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Science Advances Jun 2024Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection...
Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.
Topics: Animals; Alzheimer Disease; Male; Cognitive Dysfunction; Mice; Brain; Humans; Blood-Brain Barrier; Disease Models, Animal; Androgen Antagonists; Prostatic Neoplasms; Natalizumab; Plaque, Amyloid
PubMed: 38905345
DOI: 10.1126/sciadv.adn8709 -
The Tokai Journal of Experimental and... Jul 2024Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with...
Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with high-intensity focused ultrasound (HIFU) for a patient with a localized reducted solitary lesion in the prostate, which was diagnosed with magnetic resonance imaging (MRI)-transrectal ultrasound fusion image-guided target biopsy with PSA level of 0.24 ng/mL, after androgen receptor signaling inhibitors (ARSIs) and chemotherapy for metastatic PC. Prostate specific antigen levels decreased to 0.01ng/mL at 1 month after the treatment, and cancer suspicious lesion disappeared on MRI. During the follow-up of 24 months, there was no elevation of PSA level with no severe complication related to the treatment. HIFU has possibility to be an effective and minimally invasive treatment as a local treatment for the localized reducted solitary lesion in the prostate after ARSIs and chemotherapy for metastatic PC.
Topics: Humans; Male; Prostatic Neoplasms; Treatment Outcome; Prostate-Specific Antigen; Magnetic Resonance Imaging; Aged; High-Intensity Focused Ultrasound Ablation; Image-Guided Biopsy; Androgen Receptor Antagonists; Prostate
PubMed: 38904239
DOI: No ID Found -
Frontiers in Endocrinology 2024The relationship between cathepsins and prostate cancer (PCa) has been reported. However, there is a lack of research on cathepsins and benign prostate diseases (BPDs)....
OBJECTIVES
The relationship between cathepsins and prostate cancer (PCa) has been reported. However, there is a lack of research on cathepsins and benign prostate diseases (BPDs). This study investigated the potential genetic link between cathepsins and BPDs through the utilization of Mendelian randomization (MR) analysis to determine if a causal relationship exists.
METHODS
Publicly accessible summary statistics on BPDs were obtained from FinnGen Biobank. The data comprised 149,363 individuals, with 30,066 cases and 119,297 controls for BPH, and 123,057 individuals, with 3,760 cases and 119,297 controls for prostatitis. The IEU OpenGWAS provided the Genome-wide association data on ten cathepsins. To evaluate the causal relationship between BPDs and cathepsins, five distinct MR analyses were employed, with the primary method being the inverse variance weighted (IVW) approach. Additionally, sensitivity analyses were conducted to examine the horizontal pleiotropy and heterogeneity of the findings.
RESULTS
The examination of IVW MR findings showed that cathepsin O had a beneficial effect on BPH (IVW OR=0.94, 95% CI 0.89-0.98, P=0.0055), while cathepsin X posed a threat to prostatitis (IVW OR=1.08, 95% CI 1.00-1.16, P=0.047). Through reverse MR analysis, it was revealed that prostatitis had an adverse impact on cathepsin V (IVW OR=0.89, 95% CI 0.80-0.99, P=0.035), while no favorable association was observed between BPH and cathepsins. The results obtained from MR-Egger, weighted median, simple mode, and weighted mode methods were consistent with the findings of the IVW approach. Based on sensitivity analyses, heterogeneity, and horizontal pleiotropy are unlikely to distort the results.
CONCLUSION
This study offers the initial evidence of a genetic causal link between cathepsins and BPDs. Our findings revealed that cathepsin O was beneficial in preventing BPH, whereas cathepsin X posed a potential threat to prostatitis. Additionally, prostatitis negatively affected cathepsin V level. These three cathepsins could be targets of diagnosis and treatment for BPDs, which need further research.
Topics: Humans; Male; Mendelian Randomization Analysis; Cathepsins; Prostatic Hyperplasia; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Case-Control Studies; Genetic Predisposition to Disease; Prostatic Neoplasms; Prostatitis; Prostatic Diseases
PubMed: 38904040
DOI: 10.3389/fendo.2024.1348310 -
Journal of Health, Population, and... Jun 2024According to our knowledge, the relationship between dietary patterns such as pro-healthy, pro-vegetarian, and non-healthy dietary patterns and prostate cancer risk has...
INTRODUCTION
According to our knowledge, the relationship between dietary patterns such as pro-healthy, pro-vegetarian, and non-healthy dietary patterns and prostate cancer risk has not been clearly investigated in Iranian men. Therefore, we aimed to investigate the relationship between adherence to a pro-healthy (PHDI), pro-vegetarian (PDP), and non-healthy dietary indices (NHDI) and the risk of prostate cancer.
METHOD
In this matched case-control study, 125 participants (62 cases and 63 hospital-based controls) were enrolled from April to September 2015. Participants' dietary intakes were evaluated using a valid and reliable 160-item semi-quantitative food frequency questionnaire. Dietary indices calculated based on previous studies. The relationship between dietary indices (PHDI, NHDI and PDP) and prostate cancer risk was assessed using binary regression models.
RESULTS
According to adjusted model, significant negative correlations were found between PHDI and PDP with prostate cancer (PHDI: OR = 0.31; 95% CI; 0.11-0.85; P = 0.023 - PDP: OR = 0.34; 95% CI; 0.15-0.75; P = 0.008). Also, a positive association was seen between NHDI and prostate cancer (OR = 3.01; 95% CI; 1.20-7.57; P = 0.019).
CONCLUSION
We found that adherence to healthy dietary indices which includes high amounts of fruits, vegetables, and whole grains reduces the risk of prostate cancer. While adherence to a dietary pattern high in red and processed meat, refined grains, and sweetened beverages increases the risk of prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms; Case-Control Studies; Iran; Middle Aged; Diet, Healthy; Risk Factors; Aged; Diet; Diet, Vegetarian; Feeding Behavior; Adult; Diet Surveys
PubMed: 38902815
DOI: 10.1186/s41043-024-00578-4 -
Journal of Experimental & Clinical... Jun 2024The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL),...
BACKGROUND
The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL), used in bipolar androgen therapy, inhibits growth of PCa suggesting a tumor-suppressive activity by SAL. SAL was shown to induce cellular senescence in PCa.
METHODS
RNA-seq and transcriptome analysis, ChIP-seq, human 3D PCa spheroids, mouse xenografted castration-resistant PCa, knockdown and overexpression, Co-immunoprecipitation (Co-IP), translocation analysis, immune detection, qRT-PCR, protein-protein interaction modelling.
RESULTS
Here, mice xenografts with castration-resistant PCa tumors show that SAL inhibits cancer growth in vivo suggesting that SAL activates a tumor-suppressive mechanism. RNA-seq and ChIP-seq revealed the clock gene BHLHE40 is a novel direct AR target. Compared to adjacent human prostate tissues, the expression of BHLHE40 is reduced in PCa tumors and associated with reduced survival. Knockdown suggests that BHLHE40 mediates SAL-induced cellular senescence including tumor spheroids. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 and SAL leading to the identification of four classes of SAL-BHLHE40 transcriptome landscapes. Co-IP and modelling suggest binding of BHLHE40 to AR and their co-translocation into nucleus by SAL treatment. Further, RNA-seq and ChIP-seq analysis indicate that the atypical tumor suppressive cyclin G2 emerged as a novel downstream target of BHLHE40 and a mediator of SAL-induced cellular senescence.
CONCLUSIONS
The data provide evidence of the tumor suppressive activity of SAL and a novel signaling by the AR-BHLHE40-CCNG2 axis for androgen-induced cellular senescence, linking circadian rhythm factor to androgen signaling as a novel tumor suppressive pathway.
Topics: Male; Humans; Cellular Senescence; Mice; Animals; Prostatic Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Androgens; Cell Line, Tumor; Homeodomain Proteins; Receptors, Androgen; Gene Expression Regulation, Neoplastic; Xenograft Model Antitumor Assays
PubMed: 38902772
DOI: 10.1186/s13046-024-03097-6 -
JCO Clinical Cancer Informatics Jun 2024Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current...
PURPOSE
Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current models are based on various clinical and pathologic parameters including Gleason grading, which suffers from a high interobserver variability. In this study, we determine whether objective machine learning (ML)-driven histopathology image analysis would aid us in better risk stratification of PCa.
MATERIALS AND METHODS
We propose a deep learning, histopathology image-based risk stratification model that combines clinicopathologic data along with hematoxylin and eosin- and Ki-67-stained histopathology images. We train and test our model, using a five-fold cross-validation strategy, on a data set from 502 treatment-naïve PCa patients who underwent radical prostatectomy (RP) between 2000 and 2012.
RESULTS
We used the concordance index as a measure to evaluate the performance of various risk stratification models. Our risk stratification model on the basis of convolutional neural networks demonstrated superior performance compared with Gleason grading and the Cancer of the Prostate Risk Assessment Post-Surgical risk stratification models. Using our model, 3.9% of the low-risk patients were correctly reclassified to be high-risk and 21.3% of the high-risk patients were correctly reclassified as low-risk.
CONCLUSION
These findings highlight the importance of ML as an objective tool for histopathology image assessment and patient risk stratification. With further validation on large cohorts, the digital pathology risk classification we propose may be helpful in guiding administration of adjuvant therapy including radiotherapy after RP.
Topics: Humans; Prostatic Neoplasms; Male; Deep Learning; Neoplasm Grading; Risk Assessment; Prostatectomy; Aged; Middle Aged; Image Processing, Computer-Assisted
PubMed: 38900978
DOI: 10.1200/CCI.23.00184 -
Oncotarget Jun 2024Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies,... (Review)
Review
Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. This research perspective defines an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. Overall, in this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.
Topics: Humans; DNA Damage; Immunotherapy; Prostatic Neoplasms; Reactive Oxygen Species; Male; Oxidative Stress; DNA Repair; Animals; Cysteine
PubMed: 38900609
DOI: 10.18632/oncotarget.28595 -
Ultrasonography (Seoul, Korea) May 2024To provide more accurate and definitive conclusions regarding the clinical and technical complications associated with the transperineal (TP) and transrectal (TR)...
PURPOSE
To provide more accurate and definitive conclusions regarding the clinical and technical complications associated with the transperineal (TP) and transrectal (TR) approaches, a comprehensive review of observational studies and randomized controlled trials was conducted. This systematic review covered all eligible studies to facilitate a thorough comparison of complications linked to the two fiducial marker insertion methods, TP and TR.
METHODS
A comprehensive search of the literature was conducted, encompassing databases such as PubMed, Embase, and the Cochrane Library, up to July 7, 2023. The relative risk and 95% confidence interval were utilized to evaluate the diagnosis and complication rates.
RESULTS
The final selection for the methodological quality analysis included 13 observational studies that utilized TP and TR gold fiducial insertion approaches. The meta-analysis revealed significantly lower risks of urinary tract infections (UTI) and rectal bleeding with the TP approach.
CONCLUSION
The use of both TP and TR techniques for placing gold seed fiducial markers has proven to be an effective, safe, and well-tolerated method for image-guided radiation therapy in prostate cancer patients. A significant benefit of the TP technique is its ability to avoid rectal puncture, thereby reducing the risk of UTIs. Although the incidence of UTIs and rectal bleeding associated with the TR method is relatively low, these complications can disrupt patient wellbeing and potentially cause delays in treatment.
PubMed: 38898635
DOI: 10.14366/usg.23229 -
Cell Communication and Signaling : CCS Jun 2024Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of...
BACKGROUND
Endocrine resistance driven by sustained activation of androgen receptor (AR) signaling pathway in advanced prostate cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors.
METHODS
Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth.
RESULTS
RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa.
CONCLUSION
In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.
Topics: Male; Humans; Drug Resistance, Neoplasm; Receptors, Androgen; GTPase-Activating Proteins; Prostatic Neoplasms; Cell Line, Tumor; Animals; Proto-Oncogene Mas; Gene Expression Regulation, Neoplastic; Phenylthiohydantoin; Mice, Nude; Nitriles; Mice; Benzamides; Cell Proliferation; Proto-Oncogene Proteins c-mdm2; Signal Transduction
PubMed: 38898473
DOI: 10.1186/s12964-024-01703-w -
Scientific Reports Jun 2024Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This...
Disulfidptosis, a newly identified programmed cell death pathway in prostate cancer (PCa), is closely associated with intracellular disulfide stress and glycolysis. This study aims to elucidate the roles of disulfidptosis-related genes (DRGs) in the pathogenesis and progression of PCa, with the goal of improving diagnostic and therapeutic approaches. We analyzed PCa datasets and normal tissue transcriptome data from TCGA, GEO, and MSKCC. Using consensus clustering analysis and LASSO regression, we developed a risk scoring model, which was validated in an independent cohort. The model's predictive accuracy was confirmed through Kaplan-Meier curves, receiver operating characteristic (ROC) curves, and nomograms. Additionally, we explored the relationship between the risk score and immune cell infiltration, and examined the tumor microenvironment and somatic mutations across different risk groups. We also investigated responses to immunotherapy and drug sensitivity. Our analysis identified two disulfidosis subtypes with significant differences in survival, immune environments, and treatment responses. According to our risk score, the high-risk group exhibited poorer progression-free survival (PFS) and higher tumor mutational burden (TMB), associated with increased immune suppression. Functional enrichment analysis linked high-risk features to key cancer pathways, including the IL-17 signaling pathway. Moreover, drug sensitivity analysis revealed varied responses to chemotherapy, suggesting the potential for disulfidosis-based personalized treatment strategies. Notably, we identified PROK1 as a crucial prognostic marker in PCa, with its reduced expression correlating with disease progression. In summary, our study comprehensively assessed the clinical implications of DRGs in PCa progression and prognosis, offering vital insights for tailored precision medicine approaches.
Topics: Humans; Male; Tumor Microenvironment; Prostatic Neoplasms; Biomarkers, Tumor; Immunotherapy; Prognosis; Gene Expression Regulation, Neoplastic; Transcriptome; Nomograms; Kaplan-Meier Estimate
PubMed: 38898043
DOI: 10.1038/s41598-024-61679-y