenic adenocarcinoma of mouse prostate (TRAMP), a well-established animal model for the study of PCa pathogenesis. All the animals were fed on a high-fat diet (HFD with 40% fat) and divided into two groups, one received ICT solution of 30 mg/kg body bwt (i.p) while the other group served as control without any ICT treatment. The mortality rate, tumor formation and fat ratio were assessed by histopathological and magnetic resonance analysis at different time points of 20th, 24th and 28th weeks. The protein expression of HER2 and serum levels of adipokines were measured using western blotting, IHC and multiplex immunoassays. The PCa grade in 12 TRAMP mice were longitudinally evaluated to visualize PCa development and progression upon post-surgery using PET/CT scanning.Results: We observed that ICT treatment significantly reduces the total mortality rate of TRAMP mice (p = 0.045) and the percentage of prostate intraepithelial neoplasia (PIN) or PCa (p = 0.029). Interestingly, significantly decreased levels of leptin (p = 0.006 @20th wk) and the elevated levels of adiponectin (p = 0.030 @20th wk) were observed in different subgroups upon ICT treatment in a time-dependent manner. In addition, a decrease level of HER2 (p = 0.032 @28th wk) and an elevated level of PEA3 (p = 0.014 @28th wk) were also detected in ICT treated group. The PET/CT-based imaging showed that ICT vs non-ICT treated mice had different standard uptake value and metastasis.Discussion and Conclusion: Our results showed potent anti-cancer properties of ICT through the modulation of adipokine secretion may alter the expression and activation of HER2 pathway as an alternative mechanism to prevent PCa progression. Altogether, our findings indicate that ICT could be a promising cancer preventive agent with the potential to target and eradicate tumor cells in obese PCa patients.

Expression of 34β E 12 in prostatic lesion

Introduction: Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide, To diagnose prostate cancer, no specific single histologic feature is sufficiently available. It is a challenging task to accurately diagnose small foci of prostate cancer for pathologists and to distinguish cancer from its benign mimickers. Material and Methods: The present study was a prospective study. Establishing a definitive diagnosis of malignancy in prostate needle biopsies with very little foci of adenocarcinoma is a major diagnostic challenge for pathologists. A negative diagnostic marker specific for prostatic adenocarcinoma may enhance the ability to detect limited prostate cancer and reduce errors in diagnosis. The recent discovery of the 34βE12 in prostate cancer is a successful example of translating an advanced molecular finding into clinical practice. Results: Among 37 cases 19 were prostatic cancer, 5 were prostatic intraepithelial neoplasia, 1 case was atypical foci, and 9 were benign prostatic hyperplasia cases. 34βE12has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma. This study focuses on the study of 34βE12 expression in prostate cancer, premalignant lesions, benign prostate tissues, and other normal and malignant tissues and a discussion of its clinical usefulness. Conclusion: The present study recommends the interpretation of the 34βE12 immunohistochemical results in routine surgical pathology practice and also discuss the potential future applications of this marker in diagnosis of various lesions.

Prostate Specific Antigen Nadir After Radical Cystoprostatectomy in Patients With Benign Prostatic Tissue: A Benchmark To Define Biochemical Recurrence after Radical Prostatectomy.

Biochemical failure after radical prostatectomy has been defined based on retrospective studies in men who underwent RP for localized prostate cancer. Nevertheless, retrospective strategy and possibility of extra-prostatic extension overshadowed the accurateness of the aforementioned cut-off value. To define a more precise PSA nadir value, we estimated serum PSA after cystoprostatectomy in cases with bladder urothelial cancer and no evidence of prostate cancer. Study population consists of 52 subsequent patients who underwent radical cystoprostatectomy for muscle-invasive bladder cancer between December 2010 and December 2013. Patients with prostate adenocarcinoma and/or high grade prostate intraepithelial neoplasia were excluded from enrollment. Other exclusion criteria were prostate involvement with urothelial carcinoma, neoadjuvant or adjuvant chemotherapy and radiation therapy. Between all cases, 41 were enrolled for study. Serum PSA level was measured using immunochemiluminescence method among 6 months to 3 years after operation in study participants. Forty-one patients with mean age of 66.4 ± 8.9 were assessed in this study. Average serum PSA level after radical cysto-prostatectomy was .037 ± .031 ng/mL (from .002 to .1). Serum PSA level was not impressed with type of diversion or interval between operation and PSA measurement. Average serum PSA level in this study was meaningfully lesser than .2 ng/mL which is contemplated as PSA nadir value after RP. Serum PSA level of 0.2 ng/mL as the definition for biochemical recurrence after RP may delay salvage treatment. Our results showed that cut off value of ?0.1 ng/mL may be more precise in the era of early salvage treatment.

Targeting Wistar rat as a model for studying benign, premalignant and malignant lesions of the prostate

AimsThe purpose of this study was to describe a suitable experimental model for studying aging-related prostate disorders including cancer. Materials and methods12-month old Wistar rats were kept in control conditions (n = 12) or treated (n = 16) for 6 months with Silastic implants filled with testosterone (T) and estradiol (E2). After the experiment period (at 18 months of age), animals were euthanized and the prostate and other organs were harvested, dissected, weighed, and processed for morphological, ultrastructural and molecular analyses. Key findingsWe demonstrated that male rats of Wistar strain nicely recapitulate the carcinogenesis process taking place in the aging prostate through the arising of benign, precancerous and malignant lesions, and above all yields a modest incidence of spontaneous PCa (~36%). Moreover, our results highlight that 100% incidence of PCa and precancerous lesions such as prostatic intraepithelial neoplasia and proliferative inflammatory atrophy were achieved in this rat strain after T + E2 treatment, without changing the broad spectrum of changes that naturally emerge in the prostate at advanced ages. Such enhancement of precancerous lesions and tumors was linked to a decreased expression of E-cadherin and β-catenin in parallel with an increase in Vimentin and N-cadherin, hallmark modifications of epithelial-mesenchymal transition. SignificanceOur findings provide solid evidence that aged Wistar rats may be an excellent model for studies regarding human prostate biology and related disorders including cancer.

The clinical predictive factors and postoperative histopathological parameters associated with upgrading after radical prostatectomy: A contemporary analysis with grade groups.

Upgrading after radical prostatectomy (RP) is an ongoing problem since first description of Gleason score. In this retrospective study, our aim is to investigate upgrading after RP in grade groups (GG) and clinical predictive, and postoperative histopathological factors associated with GG upgrading (GGU). A total of 753 patients undergoing RP between January 2006 and June 2019 at our institution were investigated. Overall cohort were divided into two groups according to GGU status after RP as nonupgrading and upgrading. Retrospectively documented preoperative clinical and postoperative histopathological parameters were compared between two groups. Furthermore, we investigated a subgroup of institutional cohort (n = 398) whose prostate biopsy (Pbx) and RP were performed in our institution and we also divided this cohort into two groups according to GGU status. χ2 and Mann-Whitney U tests were used for comparative analyses. The independent preoperative predictive and postoperative histopathological factors associated with GGU were investigated using multivariate logistic regression analysis. The total GGU was 55.8% in overall cohort and 45.2% in institutional cohort. The GGU was found as the most common in bioptic GG1 group in both overall (64.0%), and institutional (54.5%) cohorts. In multivariate analyses, the noninstitutional Pbx (odds ratio [OR] = 2.56; 95% confidence interval [CI]: 1.86-3.51;P < .001), tumor positive core numbers in Pbx (OR = 1.11; 95%CI: 1.04-1.19;P = .003), increased prostate specific antigen (PSA) density (OR = 3.59; 95%CI: 1.03-12.52, P = .045) and age (OR = 1.03; 95%CI: 1.00-1.05, P = .046) were independent clinical predictors of GGU in overall cohort whereas only increased PSA density (OR = 5.94; 95%CI: 1.28-27.50;P = .023) was independent predictor in institutional cohort. Among postoperative histopathological factors, perineural invasion (OR = 1.57; 95%CI: 1.70-3.87;P < .001 and OR = 2.53; 95%CI: 1.46-4.40;P = .001, respectively), increased maximum tumor diameter (OR = 1.46; 95%CI: 1.23-1.73;P < .001 and OR = 1.33; 95%CI: 1.07-1.66;P = .010, respectively), and high-grade prostatic intraepithelial neoplasia (HGPIN) existence at tumor surrounding tissue (OR = 1.96; 95%CI: 1.32-2.90;P = .001 and OR = 1.87; 95%CI: 1.10-3.21;P = .022, respectively) were independently associated with GGU after RP, in both of overall and institutional cohorts. Noninstitutional prostate biopsy, increased PSA density, higher tumor positive cores in Pbxand older age are the clinical predictors of upgrading after RP in contemporary GG. Perineural invasion, increased maximum tumor diameter, and HGPIN existence at tumor surrounding tissue are postoperative histopathological factors associated with GGU.

Stratification of Atypical Intraepithelial Prostatic Lesions Based on Basal Cell and Architectural Patterns.

High-grade prostatic intraepithelial neoplasia (HPIN) and atypical cribriform lesion of the prostate are considered the precursors or associators of invasive prostate cancer (iPCa). Given loss of basal cells being the hallmark of iPCa, we hypothesized that a subset of these atypical intraepithelial lesions (AILs) with sparse basal cells can be classified as prostatic intraepithelial carcinoma (PIC) with frequent iPCa association and that different morphologic patterns of PIC are associated with specific Gleason (G) patterns and scores for iPCa. We stratified 153 foci of AILs from 110 patients based on the integrity of the basal cell layer and architectural patterns and their association with iPCa. We demonstrated that AILs could be stratified into usual HPIN (intact basal cell layer and simple patterns) with low-risk of iPCa association and PIC (sparse basal cell layer) with high risk of iPCa association. Furthermore, PIC could be divided into low-grade (simple patterns and associated with G3 and G3/4 iPCa) and high-grade PIC (complex patterns and associated with G4 and G3/4/5 iPCa). Such stratification is of great clinical significance and instrumental to clinical patient management. It not only increases the predictability of AILs for iPCa but also accommodates a clinical scenario for lesions with features of intraductal carcinoma when iPCa is not found, particularly in biopsies.

PTEN deletion drives aberrations of DNA methylome and transcriptome in different stages of prostate cancer.

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is a tumor suppressor gene and one of the most frequently mutated/deleted genes in human prostate cancer (PCa). However, how PTEN deletion would impact the epigenome and transcriptome alterations remain unknown. This hypothesis was tested in a prostate-specific PTEN-/- (KO) mouse prostatic adenocarcinoma model through DNA methyl-Seq and RNA-Seq analyses. Examination of cancer genomic datasets revealed that PTEN is expressed at lower levels in PTEN-deleted tumor samples than in normal solid tissue samples. Methylome and transcriptome profiling identified several inflammatory responses and immune response signaling pathways, including NF-kB signaling, IL-6 signaling, LPS/IL-1-mediated inhibition of RXR Function, PI3K in B lymphocytes, iCOS-iCOSL in T helper cells, and the role of NFAT in regulating the immune response, were affected by PTEN deletion. Importantly, a small subset of genes that showed DNA hypermethylation or hypomethylation was correlated with decreased or increased gene expression including CXCL1. quantitative polymerase chain reaction analyses of representative genes validated the RNA-Seq results. Histopathological examinations showed that the severity of prostatic intraepithelial neoplasia and inflammation development gradually increased as PTEN null mice aged. Collectively, these findings suggest that loss of PTEN drives global changes in DNA CpG methylation and transcriptomic gene expression and highly associated with several inflammatory and immune molecular pathways during PCa development. These biomarkers could be valuable molecular targets for cancer drug discovery and development against PCa.

The comprehensive role of E-cadherin in maintaining prostatic epithelial integrity during oncogenic transformation and tumor progression.

E-cadherin complexes with the actin cytoskeleton via cytoplasmic catenins and maintains the functional characteristics and integrity of the epithelia in normal epithelial tissues. Lost expression of E-cadherin disrupts this complex resulting in loss of cell polarity, epithelial denudation and increased epithelial permeability in a variety of tissues. Decreased expression of E-cadherin has also been observed in invasive and metastatic human tumors. In this study, we investigated the effect of E-cadherin loss in prostatic epithelium using newly developed genetically engineered mouse models. Deletion of E-cadherin in prostatic luminal epithelial cells with modified probasin promoter driven Cre (PB-Cre4) induced the development of mouse prostatic intraepithelial neoplasia (PIN). An increase in levels of cytoplasmic and nuclear β-catenin appeared in E-cadherin deleted atypical cells within PIN lesions. Using various experimental approaches, we further demonstrated that the knockdown of E-cadherin expression elevated free cytoplasmic and nuclear β-catenin and enhanced androgen-induced transcription and cell growth. Intriguingly, pathological changes representing prostatic epithelial cell denudation and increased apoptosis accompanied the above PIN lesions. The essential role of E-cadherin in maintaining prostatic epithelial integrity and organization was further demonstrated using organoid culture approaches. To directly assess the role of loss of E-cadherin in prostate tumor progression, we generated a new mouse model with bigenic Cdh1 and Pten deletion in prostate epithelium. Early onset, aggressive tumor phenotypes presented in the compound mice. Strikingly, goblet cell metaplasia was observed, intermixed within prostatic tumor lesions of the compound mice. This study provides multiple lines of novel evidence demonstrating a comprehensive role of E-cadherin in maintaining epithelial integrity during the course of prostate oncogenic transformation, tumor initiation and progression.

Green tea catechins for chemoprevention of prostate cancer in patients with histologically-proven HG-PIN or ASAP. Concise review and meta-analysis.

A focused, single outcome meta-analysis on the protective role of extracts of green tea catechins against prostate cancer. Randomized, placebo-controlled studies enrolling patients with a histologically confirmed diagnosis of high-grade Prostate Intraepithelial Neoplasia or Atypical Small Acinar proliferation but no prostate cancer were included. Meta-analysis for binary data was performed using Mantel-Haenszel statistics, using a random-effects model. Heterogeneity was investigated by calculating the I2. Four studies matched the inclusion criteria for the review. The pooled population was 223 patients; 114 and 109 patients were randomized to catechin and placebo groups, respectively. Nine cases of prstate cancer occurred in the catechin arm (7.9%), and 24 cases were reported in the placebo arm (22%). Pooled analysis resulted in a significant reduction of cancer risk in favor of the catechin arm (risk-ratio = 0.41; 95% CI: 0.19- 0.86; I2 = 0). In conclusion, our data suggest that the intake of concentrated green tea catechin preparations may confer a significant protective effect to carriers of early neoplastic lesions in the prostate. The quality of the evidence is moderate, and additional, largescale studies are warranted to substantiate these preliminary findings.

Lactoferrin CpG Island Hypermethylation and Decoupling of mRNA and Protein Expression in the Early Stages of Prostate Carcinogenesis

Lactoferrin (LTF) is an iron-binding protein canonically known for its innate and adaptive immune functions. LTF may also act as a tumor suppressor with antiproliferative action. LTF is inactivated genetically or epigenetically in various cancers, and a CpG island spanning the transcriptional start site of LTF is hypermethylated in prostate cancer cell lines. We, therefore, hypothesized that LTF expression is silenced via CpG island hypermethylation in the early stages of prostate tumorigenesis carcinogenesis. Targeted methylation analysis was performed using a combination of methylated-DNA precipitation and methylation-sensitive restriction enzymes, and laser-capture microdissection followed by bisulfite sequencing on DNA isolated from prostate tissue samples, including both primary and metastatic disease. LTF mRNA in situ hybridization and LTF protein immunohistochemistry were also performed. We report that the LTF CpG island is frequently and densely methylated in high-grade prostatic intraepithelial neoplasia, primary prostate carcinoma, and metastases. We further report a decoupling of lactoferrin mRNA and protein expression, including in lesions where LTF mRNA has presumably been silenced via CpG island methylation. We conclude that LTF mRNA expression is silenced in prostate tumorigenesis via hypermethylation, supporting a role for LTF as a prostate cancer tumor suppressor gene. Likewise, the frequency at which the LTF CpG island is methylated across samples suggests it is an important and conserved step in prostate cancer initiation.

MTA1-Dependent Anticancer Activity of Gnetin C in Prostate Cancer.

The overexpression of metastasis-associated protein 1 (MTA1) in prostate cancer (PCa) contributes to tumor aggressiveness and metastasis. We have reported the inhibition of MTA1 by resveratrol and its potent analog pterostilbene in vitro and in vivo. We have demonstrated that pterostilbene treatment blocks the progression of prostatic intraepithelial neoplasia and adenocarcinoma in mouse models by inhibiting MTA1 expression and signaling. In the current study, we investigated the MTA1 targeted anticancer effects of Gnetin C, a resveratrol dimer, in comparison with resveratrol and pterostilbene. Using DU145 and PC3M PCa cells, we found that Gnetin C downregulates MTA1 more potently than resveratrol and pterostilbene. Further, Gnetin C demonstrated significant MTA1-mediated inhibitory effect on cell viability, colony formation, and migration, while showing a more potent induction of cell death than resveratrol or pterostilbene. In addition, we identified Gnetin C-induced substantial ETS2 (erythroblastosis E26 transformation-specific 2) downregulation, which is not only MTA1-dependent, but is also independent of MTA1 as a possible mechanism for the superior anticancer efficacy of Gnetin C in PCa. Together, these findings underscore the importance of novel potent resveratrol dimer, Gnetin C, as a clinically promising agent for the future development of chemopreventive and possibly combinatorial therapeutic approaches in PCa.

Assessment of Glutathione-S-Transferase (GSTP1) methylation status is a reliable molecular biomarker for early diagnosis of prostatic intraepithelial neoplasia

Assessment of Glutathione-S-Transferase (GSTP1) methylation status is a reliable molecular biomarker for early diagnosis of prostatic intraepithelial neoplasia

The role of WNT10B in normal prostate gland development and prostate cancer

WNT signaling is implicated in embryonic development, and in adult tissue homeostasis, while its deregulation is evident in disease. This study investigates the unique roles of canonical WNT10B in both normal prostate development and prostate cancer (PCa) progression. Organ culture and rat ventral prostates (VPs) were used to study Wnt10b ontogeny and growth effect of WNT10B protein. PB-SV40 LTag rat VPs were utilized for Wnt expression polymerase chain reaction (PCR) array and immunohistochemistry. Human localized PCa tissue microarrays (TMAs) were investigated for differential WNT10B expression. Human RNA-seq data sets were queried for differential expression of WNT10B in metastatic and localized PCa. Knockdown of WNT10B in PC3 cells was utilized to study its effects on proliferation, stemness, epithelial to mesenchymal transition (EMT), and xenograft propagation. Wnt10b expression was highest at birth and rapidly declined in the postnatal rat VP. Exogenous WNT10B addition to culture developing VPs decreased growth suggesting an antiproliferative role. VPs from PB-SV40 LTag rats with localized PCa showed a 25-fold reduction in Wnt10b messenger RNA (mRNA) expession, confirmed at the protein level. Human PCa TMAs revealed elevated WNT10B protein in prostate intraepithelial neoplasia compared with normal prostates but reduced levels in localized PCa specimens. In contrast, RNA-seq data set of annotated human PCa metastasis found a significant increase in WNT10B mRNA expression compared with localized tumors suggesting stage-specific functions of WNT10B. Similarly, WNT10B mRNA levels were increased in metastatic cell lines PC3, PC3M, as well as in HuSLC, a PCa stem-like cell line, as compared with disease-free primary prostate epithelial cells. WNT10B knockdown in PC3 cells reduced expression of EMT genes, MMP9 and stemness genes NANOG and SOX2 and markedly reduced the stem cell-like side population. Furthermore, loss of WNT10B abrogated the ability of PC3 cells to propagate tumors via serial transplantation. Taken together, these results suggest a dual role for WNT10B in normal development and in PCa progression with opposing functions depending on disease stage. We propose that decreased WNT10B levels in localized cancer allow for a hyperproliferative state, whereas increased levels in advanced disease confer a stemness and malignant propensity which is mitigated by knocking down WNT10B levels. This raises the potential for WNT10B as a novel target for therapeutic intervention in metastatic PCa.