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Introduction. Prostate cancer (PCa) remains an urgent problem of modern oncological urology due to high morbidity and mortality rates.Objective. To evaluate the expression of angiotensin II type 2 receptor (AT2-R) and syndecan-1 (CD138) receptors in prostatic intraepithelial neoplasia (PIN) and PCa.Materials & methods. For the immunohistochemical (IHC) study, the prostate biopsy cores of 20 men was used: 10 men with PIN, 10 men with PCa. Primary antibodies to AT2-R and CD138 antibodies were used for IHC staining, the EnVision FLEX imaging system. Formulation of IHC reactions, interpretation of the results obtained were carried out according to generally accepted rules.Results. The results of the study showed that AT2-R deficiency increases in the range of PIN-3 – PCa. Mild AT2-R expression or its absence was noted in tumor cells with PCa, while the AT2-R localisation was nuclear. In PIN-3, the expression of syndecan-1 was localised on the membrane of basal cells and the basolateral side of secretory epithelial cells, without expression in the adjacent stroma, while the expression level of syndecan-1 always remained high. In PCa, the membrane expression of syndecan-1 was preserved. With a decrease or absence of AT2-R nuclear expression in PCa tissue with an increase in ISUP, the expression level of syndecan-1 decreased.Conclusion. Simultaneous decrease in the expression levels of AT2-R and syndecan-1 in PCa has been demonstrated for the first time. A comprehensive determination of the expression levels of AT2-R and syndecan-1 seems to be promising for the development of diagnostic and prognostic markers of PCa initiation and development.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.

Purpose: Investigation of Microtubuli-associated Protein 2 (MAP2) expression and its clinical relevance in prostate cancer. Material and Methods: MAP2 expression was immunohistochemically analysed on radical prostatectomy specimens using whole block sections (n = 107) and tissue microarrays (TMA; n = 310). The staining intensity was evaluated for carcinoma, benign tissue and prostatic intraepithelial neoplasia. Expression data were correlated with clinicopathological parameters and biochemical recurrence-free survival. Additionally, MAP2 protein expression was quantitatively analysed in the serum of histologically confirmed prostate carcinoma patients and the control group using a commercial enzyme-linked immunosorbent assay. Results: MAP2 staining was significantly stronger in neoplastic tissue than in non-neoplastic prostatic glands, both in whole block sections (p < 0.01) and in TMA sections (p < 0.05). TMA data revealed significantly stronger MAP2 staining in high-grade tumors. Survival analysis showed a significant correlation between strong MAP2 staining in carcinoma and shortened biochemical recurrence-free survival after prostatectomy (p < 0.001). Multivariate Cox regression analysis confirmed MAP2 as an independent predictor for an unfavourable course. Mean MAP2 serum levels for non-PCA vs. PCA patients differed significantly (non-PCA = 164.7 pg/ml vs. PCA = 242.5 pg/ml, p < 0.001). Conclusion: The present data support MAP2 as a novel biomarker in PCA specimens. MAP2 is correlated with tumor grade and MAP2 high-expressing PCA is associated with an increased risk of biochemical recurrence after radical prostatectomy. Future studies are necessary to evaluate MAP2 as a valuable immunohistochemical biomarker in preoperative PCA diagnostic procedures, in particular with regard to treatment modalities. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to assess the histopathological features of different types of hyperplasia of prostate, prostatic intraepithelial neoplasia and prostatic carcinoma in transurethral resection of prostate (TURP) samples and needle core biopsies. Methods: This prospective study was undertaken at the Akash Institute of Medical Sciences from 2019 to 2021. 120 patients were included in the study. Results: Most of the cases in the present study were in the range of 61 to 70 years of age (60 cases) followed by 71 to 80 years (37 cases) and 51 to 60 years (19 cases) respectively at the time of biopsy for symptomatic obstructive uropathy. Out of the total 120 cases studied, 109 cases (90.8%) were nonneoplastic and 11 cases (9.2%) harbored neoplasms. The most common clinical symptoms in nonneoplastic lesions are as follows: frequency, retention, hesitancy, urgency dysuria. On digital examination, of 109 non-neoplastic cases, 105 were firm whereas 4 cases were hard in consistency. Out of 11 neoplastic cases, all 11 cases were hard in consistency. On comparing neoplastic and nonneoplastic cases, hard nodule was significantly associated with neoplasms. Serum Prostate Specific Antigen levels were assayed using immunoassay and were available for 80 cases (67.5%). Among these 80 cases, PSA values in 04 (5%) were within normal range (up to 4 ng/dl). In the 109 cases of benign hyperplasia of prostate, varying proportions of glands and stroma was noted, from which, cases showing a characteristic pattern or predominance was identified. Of the 109 cases of benign prostatic hyperplasia, Corpora amylacea were seen in 30.2% of cases. The other findings were basal cell hyperplasia (3.7%) and squamous cell metaplasia (0.9%). Other stromal findings encountered were ectatic thick-walled blood vessels and stromal edema. Conclusion: TURP plays a significant role in the diagnosis of prostatic lesions. The benign lesions are more common the malignant ones. The modified Gleason score is applied for prostatic cancer, which is simple and accurate to grade these malignancies. [ABSTRACT FROM AUTHOR]

Endocrine disruptors (ED) are compounds dispersed in the environment that modify hormone biosynthesis, affecting hormone-dependent organs such as the prostate. Studies have only focused on evaluating the effects of ED alone or in small groups and short intervals and have not adequately portrayed human exposure. Therefore, we characterized the prostate histoarchitecture of rats exposed to an ED mixture (ED Mix) mimicking human exposure. Pregnant females of the Sprague–Dawley strain were randomly distributed into two experimental groups: Control group (vehicle: corn oil, by gavage) and ED Mix group: received 32.11 mg/kg/day of the ED mixture diluted in corn oil (2 ml/kg), by gavage, from gestational day 7 (DG7) to post-natal day 21 (DPN21). After weaning at DPN22, the male pups continued to receive the complete DE mixture until they were 220 days old when they were euthanized. The ED Mix decreased the epithelial compartment, increased the fractal dimension, and decreased glandular dilation. In addition, low-grade prostatic intraepithelial neoplasia was observed in addition to regions of epithelial atrophy in the group exposed to the ED Mix. Exposure to the mixture decreased both types I and III collagen area in the stroma. We concluded that the ED Mix was able to cause alterations in the prostatic histoarchitecture and induce the appearance of preneoplastic lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence of prostate cancer is rising, primarily due to its prevalence among elderly men, and with increased life expectancy, these numbers are expected to continue increasing. Prostate cancer can remain indolent for many years, but treatment options are limited once the cancer progresses to an aggressive stage. Pre-clinical models have played a vital role in gaining insights into this particular cancer, revealing essential information about the molecular alterations that drive cancer progression. The mouse model has been invaluable for studying prostate cancer, employing both genetically modified strains and the inoculation of prostate cancer cells. This review will focus on the development of pre-clinical models for studying prostate cancer and discuss future directions for enhancing our understanding and developing interventions for prostate cancer. Prostate cancer is a common cancer among men and typically progresses slowly for several decades before becoming aggressive and spreading to other organs, leaving few treatment options. While large animals have been studied, the dog's prostate is anatomically similar to humans and has been used to study spontaneous prostate cancer. However, most research currently focuses on the mouse as a model organism due to the ability to genetically modify their prostatic tissues for molecular analysis. One milestone in this research was the identification of the prostate-specific promoter Probasin, which allowed for the prostate-specific expression of transgenes. This has led to the generation of mice with aggressive prostatic tumors through overexpression of the SV40 oncogene. The Probasin promoter is also used to drive Cre expression and has allowed researchers to generate prostate-specific loss-of-function studies. Another landmark moment in the process of modeling prostate cancer in mice was the orthoptic delivery of viral particles. This technology allows the selective overexpression of oncogenes from lentivirus or the use of CRISPR to generate complex loss-of-function studies. These genetically modified models are complemented by classical xenografts of human prostate tumor cells in immune-deficient mice. Overall, pre-clinical models have provided a portfolio of model systems to study and address complex mechanisms in prostate cancer for improved treatment options. This review will focus on the advances in each technique. [ABSTRACT FROM AUTHOR]

BACKGROUND: Corpora amylacea (CAM), in benign prostatic acini, contain acute-phase proteins. Do CAM coincide with carcinoma? METHODS: Within 270 biopsies, 83 prostatectomies, and 33 transurethral resections (TURs), CAM absence was designated CAM 0; corpora in less than 5% of benign acini: CAM 1; in 5% to 25%: CAM 2; in more than 25%: CAM 3. CAM were compared against carcinoma presence, clinicopathologic findings, and grade groups (GG) 1 to 2 vs 3 to 5. The frequency of CAM according to anatomic zone was counted. A pilot study was conducted using paired initial benign and repeat biopsies (33 benign, 24 carcinoma). RESULTS: A total of 68.9% of biopsies, 96.4% of prostatectomies, and 66.7% of TURs disclosed CAM. CAM ≥1 was common at an older age (P = .019). In biopsies, 204 cases (75%) had carcinoma; and CAM of 2 to 3 (compared to 0-1) were recorded in 25.0% of carcinomas but only 7.4% of benign biopsies (P = .005; odds ratio [OR] = 5.1). CAM correlated with high percent Gleason pattern 3, low GG (P = .035), and chronic inflammation (CI). CI correlated inversely with carcinoma (P = .003). CAM disclosed no association with race, body mass index, serum prostate specific antigen (PSA), acute inflammation (in biopsies), atrophy, or carcinoma volume. With CAM 1, the odds of GG 3 to 5 carcinoma, by comparison to CAM 0, decreased more than 2× (OR = 0.48; P = .032), with CAM 2, more than 3× (OR = 0.33; P = .005), and with CAM 3, almost 3× (OR = 0.39, P = .086). For men aged less than 65, carcinoma predictive model was: Score = (2 × age) + (5 × PSA) - (20 × degree of CAM); using our data, area under the ROC curve was 78.17%. When the transition zone was involved by cancer, it showed more CAM than in cases where it was uninvolved (P = .012); otherwise zonal distributions were similar. In the pilot study, CAM ≥1 predicted carcinoma on repeat biopsy (P

The aim of the research. We have a detailed representation of the results of our analysis of 21 microelement’s concentration in blood of patients with different forms of pathology of the prostate. We haven’t succeeded in finding similar works on great amount of microelements in prostate cancer and prostate precancer. This work is made in the clinics of urology, on the chairs of urology and biochemistry and in heavy metals diagnosis laboratory of nephrology, medical and professional diseases clinics (of the I.M. Sechenov First Moscow State Medical University).

The content of vitamins and relative biologically active substances including the products of lipids peroxidation has been studied in the blood of 115 males -patients of Department of Urology of I.M.Sechenov First Moscow State Medical University. The patients have been divided to four groups: prostatic carcinoma (PC); high grade prostatic intraepithelial neoplasia (HG PIN) or precancer; mixed group of conditional control – low grade PIN, benign prostatic hyperplasia, chronic prostatitis or their combination; control group of healthy men without prostate pathology. Further statistically reliable differences have been found: patients with PC had lower level of antioxidants – lycopene, vitamin E and enhanced level of diene conjugates (products of lipid peroxidation); patients with HG PIN low level of vitamin C, total carotenoids and increased diene conjugates. The difference in vitamins-antioxidants levels in patients with PC and HG PIN has not been found out.

Background: Most occurrences of prostatic disease are caused by benign prostatic hyperplasia (BPH), then prostatic cancer. An adult male with prostatic hyperplasia requires a thorough study because prostate cancer is the second most frequently diagnosed malignancy in males. Different prostatic lesions have the same clinical characteristics; however, identification is crucial because treatment and prognosis vary greatly. Material & Methods: Study Design: A prospective hospital based observational study. Study area: Department of Pathology, Government Medical College, Kadapa, Andhra Pradesh. Study Period: 1 year. Study population: This prospective study includes TURP specimens that were collected during the study period. Sample size: The study consisted of 100 cases. Sampling method: Simple random technique. Results: Foci of Prostatic Intra-Epithelial Neoplasia (PIN) were identified in 10% of all cases that were studied. 40% of the HG PIN lesions were identified in association with adenocarcinoma of prostate and the rest (60%) were found along with BPH. Highest incidence of PIN was noted in 7th decade followed by 6th decade. Atypical adenomatous hyperplasia was found in 4 (4%) of all cases. Conclusion: Malignant lesions are less frequent than benign ones. BPH is the most common type of prostatic lesion among the histopathological patterns. In order to recognise premalignant lesions, proliferative activity, and degree of inflammation, it is required to examine all prostate biopsies (TURP and needle core). [ABSTRACT FROM AUTHOR]

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.

Prostate cancer (PCa) is the most diagnosed cancer in 112 countries and the second leading cause of death in men in 48 countries. We studied the outstanding agents silver nanoparticles (AgNPs) and Spirulina algae (Sp) for the management of PCa once as monotherapy or last as a combination. PCa in rats was induced using bicalutamide (Casodex®) and testosterone, followed by (7, 12-dimethylbenz[a]anthracene). Then, testosterone was injected s.c. for 3 months. Rats were divided into six groups, with 12 rats in each group. Group I was assigned as the control (co), group II as the PCa model, group III treated with AgNPs, group IV treated with Spirulina extract, group V treated with a combination of AgNPs plus Spirulina, and group VI treated with bicalutamide. The results show that AgNPs could normalize IL-6 levels and could overcome the hormonal disturbance induced in PCa rats along the hypothalamic–pituitary–testis axis. Spirulina revealed a significant reduction in the level of total and free prostatic specific antigen (PSA) to the same level as bicalutamide treatment, which was the same as the control group. Histopathological study revealed regression (75%) of the histological pattern of high-grade prostatic intraepithelial neoplasia (HGPIN) for Spirulina alone, and (50%) for bicalutamide. The best effect on IL-6 decline was reached with the AgNPs/Spirulina combination as well as bicalutamide treatment compared with the PCa group. Bicalutamide treatment significantly decreased the PSA concentration relative to the PCa group and reached the normal level. Adding Spirulina to AgNPs as a combination enhanced its effect on all mentioned drawbacks associated with PCa except hormonal imbalance that needs more adjustments. [ABSTRACT FROM AUTHOR]

The tumor suppressor p16Ink4a, encoded by the INK4a gene, is an inhibitor of cyclin D-dependent kinases 4 and 6, CDK4 and CDK6. This inhibition prevents the phosphorylation of the retinoblastoma protein (pRb), resulting in cellular senescence through inhibition of E2F-mediated transcription of S phase genes required for cell proliferation. The p16Ink4a plays an important role in tumor suppression, whereby its deletion, mutation, or epigenetic silencing is a frequently observed genetic alteration in prostate cancer. To assess its roles and related molecular mechanisms in prostate cancer initiation and progression, we generated a mouse model with conditional deletion of p16Ink4a in prostatic luminal epithelium. The mice underwent oncogenic transformation and developed prostatic intraepithelial neoplasia (PIN) from eight months of age, but failed to develop prostatic tumors. Given the prevalence of aberrant androgen signaling pathways in prostate cancer initiation and progression, we then generated R26hARL/wt:p16L/L: PB-Cre4 compound mice, in which conditional expression of the human AR transgene and deletion of p16Ink4a co-occur in prostatic luminal epithelial cells. While R26hARL/wt:PB-Cre4 mice showed no visible pathological changes, R26hARL/wt:p16L/L: PB-Cre4 compound mice displayed an early onset of high-grade PIN (HGPIN), prostatic carcinoma, and metastatic lesions. Strikingly, we observed tumors resembling human sarcomatoid carcinoma with intermixed focal regions of signet ring cell carcinoma (SRCC) in the prostates of the compound mice. Further characterization of these tumors showed they were of luminal epithelial cell origin, and featured characteristics of epithelial to mesenchymal transition (EMT) with enhanced proliferative and invasive capabilities. Our results not only implicate a biological role for AR expression and p16Ink4a deletion in the pathogenesis of prostatic SRCC, but also provide a new and unique genetically engineered mouse (GEM) model for investigating the molecular mechanisms for SRCC development.

Background: Benign prostatic hyperplasia (BPH) and prostatic cancer are a significant source of morbidity and mortality among adult males. The other prostatic lesions include inflammatory condition and in situ lesions. TURP is necessary to identify these lesions and specifically for prostatic cancer. Objectives: To evaluate the histomorphological spectrum of various prostatic lesions in TURP specimens. Materials and Methods: Total of 85 TURP specimens received during period of two years, April 2018 to March 2020 were studied. Cases were studied with regard to complete history, clinical examination and histopathological findings. Diagnostic criteria was adapted from guidelines laid down by World Health Organization (WHO). Results: A total of 85 prostate TURP specimens were studied over a 2-year period which included 81 cases of benign lesions (95.2%) and 4 cases of malignant lesions (4.8%). Among the benign lesions Benign prostatic hyperplasia (BPH) 54, BPH with prostatitis 24 and granulomatous prostatitis 2, 4 cases of malignant lesions. Conclusion: TURP plays a significant role in the diagnosis of prostatic lesions. The benign lesions are more common the malignant ones. The modified Gleason score is applied for prostatic cancer, which is simple and accurate to grade these malignancies. [ABSTRACT FROM AUTHOR]

Abstract Background The inverted (hobnail) variant of high-grade prostatic intraepithelial neoplasia (HGPIN) has been reported in two previous series and one case of inverted polarity in invasive adenocarcinoma has been reported. We reported an additional case of invasive carcinoma with this peculiar morphology. Case presentation We reported an additional case of invasive carcinoma with this peculiar morphology. A prostatectomy specimen of a 64-year-old patient showed a GG2 adenocarcinoma with extensive intraprostatic perineural infiltration and extraprostatic extension. Half of the entire tumor showed a distinctive inverted morphology. Conclusion Although pseudohyperplastic adenocarcinoma is believed to be a low-grade tumor to be graded as Gleason pattern 3, awareness of this morphology is important to collect more information on its biologic behavior and clinical implication.

Prostate Cancer represents the second leading cause of cancer death among men in the United States, and the third leading cause of cancer death among men in Europe. We have previously shown that cells possessing Cancer Stem Cell (CSC) characteristics can be grown from human PrCa tissue harvested at the time of prostatectomy. However, the cellular origin of these CSCs was not previously known. In most cases, simple hematoxylin and eosin (H&E) stained sections are sufficient to make a definitive diagnosis of prostatic adenocarcinoma (PrCa) in needle biopsy samples. We utilized six different antibodies specific for stem cell antigens to examine paraffin sections of PrCa taken at the time of needle-biopsy diagnosis. These antisera were specific for CD44, CD133, ALDH7A1, LGR-5, Oct-4 and NANOG. We demonstrate specific staining of tumor cells with all six antisera specific for stem cell antigens. Some of these antibodies also react with cells of hyperplastic glands, but the patterns of reactivity differ from those of malignant glands. These findings demonstrate that at the time of diagnosis, PrCa consists of cells exhibiting properties of CSCs and consistent with the possibility that PrCa is a stem cell disease.

Latar Belakang: Gangguan regulasi mikroRNA(miR) dan inflamasi kronik dapat mengubah tumor menjadi karsinoma dan kanker dengan metastasis melalui perubahan seluler dan genomik. Lesi prekanker memiliki peluang 33,3 persen menjadi kanker. Penelitian ini bertujuan untuk mengkaji peran miR-155-5p terhadap mRNA SOCS1 dan populasi makrofag terhadap progresivitas penyakit yang berhubungan dengan Benign Prostate Hyperplasia (BPH), High Grade Prostatic Intraepithelial Neoplasia (HGPIN), dan Prostate Adenocarcinoma (PRAD). Metode: Penelitian ini merupakan penelitian potong lintang dengan 3 kelompok, yaitu BPH,HGPIN, dan PRAD. Sampel jaringan didapatkan dari Tindakan TURP. Ekspresi miR-155 dianalisis menggunakan qPCR dan dikalkulasi menggunakan metode Livak. Ekspresi mRNA SOCS-1 dianalisis menggunakan reverse transcriptase PCR. Penanda pan makrofag, anti CD-68 monoclonal antibody(MoAb) digunakan untuk mendeteksi populasi makrofag pada jaringan dengan imunohistokimia. Hasil: Ekspresi miR-155 lebih tinggi pada HGPIN dibandingkan BPH dan PRAD (p=0,14). Ekspresi mRNA SOCS1 pada HGPIN paling rendah diantara ketiga sampel (p=0,96). Terdapat korelasi negative antara miR-155 dan mRNA SOCS1 (p=0,02). Terdapat peningkatan persentase populasi makrofag yang signifikan pada HGPIN (6,03 persen) dibandingkan BPH (0.89 persen) dengan p=0,00. Kesimpulan: Pada penelitian ini, terdapat perubahan persentase makrofag dan miR-155 pada HGPIN. Variasi ekspresi miR-155 dan persentase populasi makrofag dapat disebabkan karena perubahan epigenetik. Oleh sebab itu, perlu penelitian lebih lanjut untuk memvalidasi hasil tersebut dan memahami kemungkinan menjadi biomarker pada penyakit prekanker pada prostat. Kata Kunci: Prostatic Intaepithelial Neoplasia, miR-155, Makrofag Abstract Background: Impaired microRNA(miR) regulation and chronic inflammation could transform tumors into carcinoma and cancer by metastasis through cellular and genomic changes. Precancerous lesions have a 33.3 percent chance of becoming cancerous. This study investigated the role of miR-155 related to SOCS1 mRNA and macrophage population in disease progression associated with Benign Prostate Hyperplasia (BPH), High-Grade Prostatic Intraepithelial Neoplasia (HGPIN), and Prostate Adenocarcinoma (PRAD). Methods: This was a cross-sectional study using three groups of samples, namely BPH, HGPIN, and PRAD. Tissue samples were obtained from TURP Action. The expression of miR-155 was analyzed using real-time qPCR and calculated using the Livak method. The expression of SOCS1 mRNA was analyzed using reverse transcriptase PCR. The macrophage pan-marker, anti-CD68 monoclonal antibody (MoAb), was used to detect macrophage population in tissues by immunohistochemistry. Results: The expression of miR-155 was higher in HGPIN than BPH and PRAD (p=0.14). The expression of SOCS1 mRNA in HGPIN was the lowest among the three samples (p=0.96). There was a negative correlation between miR-155 and SOCS1 mRNA (p=0.02). There was a significant increase in the percentage of the macrophage population in HGPIN (6.03 percent) compared to BPH (0.89 percent) with p=0.00. Conclusion: In this study, there were changes in the percentage of macrophage and miR-155 in HGPIN. The variation in miR-155 expression and the percentage of the macrophage may be caused by epigenetic changes. Therefore, further research is needed to validate these results and understand the possibility of being a biomarker in precancerous disease of the prostate. Keywords: Prostatic Intraepithelial Neoplasia, miR-155, Macrophage

Prostate cancer (PCa) remains a leading cause of cancer‐related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes. We observed P2X4 protein expression primarily in epithelial cells of the prostate, a subset of CD66+ neutrophils, and most CD68+ macrophages. Our analysis of tissue microarrays representing 491 PCa cases demonstrated significantly elevated P2X4 expression in cancer‐ compared with benign‐tissue spots, in prostatic intraepithelial neoplasia, and in PCa with ERG positivity or with PTEN loss. High‐level P2X4 expression in benign tissues was likewise associated with the development of metastasis after radical prostatectomy. Treatment with the P2X4‐specific agonist cytidine 5′‐triphosphate (CTP) increased Transwell migration and invasion of PC3, DU145, and CWR22Rv1 PCa cells. The P2X4 antagonist 5‐(3‐bromophenyl)‐1,3‐dihydro‐2H‐benzofuro[3,2‐e]‐1,4‐diazepin‐2‐one (5‐BDBD) resulted in a dose‐dependent decrease in viability of PC3, DU145, LNCaP, CWR22Rv1, TRAMP‐C2, Myc‐CaP, BMPC1, and BMPC2 cells and decreased DU145 cell migration and invasion. Knockdown of P2X4 attenuated growth, migration, and invasion of PCa cells. Finally, knockdown of P2X4 in Myc‐CaP cells resulted in significantly attenuated subcutaneous allograft growth in FVB/NJ mice. Collectively, these data strongly support a role for the P2X4 purinergic receptor in PCa aggressiveness and identify P2X4 as a candidate for therapeutic targeting. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In human prostate cancer, the microRNA biogenesis machinery increases with prostate cancer progression. Here, we show that deletion of the Dgcr8 gene, a critical component of this complex, inhibits tumor progression in a Pten-knockout mouse model of prostate cancer. Early stages of tumor development were unaffected, but progression to advanced prostatic intraepithelial neoplasia was severely inhibited. Dgcr8 loss blocked Pten null-induced expansion of the basal-like, but not luminal, cellular compartment. Furthermore, while late-stage Pten knockout tumors exhibit decreased senescence-associated beta-galactosidase activity and increased proliferation, the simultaneous deletion of Dgcr8 blocked these changes resulting in levels similar to wild type. Sequencing of small RNAs in isolated epithelial cells uncovered numerous miRNA changes associated with PTEN loss. Consistent with a Pten-Dgcr8 association, analysis of a large cohort of human prostate tumors shows a strong correlation between Akt activation and increased Dgcr8 mRNA levels. Together, these findings uncover a critical role for microRNAs in enhancing proliferation and enabling the expansion of the basal cell compartment associated with tumor progression following Pten loss.

Prostate carcinoma (PCa) is one of the most common cancers in men. Prostate-specific antigen (PSA) has been widely used to predict the outcome of PCa and screening with PSA has resulted in a decline in mortality. However, PSA is not an optimal prognostic tool as its sensitivity may be too low to reduce morbidity and mortality. Consequently, there is a demand for additional robust biomarkers for prostate cancer. Death receptor 5 (DR5) has been implicated in the prognosis of several cancers and it has been previously shown that it is negatively regulated by Yin Yang 1 (YY1) in prostate cancer cell lines. The present study investigated the clinical significance of DR5 expression in a prostate cancer patient cohort and its correlation with YY1 expression. Immunohistochemical analysis of protein expression distribution was performed using tissue microarray constructs from 54 primary PCa and 39 prostatic intraepithelial neoplasia (PIN) specimens. DR5 expression was dramatically reduced as a function of higher tumor grade. By contrast, YY1 expression was elevated in PCa tumors as compared with that in PIN, and was increased with higher tumor grade. DR5 had an inverse correlation with YY1 expression. Bioinformatic analyses corroborated these data. The present findings suggested that DR5 and YY1 expression levels may serve as progression biomarkers for prostate cancer.

The tumor microenvironment plays a critical role in cancer progression, but the precise mechanisms by which stromal cells influence the epithelium are poorly understood. Here we show that p62 levels were reduced in the stroma of several tumors and that its loss in the tumor microenvironment or stromal fibroblasts resulted in increased tumorigenesis of epithelial prostate cancer cells. The mechanism involves the regulation of cellular redox through an mTORC1/c-Myc pathway of stromal glucose and amino acid metabolism, resulting in increased stromal IL-6 production, which is required for tumor promotion in the epithelial compartment. Thus, p62 is an anti-inflammatory tumor suppressor that acts through the modulation of metabolism in the tumor stroma.

Introduction: Prostate disease is an important growing health problem, presenting a challenge to urologists, radiologists, and pathologists. Objectives: The aim of the study is to correlate prostatic-specific antigen test with histopathological examination in prostatic lesions and to recommend combine approach for management of the patients of prostatic lesions. Materials and Methods:This was a prospective study conducted at the department of pathology in a tertiary care center over 6 months. Data were collected from histopathology record department. The 2002 WHO classification was used to diagnose and classify prostate tumors. Gleason’s grading system was used for the cases of adenocarcinoma. Results: In our study, a total of 119 cases of prostatic lesions were noticed. The lesions diagnosed were benign prostatic hyperplasia (79% of cases), adenocarcinoma (6% of cases), prostatic intraepithelial neoplasia (4% of cases), stromal nodules of hyperplasia (4% of cases), and atypical adenomatous hyperplasia (4% of cases). A total of 3% of cases were inadequate. Majority of prostatic lesions were belonging to the 6th decade followed by the 7th decade. All cases of adenocarcinoma were belonging to the 6th decade. The test of prostatic-specific antigen was higher (more than 10 ng) in cases of adenocarcinoma. Conclusions: The study is conducted to see that combine approach of prostate-specific antigen and histopathological examination is useful for its recommendation, for better management of prostatic lesions in tertiary care center.

Abstract Background Chronic prostatitis has been supposed to be associated with preneoplastic lesions and cancer development. The objective of this study was to examine how chronic inflammation results in a prostatic microenvironment and gene mutation in C57BL/6 mice. Methods Immune and bacterial prostatitis mouse models were created through abdominal subcutaneous injection of rat prostate extract protein immunization (EAP group) or transurethral instillation of uropathogenic E. coli 1677 (E. coli group). Prostate histology, serum cytokine level, and genome-wide exome (GWE) sequences were examined 1, 3, and 6 months after immunization or injection. Result In the EAP and E. coli groups, immune cell infiltrations were observed in the first and last months of the entire experiment. After 3 months, obvious proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) were observed accompanied with fibrosis hyperplasia in stroma. The decrease in basal cells (Cytokeratin (CK) 5+/p63+) and the accumulation of luminal epithelial cells (CK8+) in the PIA or PIN area indicated that the basal cells were damaged or transformed into different luminal cells. Hic1, Zfp148, and Mfge8 gene mutations were detected in chronic prostatitis somatic cells. Conclusion Chronic prostatitis induced by prostate extract protein immunization or E. coli infection caused a reactive prostatic inflammation microenvironment and resulted in tissue damage, aberrant atrophy, hyperplasia, and somatic genome mutation.

OBJECTIVE The objective of the study was to investigate the relationship between histopathological features of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) and carcinoma risk in repeat prostate needle biopsies of 6 versus 12 cores. METHODS Of 114 isolated HGPIN cases were included; 64 with 6 (1st group) and 50 with 12 cores (2nd group). The number of cores with HGPIN, laterality, structural PIN subtypes, prominent nucleolus, and nuclear pleomorphism was examined in the first and follow-up biopsies. The relationship between the results of follow-up biopsies and clinicopathological findings was evaluated statistically. Furthermore, a systematic literature review was carried out. RESULTS Carcinoma was found in repeat biopsies in 15.6% of the cases in 6-core and 24% of cases with 12-core biopsies (p=0.006). Carcinoma detection rate was significantly higher in cases with ≥2 cores with HGPIN than in cases with a single core of HGPIN (p=0.007). The rates of carcinoma and persistent HGPIN were higher in multifocal and bilateral HGPIN cases, compared to unifocal, or multifocal but unilateral cases (p=0.018). In both groups, prominent nuclear pleomorphism was significantly more common in cases with carcinoma (p=0.023). The systematic literature review revealed 25.6% of carcinoma risk out of 5580 isolated HGPIN patients. CONCLUSION Carcinoma detection rate in repeat biopsies of 12-cores was significantly higher than cases with 6-core biopsies. The HGPIN cases with ≥2 cores, bilaterality, and presence of prominent nuclear pleomorphism were found to be significant histopathological markers in predicting patients with carcinoma. Close follow- up of high risk patients with repeat biopsies in addition to clinical parameters was recommended. [ABSTRACT FROM AUTHOR]

Paneth cell-like neuroendocrine metaplasia of benign and cancerous prostate was described in 1992. Here, we note that P504S (AMACR), the cytoplasmic marker for prostate cancer used alone or in concert with basal cell markers, can be strongly reactive in benign prostatic acini with Paneth cell-like change.

This report summarizes the presentations and discussions that took place at the Sixth Joint Meeting of J-CaP and CaPSURE held in San Francisco, USA, in August 2012. The J-CaP and CaPSURE Joint Initiative was established in 2007 with the objective of analyzing, reviewing, comparing and contrasting data for prostate cancer patients from Japan and the USA within the two important large-scale, longitudinal, observational databases-J-CaP and CaPSURE. Since this initial collaboration between teams in the USA and Japan, the initiative has now expanded to include representatives of other Asian countries, several of whom have either established or are planning their own national prostate cancer databases. Several key topics were considered at this Sixth Joint Meeting including the current status of the J-CaP and CaPSURE databases and opportunities for collaboration with the more recently developed Asian prostate cancer databases. The latest comparative data from J-CaP and CaPSURE regarding outcomes following androgen deprivation therapy and combined androgen blockade were also reviewed. The possibility of a global chemoprevention trial to investigate the influence of soy isoflavones on prostate cancer incidence was considered. In addition, the ongoing debate regarding the role of screening and the use of active surveillance as a treatment option in the USA was discussed. The collaborators agreed that sharing of data and treatment practices on a global scale would undoubtedly benefit the clinical management of prostate cancer patients worldwide.

Expression of Sprouty genes is frequently decreased or absent in human prostate cancer, implicating them as suppressors of tumorigenesis. Here we show they function in prostate tumor suppression in the mouse. Concomitant inactivation of Spry1 and Spry2 in prostate epithelium causes ductal hyperplasia and low-grade prostatic intraepithelial neoplasia (PIN). However, when Spry1 and Spry2 loss-of-function occurs in the context of heterozygosity for a null allele of the tumor suppressor gene Pten, there is a striking increase in PIN and evidence of neoplastic invasion. Conversely, expression of a Spry2 gain-of-function transgene in Pten null prostatic epithelium suppresses the tumorigenic effects of loss of Pten function. We show that Sprouty gene loss-of-function results in hyperactive RAS/ERK1/2 signaling throughout the prostate epithelium and cooperates with heterozygosity for a Pten null allele to promote hyperactive PI3K/AKT signaling. Furthermore, Spry2 gain-of-function can suppress hyperactivation of AKT caused by the absence of PTEN. Together, these results point to a key genetic interaction between Sprouty genes and Pten in prostate tumorigenesis and provide strong evidence that Sprouty genes can function to modulate signaling via the RAS/ERK1/2 and PI3K/AKT pathways. The finding that Sprouty genes suppress tumorigenesis caused by Pten loss-of-function suggests that therapeutic approaches aimed at restoring normal feedback mechanisms triggered by receptor tyrosine kinase signaling, including Sprouty gene expression, may provide an effective strategy to delay or prevent high-grade PIN and invasive prostate cancer.

PurposeProstate cancer is detected with increasing frequency but has a highly variable natural history and prognosis and active surveillance of men with low-risk prostate cancer would benefit greatly from minimally invasive methods to identify progression. We describe here two novel in vivo metrics of cell proliferation in men with prostate neoplasia.Experimental designThree groups of men drank heavy water, a nonradioactive, stable isotopic tracer for 14 to 28 days: (i) healthy men, (ii) men scheduled for transrectal core needle biopsy, and (iii) men scheduled for radical prostatectomy. Prostate epithelial cells (PEC) were isolated from ejaculated seminal fluid in all subjects. Histologically graded lesions were microdissected from tissue slides obtained from subjects undergoing surgery and proliferation rates were measured from isolated cells via mass spectrometry.ResultsProliferation rates of seminal PEC in healthy men (0.10%-0.27%/d) were stable on repeat sampling. Rates above 0.34%/d were seen only in patients with cancer where rates increased progressively from normal tissue through benign prostate hyperplasia, prostate intraepithelial neoplasia, and tumor grades III and IV in all subjects. Seminal PEC kinetics correlated highly with the most proliferative microdissected region in each subject (r(2) = 0.94).ConclusionsProstate cell proliferation can be measured in vivo from microdissected histopathology sections or noninvasively from seminal fluid where the latter reflects the most proliferative region of the gland. This approach may allow monitoring of progression in men with low-risk prostate cancer.

MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.

Immunostaining of p21, p27, p53, cyclin D1, c-myc was evaluated in normal canine prostate and prostate with proliferative disorders to verify the interaction between these regulators of cell cycle progression. From 106 samples of canine prostate obtained from a TMA block, 15 were considered normal, 16 diagnosed as benign prostatic hyperplasia (BPH), 30 as proliferative inflammatory atrophy (PIA), 20 as prostatic intraepithelial neoplasia (PIN), and 25 as prostatic carcinoma (PC). There was positive correlation between p21 and p27 for number of stained cells and staining intensity in all conditions and between c-myc and p53 in prostates with PIN. Considering the number of labeled cells, there was positive correlation between p21 and p53 in the normal prostate. Relative to the intensity of staining, there was positive correlation between p21 and p53 in prostate tissue with PIN and between p27 and c-myc in prostates with PIA. A negative correlation between c-myc and cyclin D1 was also identified in the glands with PIN, considering the number of labeled cells, and between p27 and c-myc in the prostates with PC for staining intensity. In conclusion, the expression of p21, p27, p53, cyclin D1 and c-myc varies according to type of proliferative lesion in canine prostate. Taken together, the results indicate low growth potential of the canine PC in the presence of p21 and p27 overexpression, cyclin D1 low expression and regular expression of c-myc, even with the expression of p53 mutant type. Further, it was possible reaffirm the premalignant potential of PIA and PIN in canine prostate.

Epidemiological studies have shown that one of the strongest risk factors for prostate cancer is a family history of the disease, suggesting that inherited factors play a major role in prostate cancer susceptibility. Germline mutations in BRCA2 predispose to breast and ovarian cancer with its predominant tumour suppressor function thought to be the repair of DNA double-strand breaks. BRCA2 has also been implicated in prostate cancer etiology, but it is unclear the impact that mutations in this gene have on prostate tumourigenesis. Here we have undertaken a genetic analysis in the mouse to determine the role of Brca2 in the adult prostate. We show that deletion of Brca2 specifically in prostate epithelia results in focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN) in animals over 12 months of age. Simultaneous deletion of Brca2 and the tumour suppressor Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals from 12 months. Epithelial cells in these lesions show an increase in DNA damage and have higher levels of proliferation, but also elevated apoptosis. Castration of Brca2;Trp53 mutant animals led to regression of PIN lesions, but atypical cells persisted that continued to proliferate and express nuclear androgen receptor. This study provides evidence that Brca2 can act as a tumour suppressor in the prostate, and the model we describe should prove useful in the development of new therapeutic approaches.

Objective Sarcosine was postulated in 2009 as a biomarker for prostate cancer (PCa). Here, we assess plasma sarcosine as a biomarker that is complementary to prostate-specific antigen (PSA). Methods Plasma sarcosine was measured using gas chromatography-mass spectrometry (GC-MS) in adults classified as noncancerous controls (with benign prostate hyperplasia [BPH], n = 36), with prostatic intraepithelial neoplasia (PIN, n = 16), or with PCa (n = 27). Diagnostic accuracy was assessed using receiver operating characteristic curve analysis. Results Plasma sarcosine levels were higher in the PCa (2.0 µM [1.3–3.3 µM], P <.01) and the PIN (1.9 µM [1.2–6.5 µM], P <.001) groups than in the BPH (0.9 µM [0.6–1.4 µM]) group. Plasma sarcosine had "good" and "very good" discriminative capability to detect PIN (area under the curve [AUC], 0.734) and PCa (AUC, 0.833) versus BPH, respectively. The use of PSA and sarcosine together improved the overall diagnostic accuracy to detect PIN and PCa versus BPH. Conclusion Plasma sarcosine measured by GC-MS had "good" and "very good" classification performance for distinguishing PIN and PCa, respectively, relative to noncancerous patients diagnosed with BPH. [ABSTRACT FROM AUTHOR]

Androgens stimulate the proliferation of epithelial cells in the prostate by activating topoisomerase 2 (TOP2) and regulating the transcription of target genes. TOP2 resolves the entanglement of genomic DNA by transiently generating double‐strand breaks (DSBs), where TOP2 homodimers covalently bind to 5′ DSB ends, called TOP2‐DNA cleavage complexes (TOP2ccs). When TOP2 fails to rejoin TOP2ccs generating stalled TOP2ccs, tyrosyl DNA phosphodiesterase‐2 (TDP2) removes 5′ TOP2 adducts from stalled TOP2ccs prior to the ligation of the DSBs by nonhomologous end joining (NHEJ), the dominant DSB repair pathway in G0/G1 phases. We previously showed that estrogens frequently generate stalled TOP2ccs in G0/G1 phases. Here, we show that physiological concentrations of androgens induce several DSBs in individual human prostate cancer cells during G1 phase, and loss of TDP2 causes a five times higher number of androgen‐induced chromosome breaks in mitotic chromosome spreads. Intraperitoneally injected androgens induce several DSBs in individual epithelial cells of the prostate in TDP2‐deficient mice, even at 20 hr postinjection. In conclusion, physiological concentrations of androgens have very strong genotoxicity, most likely by generating stalled TOP2ccs. [ABSTRACT FROM AUTHOR]

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and Prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.

Objectives: Cancer pathology reports are expected to contain all information required for patient management and disease surveillance. Moreover, reports for patients with prostate cancer have become increasingly complex with the addition of more pathological details. This study aimed to compare narrative and synoptic prostate cancer reports for core needle biopsies received at a tertiary hospital in Nigeria in order to determine which form was most complete according to international standards. Methods: This study was conducted from January 2010 to December 2015 at the Lagos University Teaching Hospital, Lagos, Nigeria. All malignant prostate cancer histopathology reports received during this period were analysed for the presence of important clinicopathological parameters, including the numbers of cores taken and those involved by the tumour, percentage of tumour involvement, Gleason score and the presence of high-grade prostatic intraepithelial neoplasms (HGPINs) and perineural and lymphovascular invasion. Results: A total of 83 reports were reviewed, of which 27 were in narrative and 56 in synoptic format. The documentation of clinicopathological characteristics in narrative reports was significantly incomplete compared to synoptic reports in recording the number of cores (33.3% versus 96.4%), number of cores involved by the tumour (11.1% versus 94.6%), percentage of cores involved by the tumour (3.7% versus 100.0%) and the presence of HGPINs (7.4% versus 100.0%) and perineural (59.3% versus 98.2%) and lymphovascular (48.1% versus 100.0%) invasion (P