Normal Prostate Tissue Research Articles

Abstract 2365: Intracellular interaction of downstream molecular mediators of miR-1207-3p in prostate cancer cells

Abstract Prostate cancer (PCa) is the second most common cancer diagnosed among men in the United States. Human chromosome 8q24 is the most important PCa susceptibility locus. This region contains the MYC oncogene, which is involved in early PCa initiation. Downstream to MYC is the PVT1 gene, which is often amplified in PCa. PVT1 is a non-protein coding gene that encodes six annotated microRNAs (miRNAs), including miR-1207-3p. Our laboratory has previously demonstrated miR1207-3p to be a significant modulator in PCa and revealed that miR-1207-3p is significantly underexpressed in PCa cells and histologically confirmed PCa tissues compared to normal prostatic cells and tissues. We have also shown that miR-1207-3p has tumor suppressive activity in vivo. Moreover, we discovered that miR-1207-3p directly targets fibronectin type III domain containing 1 (FNDC1), which was found to be overexpressed in PCa cells and there is a concomitant overexpression of (FN1)/androgen receptor (AR)/c-MYC. In an effort to better understand the role of FNDC1/FN1/AR/c-MYC in PCa progression we examined the interaction between FNDC1/FN1/AR/c-MYC and found direct physical interaction through coimmunoprecipitation. We also examined the spatial localization of the FNDC1/FN1/AR/c-MYC pathway by performing immunofluorescence staining in PCa cells. Single staining analysis revealed that FNDC1 and c-MYC localize to the nucleus and cytoplasm while AR localizes to the nucleus and FN1 localizes to the cytoplasm in PCa cells. However, in normal prostate epithelial cells FNDC1, AR and c-MYC localize to the nucleus whereas FN1 localize to the cytoplasm. These results suggest that the underexpression of miR1207-3p may be affecting the localization of FNDC1 to cytoplasm and thus promoting interaction between FNDC1/FN1/AR/c-MYC. Future studies include examining the effect of miR-1207 on the spatial organization and interactions of the FNDC1/FN1/AR/c-MYC pathway through immunofluorescence and co-immunoprecipitation assays. Thus, understanding this molecular interaction could reveal interesting insight into the biology of microRNA-1207-3p regulation in PCa. Citation Format: Priyanka Ghosh, Oloronseun Ogunwobi. Intracellular interaction of downstream molecular mediators of miR-1207-3p in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2365.

Abstract 2364: MicroRNA-1205 directly targets ONECUT2 in neuroendocrine prostate cancer cells

Abstract One of six deaths globally is due to cancer. In 2018, prostate cancer (PCa) represented 1.28 million cases worldwide, the second most frequent cancer diagnosis and fifth leading cause of death in men. Currently, the mortality rate of PCa has experienced a steady increase due to the progression of metastatic castration-resistant prostate cancer (mCRPC). As an androgen driven disease, androgen deprivation therapies (ADTs) have been employed for treatment. However, despite ADTs, mCRPC develops by maintaining AR signaling, which can eventually lead to progression of AR-independent neuroendocrine PCa (NEPC). NEPC is observable in 1 in 5 men with mCRPC and associated with poor outcome. Therefore, further understanding the mechanisms of progression to mCRPC and NEPC is required. The 8q24 human chromosomal region associated with Increased PCa incidence and aggressiveness contains the PVT1 (Plasmocytoma Variant Translocation 1) locus. The PVT1 locus encodes six microRNAs, including microRNA-1205 (miR-1205) in PCa. Our laboratory previously confirmed that miR-1205 is underexpressed in PCa tissue in comparison to normal prostatic tissue and in CRPC cells in comparison to non-CRPC cells. To understand the molecular mechanism of miR-1205, we performed RNA pull down and RNA sequencing analysis to identify miR-1205 molecular targets in non-tumorigenic RWPE-1 prostate epithelial cells and PCa cells (MDA PCa 2b (metastatic PCa), PC-3 (NEPC), and C4-2B (CRPC)). We identified one cut homeobox 2 (ONECUT2 or OC2) as a direct molecular target of miR-1205. ONECUT2 is a master regulator of transcriptional factors that drives NEPC by through regulating hypoxia signaling or inducing neuroendocrine markers. ONECUT2 enrichment was approximately 3-fold higher in RWPE-1 (P=0.26), 2-fold in PC-3 (P=0.06), 1-fold in C4-2B (P=0.05) and MDA PCa 2b (P=0.02) cells. The significant binding of miR-1205 to ONECUT-2 in the PC-3 NEPC cell line suggests that miR-1205 regulation of ONECUT2 may be an important molecular mechanism in NEPC. Consequently, further study of miR-1205 and ONECUT2 in NEPC is required. Citation Format: Bachelard Dieujuste, Michelle Naidoo, Olorunseun Ogunwobi. MicroRNA-1205 directly targets ONECUT2 in neuroendocrine prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2364.

Expression and Clinical Significance of HKII and HIF-1α in Grade Groups of Prostate Cancer.

Prostate cancer (PCA) is the second leading cause of cancer-related mortality in men. The glycolytic enzymes hexokinase II (HKII) and the major regulator hypoxia-inducible factor-1α (HIF-1α) are PCA-specific biomarkers. Some studies have shown that HKII and HIF-1α are highly expressive in PCA and are associated with the growth and metastasis of treatment. Whether HKII and HIF-1α regulate the different differentiation of PCA remains largely unknown. Therefore, the study aims to explore the value of HKII and HIF-1α in different grade groups of PCA. Our data indicated that compared with normal prostate tissues, the level of mRNA and protein of HKII and HIF-1α in PCA increased significantly, besides the results showed the high expression of HKII and HIF-1α had a tendency to promote the progression and differentiation of PCA. The study also found that HKII expression was positively correlated with the expression of HIF-1α. HKII and HIF-1α were related to the degree of differentiation PCA, especially in high-grade PCA. Furthermore, the high expression of HKII was significantly associated with Gleason score and histological differentiation in clinicopathological characteristics of patients with PCA. These results were further used to confirm that the expression of HKII and HIF-1α was associated with the progression and differentiation of PCA. These experiments indicated that HKII and HIF-1α might be novel biomarkers of PCA with potential clinical application value, provide a new potential target for PCA treatment, and are expected to be used for individualized treatment in patients with PCA.

Ectopic Prostate Tissue Presenting as Urinary Bladder Tumor: The Imitation Game!

Ectopic prostate tissue is a rare phenomenon. Histologically and immunohistochemically it is indistinguishable from normal prostatic tissue but it is difficult to recognize and may be confused with malignancy when presenting as ectopic lesion in the urinary system. Therefore, awareness of this entity is essential for both urologists and pathologists to prevent misdiagnosis.

Evaluation of Weighted Diffusion Subtraction for Detection of Clinically Significant Prostate Cancer.

Diffusion-weighted imaging (DWI) is an important method for clinically significant prostate cancer (csPCa) diagnosis; however, the Prostate Imaging-Reporting and Data System (PI-RADS) requires the subjective assessment of "markedly hypointense or not" on apparent diffusion coefficient (ADC) map. We hypothesize that weighted diffusion subtraction (WDS) images, created by weighted subtraction of high and low b-value DWIs, might better show areas of ADC values below a set threshold, thus decreasing the subjectivity of the assessment. To evaluate the diagnostic ability of WDS for csPCa by comparing scores based on WDS images (DWI/WDS) with those based on PI-RADS DWI (DWI/ADC). Retrospective. Eighty-six PCa patients. 3.0 T; DWI. Four readers assessed the probability of csPCa in lesions (overall, in the peripheral zone [PZ] and transitional zone [TZ]) using 5-point DWI/ADC and DWI/WDS scores. Prostatectomy specimens were the reference standard. ADC values and contrast between csPCa and normal prostate tissue on ADC maps and WDS images were calculated with reference to the pathological map. Diagnostic ability was evaluated by Jackknife alternative free-response receiver-operating characteristic curve. Figure of merit (FOM), sensitivity, and positive predictive value (PPV) between the DWI/ADC and DWI/WDS scores were compared using paired t-test. Inter-reader agreement was analyzed using κ statistics, and the significance probability was calculated using the Z statistic. Wilcoxon signed-rank test was used to compare contrast between csPCa and normal prostate tissue on ADC maps and WDS images. A P value <0.05 was considered statistically significant. FOM and sensitivity of the DWI/WDS scores were significantly better than those of the DWI/ADC scores overall, in the PZ and TZ (FOM: overall, 0.715 vs. 0.783; PZ, 0.756 vs. 0.815; TZ, 0.653 vs. 0.738. Sensitivity: overall, 0.512 vs. 0.607; PZ, 0.485 vs. 0.573; TZ, 0.636 vs. 0.761). For PPV, a statistically significant difference was observed overall (0.727 vs. 0.777). The κ value of DWI/WDS score was significantly higher than that of DWI/ADC score overall and in the PZ (overall, 0.614 vs. 0.792; PZ, 0.609 vs. 0.797). Contrast was significantly higher overall in the PZ and TZ in WDS images (median, 1.26, 1.19, and 1.61) than in ADC maps (0.46, 0.47, and 0.41). WDS images performed better than ADC maps in the diagnosis of csPCa and in inter-reader agreement of the diagnosis. 4 Technical Efficacy Stage: 2.

Exploring the diagnostic potential of adding T2 dependence in diffusion-weighted MR imaging of the prostate.

Magnetic resonance imaging (MRI) is essential in the detection and staging of prostate cancer. However, improved tools to distinguish between low-risk and high-risk cancer are needed in order to select the appropriate treatment. To investigate the diagnostic potential of signal fractions estimated from a two-component model using combined T2- and diffusion-weighted imaging (T2-DWI). 62 patients with prostate cancer and 14 patients with benign prostatic hyperplasia (BPH) underwent combined T2-DWI (TE = 55 and 73 ms, b-values = 50 and 700 s/mm2) following clinical suspicion of cancer, providing a set of 4 measurements per voxel. Cancer was confirmed in post-MRI biopsy, and regions of interest (ROIs) were delineated based on radiology reporting. Signal fractions of the slow component (SFslow) of the proposed two-component model were calculated from a model fit with 2 free parameters, and compared to conventional bi- and mono-exponential apparent diffusion coefficient (ADC) models. All three models showed a significant difference (p<0.0001) between peripheral zone (PZ) tumor and normal tissue ROIs, but not between non-PZ tumor and BPH ROIs. The area under the receiver operating characteristics curve distinguishing tumor from prostate voxels was 0.956, 0.949 and 0.949 for the two-component, bi-exponential and mono-exponential models, respectively. The corresponding Spearman correlation coefficients between tumor values and Gleason Grade Group were fair (0.370, 0.499 and -0.490), but not significant. Signal fraction estimates from a two-component model based on combined T2-DWI can differentiate between tumor and normal prostate tissue and show potential for prostate cancer diagnosis. The model performed similarly to conventional diffusion models.

Tissue clearing techniques for three-dimensional optical imaging of intact human prostate and correlations with multi-parametric MRI.

Tissue clearing technologies have enabled remarkable advancements for in situ characterization of tissues and exploration of the three-dimensional (3D) relationships between cells, however, these studies have predominantly been performed in non-human tissues and correlative assessment with clinical imaging has yet to be explored. We sought to evaluate the feasibility of tissue clearing technologies for3Dimaging of intact human prostate and the mapping of structurally and molecularly preserved pathology data with multi-parametric volumetric MR imaging (mpMRI). Whole-mount prostates were processed with either hydrogel-based CLARITY or solvent-based iDISCO. The samples were stained with a nuclear dye or fluorescently labeled with antibodies against androgen receptor, alpha-methylacyl coenzyme-A racemase, or p63, and then imaged with 3D confocal microscopy. The apparent diffusion coefficientand Ktrans maps were computed from preoperative mpMRI. Quantitative analysis of cleared normal and tumor prostate tissue volumes displayed differences in 3D tissue architecture, marker-specific cell staining, and cell densities that were significantly correlated with mpMRI measurements in this initial, pilot cohort. 3D imaging of human prostate volumes following tissue clearing is a feasible technique for quantitative radiology-pathology correlation analysis with mpMRI and provides an opportunity to explore functional relationships between cellular structures and cross-sectional clinical imaging.

Selected Articles from This Issue

While many cancer risk prediction models have been developed, very few have been externally validated, and almost none are used routinely in clinical practice beyond identification of family risk. To address the gap in translation to practice, Rosner and colleagues simplified a summary of breast cancer risk factors, added mammographic breast density, and a 77 SNP polygenic risk score to predict 10-year risk of breast cancer. This simplified model performed well in external validation in the Mayo Mammography Health Study (AUC=0.687). Adding simplified questionnaire data and polygenic risk each improved performance over mammographic breast density and age. This approach can be easily implemented in routine mammography screening clinics.Identification and management of cancer patients' financial concerns is essential as cancer care costs rise. McLouth and colleagues aimed to describe the prevalence of financial screening, sources of financial navigation services, and availability of cancer-specific financial navigators within the National Cancer Institute's Community Oncology Research Program (NCORP). Most NCORP community oncology practice group. had a financial screening process. Practice groups reported multiple potential sources of financial navigation services, but cancer-specific financial navigators were available at only half of the practice groups. Critically, fewer NCORP practice groups serving a higher proportion of racial and ethnic minority patients screened for financial concerns and had a designated financial navigator for cancer patients. Results highlight several opportunities to improve identification of cancer patients who may be vulnerable to financial hardship and to increase services to address financial hardship in community cancer care.Observational studies suggest that men engaged in high levels of physical activity have lower risk of clinically significant prostate cancer. To investigate potential mechanisms, Pernar and colleagues evaluated molecular differences in prostate tissue in men with prostate cancer according to physical activity level. The authors identified several biological pathways that were altered between men with different levels of vigorous physical activity in adjacent normal prostate tissue, such as cancer- and immune-related pathways. These results help illuminate how physical activity may influence the prostate tissue in men with prostate cancer.Inflammation and insulin resistance/hyperinsulinemia are important pathways in hepatocarcinogenesis. Diet and lifestyle behaviors modulate inflammation and insulin response and may thus be crucial modifiable factors in primary prevention for hepatocellular carcinoma (HCC). In a cohort study that followed 119,316 US adults for 25.6 years, participants who consumed diet or had lifestyle behaviors with higher inflammatory and insulinemic potential had higher of developing HCC. These findings by Yang and colleagues suggest that inflammation and insulin resistance/hyperinsulinemia may partly underline the influence of diet and other lifestyle on HCC development, and interventions to reduce the adverse effect of pro-inflammatory and hyper-insulinemic lifestyle may reduce HCC risk.

Tumor detection of 18F-PSMA-1007 in the prostate gland in patients with prostate cancer using prostatectomy specimens as reference method.

Prostate-specific membrane antigen (PSMA) radiopharmaceuticals used with positron emission tomography/computed tomography (PET-CT) are a promising tool for managing patients with prostate cancer. This study aimed to determine the accuracy of 18F-PSMA-1007 PET-CT for detecting tumors in the prostate gland using radical prostatectomy (RP) specimens as a reference method and to determine whether a correlation exists between 18F-PSMA-1007 uptake and the International Society of Urological Pathology (ISUP) grade and prostate specific antigen (PSA) levels at diagnosis. Methods: Thirty-nine patients referred for 18F-PSMA-1007 PET-CT for initial staging and who underwent RP within four months were retrospectively included. Uptake of 18F-PSMA-1007 indicative of cancer was assessed and maximum standardized uptake values (SUVmax) and total lesion uptake (TLU) were calculated for the index tumor. Histopathology was assessed from RP specimens. True positive, false negative, and false positive lesions were calculated. Results: In 94.9% of patients, the index tumor was correctly identified with PET. SUVmax was significantly higher in the tumors vs normal prostate tissue, but no significant differences were found between different ISUP grades and SUVmax There was a poor correlation between PSA at diagnosis and SUVmax (r=0.23) and moderate agreement between PSA at diagnosis and TLU (r=0.67). When all tumors (also non-index tumors) were considered, many small tumors (approx. 1-2 mm) were not detected with PET. Conclusion: 18F-PSMA-1007 PET-CT performs well in correctly identifying the index tumor in patients with intermediate to high-risk prostate cancer. Approximately 5% of the index tumors were missed by PET, which agrees with previous studies.

Single-cell Spatial Proteomic Revelations on the Multiparametric MRI Heterogeneity of Clinically Significant Prostate Cancer.

Multiparametric MRI (mpMRI) has become an indispensable radiographic tool in diagnosing prostate cancer. However, mpMRI fails to visualize approximately 15% of clinically significant prostate cancer (csPCa). The molecular, cellular, and spatial underpinnings of such radiographic heterogeneity in csPCa are unclear. We examined tumor tissues from clinically matched patients with mpMRI-invisible and mpMRI-visible csPCa who underwent radical prostatectomy. Multiplex immunofluorescence single-cell spatial imaging and gene expression profiling were performed. Artificial intelligence-based analytic algorithms were developed to examine the tumor ecosystem and integrate with corresponding transcriptomics. More complex and compact epithelial tumor architectures were found in mpMRI-visible than in mpMRI-invisible prostate cancer tumors. In contrast, similar stromal patterns were detected between mpMRI-invisible prostate cancer and normal prostate tissues. Furthermore, quantification of immune cell composition and tumor-immune interactions demonstrated a lack of immune cell infiltration in the malignant but not in the adjacent nonmalignant tissue compartments, irrespective of mpMRI visibility. No significant difference in immune profiles was detected between mpMRI-visible and mpMRI-invisible prostate cancer within our patient cohort, whereas expression profiling identified a 24-gene stromal signature enriched in mpMRI-invisible prostate cancer. Prostate cancer with strong stromal signature exhibited a favorable survival outcome within The Cancer Genome Atlas prostate cancer cohort. Notably, five recurrences in the 8 mpMRI-visible patients with csPCa and no recurrence in the 8 clinically matched patients with mpMRI-invisible csPCa occurred during the 5-year follow-up post-prostatectomy. Our study identified distinct molecular, cellular, and structural characteristics associated with mpMRI-visible csPCa, whereas mpMRI-invisible tumors were similar to normal prostate tissue, likely contributing to mpMRI invisibility.

Quasi-Linear Viscoelastic Characterization of Soft Tissue-Mimicking Materials.

We present a novel method based on the quasi-linear viscoelastic (QLV) theory to describe the time-dependent behavior of soft materials. Unlike previous methods for deriving QLV parameters, we characterize the elastic and viscous behavior of materials separately by using two different sets of experiments. To model the nonlinear elastic behavior, we fit the elastic stress response with a one-term Ogden model. Then, we model the relaxation behavior with a Prony series to compare the stress relaxation of the material at different timescales. This new method allows us to characterize materials with narrow confidence intervals (high accuracy), independently from the loading conditions. We validate our model using samples made of phantom materials that mimic normal and cancerous prostate tissues in terms of Young's modulus. Our model is shown to distinguish materials with similar elastic (viscous) properties but different viscous (elastic) properties. Drawing a precise distinction between the phantoms, this method could be useful for prostate cancer (PCa) diagnosis; but significant clinical studies will be needed in the future.

Expression Patterns of ERα, ERβ, AR, SIRT1, SIRT2, and SIRT3 in Prostate Cancer Tissue and Normal Prostate Tissue

The purpose of this study was to examine the expression of estrogen receptor α (ERα) and β (ERβ), androgen receptor (AR), SIRT1, SIRT2 and SIRT3 in prostate cancer (PCa). From October 2010 to January 2015, 70 patients who had undergone radical prostatectomy following a PCa diagnosis were enrolled in our study. Normal prostate tissue (NPT) and prostate cancer tissues (PCAT) were separated, and the expression of each receptor in each tissue was analyzed with immunochemical staining. Univariate and multivariate analyses were performed to identify factors affecting the development of PCa. ERβ and AR were highly expressed in PCAT compared with NPT (p<0.05). SIRT2 was highly expressed in NPT and PCAT (p<0.05). Univariate and multivariate analyses showed that AR and SIRT2 affect PCa development. AR is a risk factor for PC, and SIRT2 is associated with a lower incidence of PCa.

TRPM8 protein expression in hormone naïve local and lymph node metastatic prostate cancer.

SummaryObjectiveProstate cancer (PCa) is the second most common malignancy in men. Radiotherapy and surgery successfully control organ-confined tumors, although, locally advanced/high-risk PCa frequently progress to the metastatic stage of the disease, which is uncurable. Identification of novel strategies to improve the efficacy of standard clinical protocols is a primary need. Among the molecular targets of potential clinical interest recently highlighted by accurate preclinical studies, the TRPM8 cation channel is particularly promising. In this study, we aim at establishing a standardized immunohistochemistry protocol to evaluate TRPM8 expression in normal and pathological prostate tissues.MethodsThe specificity and sensitivity of TRPM8 antibody ACC-049 was validated in different human prostate cell lines by western blot and immunocytochemistry analyses. Expression of the TRPM8 channel in normal and pathological prostate tissue was evaluated by immunohistochemistry using a tissue microarray containing 58 cases of prostate adenocarcinomas and in primary and lymph nodes metastatic human PCa matched specimens.ResultsTRPM8 expression marks luminal epithelial cells in benign prostate tissue. In malignant lesions of the prostate, TRPM8 expression is frequently more abundant in advanced stages of the disease (PCa stage III/IV). Finally, lymph node metastases and matched primary tumors show similar amounts of the channel.ConclusionsCollectively, our results reinforce the importance of TRPM8 as prostate biomarker and emphasize the value of the channel as promising novel molecular target for the treatment of prostate adenocarcinoma.

Calcium-binding and coiled-coil domain 2 promotes the proliferation and suppresses apoptosis of prostate cancer cells.

Prostate cancer (PCa) is considered to be one of the most common tumors in men. Calcium-binding and coiled-coil domain 2 (CALCOCO2) is a known important xenophagy receptor, which mediates intracellular bacterial degradation. To the best of the authors' knowledge, the present study is the first to demonstrate that CALCOCO2 functions as an oncogene in PCa. The results of the current study indicated that CALCOCO2 knockdown suppressed cell proliferation and colony formation, whereas it promoted apoptosis of PCa cells. In addition, knockdown of CALCOCO2 in PCa cells reduced cyclin-E1 and increased p53 protein expression. Bioinformatics analysis revealed that CALCOCO2 was associated with 'autophagosome assembly', 'nucleophagy' and 'nucleic acid metabolic process' biological processes and interacted with sequestosome-1, microtubule-associated proteins 1A/1B light chain 3 (MAP1LC3)B, γ-aminobutyric acid receptor-associated protein, IκB kinase subunit γ and MAP1LC3C. Moreover, CALCOCO2 protein levels were indicated to be significantly increased in PCa samples compared with normal prostate tissues. These results suggested that CALCOCO2 may be of value as a diagnostic and therapeutic target in PCa.

HHV-8 positive clinically advanced castrate-resistant prostate cancer (mCRPC): A potentially distinct molecular subset.

163 Background: Herpesvirus HHV-8 has been detected in normal prostate tissue and has been linked to the acquisition of androgen-independent growth of prostate cancer cells in vitro, early development of anti-androgen therapy resistance, and more aggressive disease in a subset of patients with mCRPC. We used comprehensive genomic profiling (CGP) to test the hypothesis that HHV-8 associated mCRPC is a distinct molecular subset of mCRPC featuring altered AR signaling compared to HHV-8 negative mCRPC. Methods: Using a hybrid capture-based FDA-approved CGP assay, a series of 4,918 mCRPC were sequenced to evaluate all classes of genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). HHV-8 status was determined by CGP-based identification of unique viral reads. Results: Overall, 128 (2.6%) of the mCRPC cases harbored HHV-8 sequences (Table). The patient age distribution was similar in the HHV-8+ and HHV-8− groups. GAs in AR, predominantly amplifications, and RAD21 were slightly reduced in HHV-8+ mCRPC cases (P = .01 for both). The frequencies of GAs in genes associated with mCRPC including PTEN, BRCA2, ATM, CDK12, and the TMPRSS2: ERG fusion were similar in the two groups. HHV-8+ patients were less likely to be of European ancestry (P = 0.001). Putative biomarkers associated with immunotherapy response (MSI status, TMB, and PD-L1 expression) were also similar in the two groups. Conclusions: HHV-8+ mCRPC is a rare sub-type of mCRPC with lower frequency of AR GAs compared to HHV-8− mCRPC cases, suggesting a potential role of HHV-8 in inducing androgen-independent prostate cancer growth. Additional alterations associated with potentially enhanced PARP inhibitor response seen in HHV-8+ mCRPC (e.g., RAD21) suggest that early performance of CGP may inform precision treatment strategies to be tested in clinical trials. [Table: see text]

USP16 regulates castration-resistant prostate cancer cell proliferation by deubiquitinating and stablizing c-Myc

Backgroundc-Myc, a well-established oncogene, plays an important role in the initiation and progression of various cancers, including prostate cancer. However, its mechanism in cancer cell remains largely unknown and whether there exist a deubiquitinase targeting c-Myc also remains elusive.MethodsBioinformatic analysis and shRNA screening methods were used to identify potential deubiquitinases that correlate with c-Myc gene signature. Cell proliferation and viability were measured by Cell-Counting-Kit 8 and colony formation assays. A mouse xenograft model of PC3 cells was established to confirm the function of USP16 in vivo. The interaction between USP16 and c-Myc protein was assessed by co-immunoprecipitation and protein co-localization assays. Immunohistochemistry staining was performed to detect the expression of USP16, Ki67, and c-Myc in xenograft tissues and clinical tumour tissues. Furthermore, the correlation between USP16 and c-Myc was confirmed by RNA sequencing.ResultsFunctional analyses identified USP16, known as a deubiquitinase, was strongly correlated with the c-Myc gene signature. Depletion of USP16 was shown to significantly suppress the growth of PCa cells both in vitro and in vivo. Co-immunoprecipitation and ubiquitination assays confirmed that USP16 served as a novel deubiquitinase of c-Myc and overexpression of c-Myc significantly rescued the effects of USP16 disruption. Immunohistochemistry staining and RNA-seq tactics were further used to confirm the positive correlation between USP16 and c-Myc expression. Expression of USP16 in human PCa tissues was higher than that seen in normal prostate tissues and its high expression was found associated with poor prognosis.ConclusionsUSP16 serves as a novel deubiquitinase of c-Myc. Downregulation of USP16 markedly suppressed PCa cell growth both in vitro and in vivo. USP16 regulates PCa cell proliferation by deubiquitinating and stabilizing c-Myc, making it a potential therapeutic candidate for the treatment of PCa.

Molecular Detection of Human Herpes Virus-8 in Prostatic Adenocarcinoma and Benign Prostatic Hyperplasia Tissues by DNA -In Situ Hybridization

Human Herpes Virus-8 (HHV-8) is a sexually transmitted viral infection that can infect the prostate epithelium in immunocompromised adults. Recently, HHV-8 was related to the development and progression of several human malignancies like prostatic adenocarcinoma. This retrospective research was designed to analyze the distribution and possible impact of HHV-8 infection on prostatic adenocarcinogenesis. A total number of one hundred formalin-fixed prostatic tissues were enrolled in this research; forty Prostate Adenocarcinoma (PAC) biopsies, forty biopsies from Benign Prostatic Hyperplasia (BPH), and twenty Apparently Normal Prostatic Tissues (ANPT) as a control group. Detection of HHV -8 DNA was achieved by a highly-sensitive variant of Chromogenic In Situ Hybridization (CISH) technique. In the mean age of PAC patients was 64.08±7.54years. Detection of CISH reactions for HHV 8- DNA was observed in tissues of 70% (28 out of 40) of PAC patients and 30% (12 out of 40) of BPH tissues, whereas no positive reactions were detected in the ANPT group. Detection of CISH reactions for HHV 8- DNA was observed in 55.6% of tissues of PAC patients with well grade histopathological examination, 87.5% of moderate grade, and 69.6% of poorly differentiated grade. It can be concluded that HHV-8 infection might contribute in prostate oncogenesis, together with other essential oncogenic viruses.

Gene Expression Pathways in Prostate Tissue Associated with Vigorous Physical Activity in Prostate Cancer.

Men engaged in high physical activity have lower risks of advanced and fatal prostate cancer. Mechanisms underlying this association are not well understood but may include systemic and tumor-specific effects. We investigated potential mechanisms linking physical activity and gene expression in prostate tissue from men with prostate cancer. We included a subset of 118 men in the Health Professionals Follow-up Study diagnosed with prostate cancer between 1986 and 2005 with whole-transcriptome gene expression profiling on tumor and adjacent normal prostate tissue and physical activity data. Long-term vigorous physical activity was self-reported as the average time spent engaged in various forms of recreational physical activity at baseline and biennially until prostate cancer diagnosis. Gene set enrichment analysis was performed among KEGG and Hallmark gene sets to identify pathways with differential expression based on vigorous physical activity. In adjacent normal tissue, we identified 25 KEGG gene sets enriched (downregulated) in the highest compared with lowest quintile of vigorous physical activity at an FDR <0.10, including a number of cancer- and immune-related pathways. Although no gene sets reached statistical significance in tumor tissue, top gene sets differentially expressed included TGF beta, apoptosis, and p53 signaling pathways. These findings suggest that physical activity may influence the tumor microenvironment. Future studies are needed to confirm these findings and further investigate potential mechanisms linking physical activity to lethal prostate cancer. Identification of gene expression alterations in the prostate associated with physical activity can improve our understanding of prostate cancer etiology.

Reference man for radiological protection: 71 chemical elements' content of the prostate gland (normal and cancerous).

Frequently knowledge of elemental content of human organs and tissues is required for a variety of applications. These can include brachytherapy and radiotherapy planning, radiation dosimetry and radiation protection. Revised reference values of chemical element mass fractions in normal and cancerous prostate tissues of the Reference (European Caucasian) Man are suggested as a result of this work. Autopsies of 37 apparently healthy males (mean age 55 ± 11years, range 41-87years) provided the prostatic tissues studied. The investigated individuals lived in a non-industrial, Central European region of Russia and had suffered sudden death. Also, tissues were studied from 62 subjects with prostate cancer (mean age 65 ± 10years, range 40-79years). Sixty-seven elemental mass fractions were determined in each of these 99 prostates. Analytical methods employed were inductively coupled plasma atomic emission spectrometry, neutron activation analysis with high-resolution spectrometry of short-lived and long-lived radionuclides, energy dispersive X-ray fluorescence analysis, and inductively coupled plasma mass spectrometry. Whichever method was employed, the necessary quality control measures were utilized. Results presented here include a systematic analysis of both the prostatic data presented here for 67 elements and also others' published findings, to make a total of 71 elemental mass fraction values.

Impact of neoadjuvant androgen deprivation therapy on magnetic resonance imaging features in prostate cancer before radiotherapy.

Background and purposeIn locally advanced prostate cancer (PC), androgen deprivation therapy (ADT) in combination with whole prostate radiotherapy (RT) is the standard treatment. ADT affects the prostate as well as the tumour on multiparametric magnetic resonance imaging (MRI) with decreased PC conspicuity and impaired localisation of the prostate lesion. Image texture analysis has been suggested to be of aid in separating tumour from normal tissue. The aim of the study was to investigate the impact of ADT on baseline defined MRI features in prostate cancer with the goal to investigate if it might be of use in radiotherapy planning.Materials and methodsFifty PC patients were included. Multiparametric MRI was performed before, and three months after ADT. At baseline, a tumour volume was delineated on apparent diffusion coefficient (ADC) maps with suspected tumour content and a reference volume in normal prostatic tissue. These volumes were transferred to MRIs after ADT and were analysed with first-order -and invariant Haralick -features.ResultsAt baseline, the median value and several of the invariant Haralick features of ADC, showed a significant difference between tumour and reference volumes. After ADT, only ADC median value could significantly differentiate the two volumes.ConclusionsInvariant Haralick -features could not distinguish between baseline MRI defined PC and normal tissue after ADT. First-order median value remained significantly different in tumour and reference volumes after ADT, but the difference was less pronounced than before ADT.