Reduced Risk Of Prostate Cancer Research Articles

Abstract 6276: In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation

Abstract Recent studies have shown that adrenergic fibers from the sympathetic nervous system (SNS), acting through stromal β2-adrenergic receptors, play an important role in the initial phases of cancer development by promoting tumor cell survival. Recent epidemiological data suggest that β-blocker intake is associated with improved survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase prostate cancer development suggesting that the use of β-blockers in these patients could also reduce prostate cancer risk. β-adrenoceptors signal through the cAMP/PKA pathway that is known to promote neuroendocrine differentiation (NED) in LNCaP prostate cancer cell line. While neuroendocrine (NE) cells expressing synaptophysin (SYN) represent a minor cell population in the epithelial compartment of normal prostate glands, the population of NE-like cells, exhibiting NE phenotypes and expressing NE markers, is increased in, and correlates with, cancer progression, androgen-independent state and poor prognosis. Expression of the routine tissue biomarker of prostate cancer AMACR in NE-like cells discriminates them from NE cells. Our aim was to investigate whether NED could also be associated with benign prostatic hyperplasia (BPH) as recent studies showed that an increase in neuroendocrine cell density occurred before development of BPH in hypertensive rats. Our results showed that a 10-day treatment with 100µM IBMX (blocking cAMP degradation) and 10µM forskolin (FSK, adenylate cyclase activator) to trigger sustained activation of the cAMP/PKA pathway led to an increase in SYN and AMACR expression in BPH-1 cells (qPCR and WB). Similar results were observed by combining the effect of the β-adrenoceptor agonist isoproterenol (1µM) and FSK. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively, as expected for NED. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β-blocker carvedilol (5µM). This data suggests that β-adrenoceptors could be linked to the development of NE-like cells in BPH, a non-lethal disease affecting the transition zone (TZ). As 20% of the prostate cancer occur in this TZ, this observation may need further investigation. Citation Format: Natascha Pigat, Laura N. Garrido, Coline Lefevre, Manon Baures, Vincent Goffin, Anne-Sophie Armand, Thierry Capiod. In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6276.

Abstract 6670: Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer

Abstract Background: Since 2006 three studies, involving 289,089 adolescents, demonstrated a significant association (1.67(0.79-3.55),1.7(1.03-2.70),2.37(1.19-4.73)) between pubertal acne and poor outcome prostate cancer(PC) 30+ years later. This suggested Cutibacterium acnes, amicroaerophylic bacterium, might be contributing to PC bacterial dysbiosis analogous to the role of H. pylori in stomach cancer and explain why circumcision reduces PC risk. Six years ago, using MALDI-TOF, we demonstrated that the presence of seven obligate anaerobe species in addition to C. acnes were increased in PC and linked to increased PSA. This presentation studies stored samples from the PROVENT chemoprevention randomised PC active surveillance phase 2 trial analysed using 16S rDNA sequencing, and comparing obligate anaerobe frequency with those detected by culture and MALDI-TOF identification and their influence on PSA expression. Methods: 89 urines of PROVENT trial patients were studied using 16S rDNA sequencing and followed for 24 months. In addition, 39 previously reported MALDI-TOF screened cohort patients (21 PCs and 18 BPHs) followed for 43 months. The frequency of 7 obligate bacterial genera (Actinobaculum, Finegoldia, Prevotella, Peptoniphilus, Peptostreptococcus & Viellonella) was studied. Results: Twenty six of 89 (29%) PROVENT urine samples had a majority of bacteria detected as obligate anaerobes (mean=68%), while it was 12 of the 39 (31%) in PC tested in MALDI-TOF. In the combined series, those patients (n=38) with obligate anaerobes had mean PSA of 9.59 ug/L, while those without obligate anaerobes had a mean PSA of 6.29 ug/L (n=90), (t=-2.925, p = 0.0058). In the MALDI-TOF series, statistically increased urological intervention rate was associated with the presence of anaerobes (p=0.045, Fisher’s exact test). Discussion: These findings suggest that obligate anaerobe bacterial dysbiosis could be contributing to raised PSA through prostate cell damage, and possibly participating in the chronic inflammation and hypervascular changes that are seen in precancerous lesions. Checkpoint inhibitors have shown little benefit in prostate cancer. Recent reports from animal model studies of BCG resistance have suggested a short course combination of anti PDLI and anti NKG2a could break immune tolerance associated with expression of HLA-E and this approach could be of use to break tolerance to bacterial dysbiosis in the future. Citation Format: Tim Oliver, Belinda Nedjai, Emily Lane, Frank Chinegwundoh, Prabhakar Rajan, Jack Cuzick. Could immunotherapy offer potential in managing bacterial dysbiosis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6670.

Association between 19 medication use and risk of common cancers: A cross-sectional and Mendelian randomisation study.

Previous studies have yielded inconsistent results concerning drug use and the risk of cancers. We conducted a large-scale cross-sectional study and a two-sample Mendelian randomisation (MR) study to reveal the causal effect between the use of 19 medications and the risk of four common cancers (breast, lung, colorectal, and prostate). We obtained information on medication use and cancer diagnosis from National Health and Nutrition Examination Survey participants. After propensity score matching, we conducted survey-weighted multivariate logistic regression and restricted cubic spline analysis to assess the observed correlation between medication use and cancer while adjusting for multiple covariates. We also performed MR analysis to investigate causality based on summary data from genome-wide association studies on medication use and cancers. We performed sensitivity analyses, replication analysis, genetic correlation analysis, and reverse MR analysis to improve the reliability of MR findings. We found that the use of agents acting on the renin-angiotensin system was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.42; 95% confidence interval (CI) = 0.27-0.63, P < 0.001), and there was a nonlinear association of 'decrease-to-increase-to-decrease' (P < 0.0001). The random-effects inverse variance weighted (IVW) model-based primary MR analysis (OR = 0.94, 95% CI = 0.91-0.97, P = 0.0007) and replication MR analysis (OR = 0.90, 95% CI = 0.85-0.96, P = 0.0006) both provided robust evidence of the causality of genetic liability for the use of agents acting on the renin-angiotensin system on a decreased risk of prostate cancer. Our study provides robust evidence that the use of drugs acting on the renin-angiotensin system can reduce prostate cancer risk. Given the high prevalence of prostate cancer, these findings have important implications for drug selection and prostate cancer prevention in patients with cardiovascular disease.

Do Obesity-Related Traits Affect Prostate Cancer Risk through Serum Testosterone? A Mendelian Randomization Study.

This study aimed to investigate whether testosterone mediates or confounds the effect of obesity-related traits on prostate cancer (PCa) using Mendelian randomization (MR) analysis. Data of obesity-related traits (body mass index [BMI], waist-to-hip ratio [WHR], and waist-to-hip ratio adjusted for body mass index [WHRadjBMI]) were obtained from up to 806,834 people of European ancestry; data of testosterone (bioavailable testosterone [BT], total testosterone [TT], and sex hormone-binding globulin [SHBG]) were extracted from up to 194,453 participants in the UK Biobank; and the summary-level data of PCa (79,194 cases and 61,112 controls) were obtained from the PRACTICAL consortium. The results supported the causal relationship between higher BMI and a reduced risk of PCa (OR = 0.91, 95% confidence interval [CI]: 0.86-0.96). Furthermore, increased BT levels were associated with an elevated risk of PCa (OR = 1.15, 95% CI: 1.06-1.24). Importantly, our analysis revealed a unidirectional causal effect-higher BMI was linked to lower BT levels (beta = -0.27, 95% CI: -0.3--0.24), but not the other way around. This suggests that BT may mediate the effect of BMI on PCa rather than confound it. Our multivariable MR results further demonstrated that considering BT as a mediator led to the weakening of BMI's effect on PCa risk (OR = 0.97, 95% CI: 0.90-1.05), while the impact of BT on PCa remained unchanged when accounting for BMI. Moreover, we identified a significant indirect effect of BMI on PCa risk (OR = 0.96, 95% CI: 0.94-0.98). Our study provided genetic evidence that serum BT can mediate the effect of BMI on the risk of PCa, indicating the possible mechanism by which obesity reduces PCa risk.

Five-alpha reductase inhibitors and risk of prostate cancer among men with benign prostatic hyperplasia: A historical cohort study using primary care data

Background: Five-alpha reductase inhibitors (5ARIs) are used in the management of benign prostatic hyperplasia (BPH). 5ARIs prevent the conversion of testosterone to dihydrotestosterone, which is important in prostate development. It has been suggested that 5ARIs can be used a chemopreventative agent for prostate cancer. The aim of this study was to assess the risk of prostate cancer associated with 5ARI use among men with BPH. Methods: Using Clinical Practice Research Datalink (CPRD) from 1992 to 2011 in UK, prostate cancer risk was retrospectively compared in men with a new diagnosis of BPH, with no history of prostate cancer who were treated with 5ARIs, to men treated with alpha blockers (ABs) and those given no pharmacological treatment. Incidence rate of prostate cancer was calculated by treatment group; the association between BPH treatment group and prostate cancer was estimated by a multivariate Cox model. Results: 77,494 men with newly diagnosed BPH were included. The crude incidence rate of prostate cancer was 892.4 cases per 100,000 person-years amongst those treated with 5ARIs, compared with 1209.0 and 1542.9 in those treated with ABs and untreated individuals, respectively. The HR adjusted for potential confounders was 0.79 (0.72-0.86) for 5ARI vs ABs and 0.72 (0.66-0.79) for 5ARI vs untreated. After excluding the first year after BPH diagnosis, adjusted HRs attenuated to 0.87 (0.79-0.97) for 5ARI vs ABs and 0.97 (0.87-1.08) for 5ARI vs untreated. Conclusion: Among men diagnosed with BPH, we found evidence of lower risks of subsequent prostate cancer in those treated with 5ARIs, but this appeared to be driven by cases diagnosed within a year of BPH, possibly reflecting prevalent prostate cancers that were initially misdiagnosed. After excluding the first year after BPH diagnosis, there was little evidence of a reduced prostate cancer risk in those taking 5ARIs.

Cruciferous Vegetable Intake and Risk of Prostate Cancer: A Systematic Review and Meta-Analysis

Introduction: The relationship between cruciferous vegetables and prostate cancer (PCa) risk remains contentious. This study aimed to assess the association between consuming cruciferous vegetables and PCa risk. Methods: We carried out a systematic search through PubMed, Embase, Web of Science, and the Cochrane Library until September 20, 2022. The results of the article will be analyzed using the Stata 14 software. This meta-analysis was reported as directed by the PRISMA guidance, and the study protocol was recorded in PROSPERO (CRD42022361556). Results: 7 case-control studies and 9 cohort studies were eventually included, including 70,201 PCa cases and 1,264,437 members. The higher the intake of cruciferous vegetables, the lower the risk of PCa. In comparison to the lowest dose of cruciferous vegetables, the overall relative risk (RR) of cruciferous vegetables having the highest dose was 0.87 (95% confidence interval [CI]: 0.80–0.95; I2 = 59.2%). A significant linear trend (p = 0.002) was observed for the association, with a combined RR of 0.955 (95% CI: 0.928–0.982) for every 15 g of cruciferous vegetables per day. Conclusions: The study revealed that consumption of cruciferous vegetables may be linked to reduced PCa risk.

Nucleoredoxin gene SINRX1 negatively regulates tomato immunity by activating SA signaling pathway

The tomato (Solanum lycopersicum) is widely consumed globally and renowned for its health benefits, including the reduction of cardiovascular disease and prostate cancer risk. However, tomato production faces significant challenges, particularly due to various biotic stresses such as fungi, bacteria, and viruses. To address this challenges, we employed the CRISPR/Cas9 system to modify the tomato NUCLEOREDOXIN (SlNRX) genes (SlNRX1 and SlNRX2) belonging to the nucleocytoplasmic THIOREDOXIN subfamily. CRISPR/Cas9-mediated mutations in SlNRX1 (slnrx1) plants exhibited resistance against bacterial leaf pathogen Pseudomonas syringae pv. maculicola (Psm) ES4326, as well as the fungal pathogen Alternaria brassicicola. However, the slnrx2 plants did not display resistance. Notably, the slnrx1 demonstrated elevated levels of endogenous salicylic acid (SA) and reduced levels of jasmonic acid after Psm infection, in comparison to both wild-type (WT) and slnrx2 plants. Furthermore, transcriptional analysis revealed that genes involved in SA biosynthesis, such as ISOCHORISMATE SYNTHASE 1 (SlICS1) and ENHANCED DISEASE SUSCEPTIBILITY 5 (SlEDS5), were upregulated in slnrx1 compared to WT plants. In addition, a key regulator of systemic acquired resistance, PATHOGENESIS-RELATED 1 (PR1), exhibited increased expression in slnrx1 compared to WT. These findings suggest that SlNRX1 acts as a negative regulator of plant immunity, facilitating infection by the Psm pathogen through interference with the phytohormone SA signaling pathway. Thus, targeted mutagenesis of SlNRX1 is a promising genetic means to enhance biotic stress resistance in crop breeding.

Systemic lupus erythematosus and prostate cancer risk: a pool of cohort studies and Mendelian randomization analysis

BackgroundCurrent observational studies suggest that there may be a causal relationship between systemic lupus erythematosus (SLE) and prostate cancer (PC). However, there is contradictory evidence. This study aimed to investigate and clarify the association between SLE and PC.MethodsWe searched PubMed, Embase, Web of Science, and Scopus until May 2022. A meta-analysis was conducted on the standard incidence rate (SIR) and 95% CI. Subgroup analysis was performed based on the follow-up duration, study quality, and appropriate SLE diagnosis. Mendelian randomization (MR) of the two samples was used to determine whether genetically elevated SLE was causal for PC. Summary MR data were obtained from published GWASs, which included 1,959,032 individuals. The results were subjected to sensitivity analysis to verify their reliability.ResultsIn a meta-analysis of 79,316 participants from 14 trials, we discovered that patients with SLE had decreased PC risk (SIR, 0.78; 95% CI, 0.70–0.87) significantly. The MR results showed that a one-SD increase in genetic susceptibility to SLE significantly reduced PC risk (OR, 0.9829; 95% CI, 0.9715–0.9943; P = 0.003). Additional MR analyses suggested that the use of immunosuppressants (ISs) (OR, 1.1073; 95% CI, 1.0538–1.1634; P < 0.001), but not glucocorticoids (GCs) or non-steroidal anti-inflammatory drugs (NSAIDs), which were associated with increased PC risk. The results of the sensitivity analyses were stable, and there was no evidence of directional pleiotropy.ConclusionsOur results suggest that patients with SLE have a lower risk of developing PC. Additional MR analyses indicated that genetic susceptibility to the use of ISs, but not GCs or NSAIDs, was associated with increased PC risk. This finding enriches our understanding of the potential risk factors for PC in patients with SLE. Further study is required to reach more definitive conclusions regarding these mechanisms.

Vitamin E Intake and Risk of Prostate Cancer: A Meta-Analysis.

Vitamin E is a group of antioxidative tocopherols and tocotrienols that play a potential role in chemoprevention. Studies investigating the association between vitamin E and prostate cancer risk have been conflicting. We identified observational and interventional studies examining the association between vitamin E intake and prostate cancer risk from PubMed, EMBASE and the Cochrane Library. A random-effects model was used to perform a meta-analysis and estimate relative risks (RRs) and the corresponding 95% confidence intervals (CIs) of prostate cancer risk according to vitamin E intake. Subgroup analyses were conducted by study design, sample size, study population characteristics, geographical region, and dose of vitamin E intake. The association between dietary (RR = 0.97; 95% CI = 0.92-1.02) and supplemental (RR = 0.99; 95% CI = 0.94-1.04) vitamin E intake on prostate cancer risk was non-significant. In subgroup analyses, supplemental vitamin E was significantly associated with reduced prostate cancer risk in studies in Europe (RR = 0.81, 95% CI = 0.69-0.97). Overall, this meta-analysis demonstrates little evidence for a beneficial effect of vitamin E intake on prostate cancer risk but suggests that there may be some conditions in which supplements could confer a protective effect on prostate cancer risk.

Recognizing the True Value of Testosterone Therapy in Health Care.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

Phytoene Is More Efficiently Absorbed Than Lycopene by In Vitro Intestinal Cells but Is Absorbed and Cleared Similarly to Lycopene by In Vitro Prostate Cancer Cells

ObjectivesConsuming tomatoes and the tomato carotenoid lycopene (LYC) is epidemiologically associated with reduced prostate cancer risk. Tomato carotenoids, including LYC, phytoene (PE), and beta-carotene (BC), are found in human prostate tissue, with greater PE: LYC ratios found in the blood and prostate tissue relative to the diet. We tested the hypothesis that PE is more efficiently absorbed by prostate cells and by absorptive intestinal cells than LYC, explaining the enrichment of PE in blood and prostate tissue. MethodsIn vitro prostate cancer (LNCaP, PC-3) and non-cancerous prostate epithelial (RWPE-1) cells were treated with human serum enriched with PE, LYC, BC, or control (final media concentration 1 uM) for 6 hours. Clearance of PE, LYC, and BC from LNCaP cells was monitored for 48 hours after a 16 hour pre-incubation with carotenoids (n = 5 trials). Differentiated in vitroabsorptive intestinal cells (Caco-2 HTB-37 cultured 21 d on a permeable support) were treated with mixed lipid micelles and either PE, LYC, BC, or no carotenoid (final media carotenoid concentration 2 uM) for 4 or 24 h (n = 5 trials). Cell and media carotenoid concentrations were measured by HPLC-PDA. ResultsPC-3s absorbed 3.8%, 1.9%, and 2.5% (not significantly different, ns) and LNCaP cells absorbed 1.5%, 2.6%, and 2.0% of the LYC, PE, and BC (ns) doses, respectively, while RWPE-1 cells absorbed more of the BC dose (8.7%) than the PE dose (0.4%, P < 0.05), and LYC dose absorption was intermediate and similar to both PE and BC (2.5%). LNCaP cells cleared PE at the same rate as BC and LYC over 48 h. Intestinal Caco-2 cells absorbed more PE dose at 4 and 24 h (16.3%, 10.8%) than LYC (0.6%, 0.9%, respectively) or BC (5.8%, 7.5% respectively) (P < 0.05), while the amount of carotenoid recovered in the basolateral media showed a similar, though non-significantly different, pattern. ConclusionsThese results align with whole body pharmacokinetic findings suggesting that differences in intestinal absorption may be a key determinant in relative tissue carotenoid accumulation, and reveal that cancer versus non-cancer cell types may differ in carotenoid absorption characteristics. Funding SourcesNIH NCCIH/ODS R01 AT008576.

A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer.

Objective:Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E–related genetic variants and their polygenic risk score (PRS).Methods:We conducted a biochemical analysis of 29 102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2 724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8 383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models.Results:No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) versus Q1 hazard ratio (HR)=0.87, 95% confidence interval (95% CI) 0.75, 1.02; p-trend=0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile versus Q1 HR=0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed.Conclusion:Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E–related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

Zinc Intakes and Health Outcomes: An Umbrella Review.

It is widely accepted that the zinc element is crucial in human beings. Zinc has gained more attention during the COVID-19 pandemic due to its utilization for the treatment and prevention of respiratory tract infections. However, some studies also pointed out that zinc intake might cause unwanted side effects and even be dangerous when overdosed. To reveal the relationship between zinc intake and health outcomes, we performed an umbrella review from human studies. In total, the umbrella review included 43 articles and identified 11 outcomes for dietary zinc intake and 86 outcomes for supplementary zinc intake. Dietary zinc intake in the highest dose would decrease the risk of overall and specific digestive tract cancers, depression, and type 2 diabetes mellitus (T2DM) in adults. Supplementary zinc consumption in adults was linked to an improvement of depression, antioxidant capacity and sperm quality, higher serum zinc concentration, and lower concentration of inflammatory markers. Zinc supplementation in children would reduce the incidence of diarrhea and pneumonia, improve zinc deficiency and boost growth. However, zinc might not decrease all-cause mortality in adults or the in-hospital mortality of COVID-19. And better maternal and neonatal outcomes may not derive from pregnant women who consumed higher or lower doses of zinc supplementation (>20 mg/day and <20 mg/day, respectively). Dose-response analyses revealed that a daily 5 mg increment of zinc would lower the risk of colorectal and esophageal cancer, whereas a large dose of zinc supplementation (daily 100 mg) showed no benefit in reducing prostate cancer risk.

Evidence on Statins, Omega-3, and Prostate Cancer: A Narrative Review.

Dietary intake selections might play a crucial role in prostate cancer (PCa) occurrence and progression. Several studies have investigated whether statin use could reduce PCa risk but with conflicting results. Nevertheless, a significantly decreased incidence of advanced PCa has been consistently noted. Statins may also reduce the risk of biochemical recurrence (BCR) in men with PCa after receiving active treatment. However, the influence of statin usage on BCR and PCa progression in men with high prostate-specific antigen levels has been found to be insignificant. In contrast, the combined use of a statin and metformin was significantly related to the survival status of PCa patients. However, some studies have revealed that the intake of long-chain omega-3 fatty acid (ω-3) from fish or fish oil supplements may elevate PCa risk. Several meta-analyses on ω-3 consumption and PCa have shown controversial results for the relationship between PCa and ω-3 consumption. However, studies with positive results for various genotypes, fatty acid intake or levels, and PCA risk are emerging. This review highlights the association among statins, ω-3, and PCa. The findings summarized here may be helpful for clinicians counseling patients related to PCa.

Could Reducing Body Fatness Reduce the Risk of Aggressive Prostate Cancer via the Insulin Signalling Pathway? A Systematic Review of the Mechanistic Pathway.

Excess body weight is thought to increase the risk of aggressive prostate cancer (PCa), although the biological mechanism is currently unclear. Body fatness is positively associated with a diminished cellular response to insulin and biomarkers of insulin signalling have been positively associated with PCa risk. We carried out a two-pronged systematic review of (a) the effect of reducing body fatness on insulin biomarker levels and (b) the effect of insulin biomarkers on PCa risk, to determine whether a reduction in body fatness could reduce PCa risk via effects on the insulin signalling pathway. We identified seven eligible randomised controlled trials of interventions designed to reduce body fatness which measured insulin biomarkers as an outcome, and six eligible prospective observational studies of insulin biomarkers and PCa risk. We found some evidence that a reduction in body fatness improved insulin sensitivity although our confidence in this evidence was low based on GRADE (Grading of Recommendations, Assessment, Development and Evaluations). We were unable to reach any conclusions on the effect of insulin sensitivity on PCa risk from the few studies included in our systematic review. A reduction in body fatness may reduce PCa risk via insulin signalling, but more high-quality evidence is needed before any conclusions can be reached regarding PCa.

Adolescent Plant Product Intake in Relation to Later Prostate Cancer Risk and Mortality in the NIH-AARP Diet and Health Study

BackgroundAlthough fruit and vegetable intake during adolescence, a potentially sensitive time period for prostate cancer (PCa) development, has been proposed to protect against PCa risk, few studies have investigated the role of adolescent plant product intake in PCa development. MethodsIntake of various vegetables, fruit, and grains by males at ages 12–13 y was examined in relation to later PCa risk and mortality in the NIH-AARP Diet and Health Study. Cox proportional hazards regression was used to calculate HRs and 95% CIs of nonadvanced (n = 14,238) and advanced (n = 2,170) PCa incidence and PCa mortality (n = 760) during 1,729,896 person-years of follow-up. ResultsNone of the plant products examined were associated consistently with all PCa outcomes. However, greater adolescent intakes of tomatoes (P-trend = 0.004) and nonstarch vegetables (P-trend = 0.025) were associated with reduced risk of nonadvanced PCa, and greater intakes of broccoli (P-trend = 0.050) and fruit juice (P-trend = 0.019–0.025) were associated with reduced risk of advanced PCa and/or PCa mortality. Positive trends were also observed for greater intakes of fruit juice (P-trend = 0.002), total fruit (P-trend = 0.014), and dark bread (P-trend = 0.035) with nonadvanced PCa risk and for greater intakes of legumes (P-trend < 0.001), fiber (P-trend = 0.001), and vegetable protein (P-trend = 0.013–0.040) with advanced PCa risk or PCa mortality. ConclusionsOur findings do not provide strong evidence to suggest that adolescent plant product intake is associated with reduced PCa risk.

Dietary tomato inhibits angiogenesis in TRAMP prostate cancer but is not protective with a Western-style diet in this pilot study

Prostate cancer (PCa) remains the second most diagnosed cancer worldwide. Higher body weight is associated with chronic inflammation, increased angiogenesis, and treatment-resistant tumor phenotypes. Dietary tomato reduces PCa risk, which may be due to tomato inhibition of angiogenesis and disruption of androgen signaling. This pilot study investigated the interplay between tomato powder (TP), incorporated into control (CON) and obesogenic (OB) diets, and PCa tumor growth and blood perfusion over time in a transgenic model of PCa (TRAMP). Ultrasound microvessel imaging (UMI) results showed good agreement with gold-standard immunohistochemistry quantification of endothelial cell density, indicating that this technique can be applied to non-invasively monitor tumor blood perfusion in vivo. Greater body weight was positively associated with tumor growth. We also found that TP significantly inhibited prostate tumor angiogenesis but that this inhibition differentially affected measured outcomes depending on CON or OB diets. TP led to reduced tumor growth, intratumoral inflammation, and intratumoral androgen-regulated gene expression (srd5a1, srd5a2) when incorporated with the CON diet but greater tumor growth and intratumoral gene expression when incorporated with the OB diet. Results from this study show that protective benefits from dietary tomato are lost, or may become deleterious, when combined with a Western-style diet.

Growth and differentiation factor 15 and NF‐κB expression in benign prostatic biopsies and risk of subsequent prostate cancer detection

ABSTRACTGrowth and differentiation factor 15 (GDF‐15), also known as macrophage inhibitory cytokine 1 (MIC‐1), may act as both a tumor suppressor and promotor and, by regulating NF‐κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation‐related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF‐15 and NF‐κB was done in a study of 503 case‐control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF‐15 and NF‐κB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF‐κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77–0.99, while GDF‐15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96–1.17. When modeling expression levels by quartiles, the highest quartile of NF‐κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29–0.92). In stratified models, NF‐κB had the strongest negative association with prostate cancer in non‐aggressive cases (p = 0.03), older men (p = 0.03), and in case‐control pairs with longer follow‐up (p = 0.02). Risk associated with GDF‐15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF‐15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF‐15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case‐control pairs with longer follow‐up. Therefore, although positively correlated in benign prostatic biopsies, NF‐κB and GDF‐15 expression appear to exert opposite effects on risk of prostate tumor development.

The presence of polymorphisms in genes controlling neurotransmitter metabolism and disease prognosis in patients with prostate cancer: a possible link with schizophrenia.

Polymorphisms of neurotransmitter metabolism genes were studied in patients with prostate cancer (PC) characterized by either reduced or extended serum prostate-specific antigen doubling time (PSADT) corresponding to unfavorable and favorable disease prognosis respectively. The ‘unfavorable prognosis’ group (40 cases) was defined by PSADT ≤ 2 months, whereas patients in the ‘favorable prognosis’ group (67 cases) had PSADT ≥ 30 months. The following gene polymorphisms known to be associated with neuropsychiatric disorders were investigated: a) the STin2 VNTR in the serotonin transporter SLC6A4 gene; b) the 30-bp VNTR in the monoamine oxidase A MAOA gene; c) the Val158Met polymorphism in the catechol-ortho-methyltransferase COMT gene; d) the promoter region C-521T polymorphism and the 48 VNTR in the third exon of the dopamine receptor DRD4 gene.The STin2 12R/10R variant of the SLC6A4 gene (OR = 2.278; 95% CI = 0.953–5.444) and the -521T/T homozygosity of the DRD4 gene (OR = 1.579; 95% CI = 0.663–3.761) tended to be overrepresented in PC patients with unfavorable disease prognosis. These gene variants are regarded as protective against schizophrenia, and the observed trend may be directly related to a reduced PC risk described for schizophrenia patients. These results warrant further investigation of the potential role of neurotransmitter metabolism gene polymorphisms in PC pathogenesis.

Cardiorespiratory fitness is not associated with reduced risk of prostate cancer: A cohort study and review of the literature.

Cardiorespiratory fitness (CRF) has a strong inverse relationship with several chronic disease outcomes, including some cancers. The association between CRF and prostate cancer is controversial. We aimed to assess the prospective association of CRF with prostate cancer risk using a cohort study and review of the literature. Cardiorespiratory fitness was assessed using a respiratory gas exchange analyser during exercise testing in 2204 cancer-free middle-aged men. Hazard ratios (HRs) with 95% confidence interval (CIs) were estimated. We corrected for within-person variability in CRF levels using repeat measurements. During a median follow-up of 24.9years, 216 prostate cancer cases occurred. The age-adjusted regression dilution ratio of CRF was 0.58 (95% CI: 0.53-0.64). The HR (95% CI) of prostate cancer per 1 standard deviation increase in CRF in age-adjusted analysis was 1.10 (0.95-1.27). The association remained consistent after further adjustment for several risk factors (HR 1.13; 95% CI 0.96-1.33). The corresponding adjusted HRs were 1.24 (95% CI: 0.87-1.77) and 1.28 (95% CI: 0.87-1.88), respectively, when comparing the extreme tertiles of CRF levels. Previous studies mostly reported no evidence of an association or an increased risk of prostate cancer in relation to high CRF. Studies reporting positive associations had short-term follow-up durations (<10years). Primary data and a review of previous studies suggest that elevated CRF is not associated with reduced prostate cancer risk. Previous findings of significant evidence of associations could be attributed to increased screening and detection as well as reverse causation bias.