Abstract Benign prostatic hyperplasia (BPH) is ostensibly linked to autoimmune (AI) diseases, but whether the prostate is a target of systemic inflammation associated with AI conditions is unknown. Prostatic inflammation is linked to fibrosis, hyperplasia, and reduced responses to BPH-related medical therapies. This study was conducted to determine if AI disease correlates with BPH diagnosis and whether systemic targeting of an inflammatory mediator limits prostatic inflammation and hyperplasia. Patient medical records (n=112,152) were evaluated to determine BPH prevalence among different AI diseases. Inflammatory cells from human BPH tissues were analyzed by single-cell (sc)RNA-seq and the tumor necrosis factor (TNF)α-antagonist etanercept was tested in two murine models of prostatic enlargement. BPH prevalence was significantly higher among patients with AI disease compared to unaffected individuals. However, AI patients treated with TNFα-antagonists had a significantly reduced incidence of BPH. Data from scRNA- seq identified macrophages as a dominant source of TNFα and in vitro assays confirmed that TNFα stimulates BPH-derived fibroblast proliferation. In the AI patient cohort and murine models, systemic treatment with TNFα-antagonists decreased prostatic epithelial proliferation, macrophage infiltration, and epithelial NFκB activation compared to control tissues. These studies are the first to show that patients with AI diseases have a heightened susceptibility to BPH and that the TNFα-signaling axis is important for BPH pathogenesis. Macrophage-secreted TNFα may mechanistically drive BPH via chronic activation of the signaling axis and NFκB. TNFα blockade appears to be a promising new pharmacological approach to target inflammation and suppress BPH. One sentence summary Patient data and mouse models suggest that repurposing tumor necrosis factor alpha blockade reduces inflammation-mediated prostatic hyperplasia.
Abstract Background To assess the feasibility of a novel DNA‐based probe panel to detect copy number alterations (CNAs) in prostate tumor DNA and its performance for predicting clinical progression. Methods A probe panel was developed and optimized to measure CNAs in trace amounts of tumor DNA (2 ng) isolated from formalin‐fixed paraffin‐embedded tissues. Ten genes previously associated with aggressive disease were targeted. The panel's feasibility and performance were assessed in 175 prostate cancer (PCa) patients who underwent radical prostatectomy with a median 10‐year follow‐up, including 42 men who developed disease progression (either metastasis and/or PCa‐specific death). Association with disease progression was tested using univariable and multivariable analyses. Results The probe panel detected CNAs in all 10 genes in tumor DNA isolated from either diagnostic biopsies or surgical specimens. A four‐gene model ( PTEN / MYC / BRCA2 / CDKN1B ) had the strongest association with disease progression; 64.3% of progressors and 22.5% of non‐progressors had at least one CNA in these four genes, odds ratio (OR) (95% confidence interval) = 6.21 (2.77‐13.87), P = 8.48E−06. The association with disease progression remained significant after adjusting for known clinicopathological variables. Among the seven progressors of the 65 patients with clinically low‐risk disease, three (42.9%) had at least one CNA in these four genes. Conclusions The probe panel can detect CNAs in trace amounts of tumor DNA from biopsies or surgical tissues at the time of diagnosis or surgery. CNAs independently predict metastatic/lethal cancer, particularly among men with clinically low‐risk disease at diagnosis. If validated, this may improve current abilities to assess tumor aggressiveness.
Background Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. Methods A case‐case study of 703 lethal PCa patients and 1455 patients with low‐risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2 . Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan‐Meier survival analysis. Results In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low‐risk PCa patients ( P = 0.31). No association was found between CHEK2 mutation status and early‐diagnosis or PCa‐specific survival time. However, the most common mutation in CHEK2 , c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low‐risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non‐Finnish European subjects from the Exome Aggregation Consortium (ExAC) ( P = 0.01). Conclusions While overall CHEK2 mutations were not significantly more common in men with lethal compared to low‐risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.
Carcinoma-associated fibroblasts (CAF) are a heterogeneous group of cells within the tumor microenvironment (TME) that can promote tumorigenesis in the prostate. By understanding the mechanism(s) by which CAF contributes to tumor growth, new therapeutic targets for the management of this disease may be identified. These studies determined whether unique sub-populations of human prostate CAF can be identified and functionally characterized.Single-cell RNA-seq of primary human prostate CAF followed by unsupervised clustering was utilized to generate cell clusters based on differentially expressed (DE) gene profiles. Potential communication between CAF and immune cells was analyzed using in vivo tissue recombination by combining CAF or normal prostate fibroblasts (NPF) with non-tumorigenic, initiated prostate epithelial BPH-1 cells. Resultant grafts were assessed for inflammatory cell recruitment.Clustering of 3321 CAF allows for visualization of six subpopulations, demonstrating heterogeneity within CAF. Sub-renal capsule recombination assays show that the presence of CAF significantly increases myeloid cell recruitment to resultant tumors. This is supported by significantly increased expression of chemotactic chemokines CCL2 and CXCL12 in large clusters compared to other subpopulations. Bayesian analysis topologies also support differential communication signals between chemokine-related genes of individual clusters. Migration of THP-1 monocyte cells in vitro is stimulated in the presence of CAF conditioned medium (CM) compared with NPF CM. Further in vitro analyses suggest that CAF-derived chemokine CCL2 may be responsible for CAF-stimulated migration of THP-1 cells, since neutralization of this chemokine abrogates migration capacity.CAF clustering based on DE gene expression supports the concept that clusters have unique functions within the TME, including a role in immune/inflammatory cell recruitment. These data suggest that CCL2 produced by CAF may be involved in the recruitment of inflammatory cells, but may also directly regulate the growth of the tumor. Further studies aimed at characterizing the subpopulation(s) of CAF which promote immune cell recruitment to the TME and/or stimulate prostate cancer growth and progression will be pursued.
Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (
Prostate cancer is the most common non-skin cancer in men and sexual dysfunction is the most frequently reported long-term side effect of prostate cancer surgery or radiation. The aim of this study was to examine the experiences of men with sexual dysfunction and their partners following prostate cancer treatment.Men with sexual dysfunction from either surgical removal or radiation therapy 1-5 years after treatment were interviewed, as well as their partners. A mixed method design was used to determine the lived experience of men with sexual dysfunction. Open-ended questions guided the interviews.Twenty seven men completed the study with a mean age of 61 years (SD = 8.0; range = 44-77 years). Nine partners also participated. The majority of men (92.6%) had surgery. The average time from treatment to the interview was 23.5 months (SD = 11.7). Themes were frustration with sexual dysfunction, importance of support and understanding from others, depression and anxiety related to sexual dysfunction, importance of intimacy with partner, factors that impact treatment satisfaction, and education and comprehensive information about sex.Prostate cancer survivors and partners need accurate information about sexual side effects before during and after treatment. Men and partners required individualized help and guidance to manage sexual dysfunction. Support and understanding from partners, family, and others was also identified as an important aspect of healing and adjustment after prostate cancer treatment. Prostate cancer education/support groups played a key role in helping men and partners gain advocacy, education, and support. Psychological problems such as depression and anxiety need to be identified and addressed in men after prostate cancer treatment. Men and partners need assistance in understanding and navigating their way through intimacy to move forward with connectedness in their relationship. Satisfaction with treatment and with providers is dependent on patient education and understanding of all aspects of prostate cancer treatment including sexual side effects and incontinence.
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