-
Nature Cell Biology Dec 2023Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate...
Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.
Topics: Male; Humans; Prostate; Monocarboxylic Acid Transporters; Cell Differentiation; Epithelial Cells; Androgen Antagonists; Lactates
PubMed: 38049604
DOI: 10.1038/s41556-023-01274-x -
Journal of Clinical Oncology : Official... Nov 2023The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR...
PURPOSE
The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods.
MATERIALS AND METHODS
Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the ). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed.
RESULTS
Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively.
CONCLUSION
BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.
Topics: Male; Humans; Prostate; Prostatic Neoplasms; Androgen Antagonists; Prostate-Specific Antigen; Adenocarcinoma
PubMed: 37639648
DOI: 10.1200/JCO.23.00617 -
The Journal of Clinical Investigation Dec 2023Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting...
Cell lineage plasticity is one of the major causes for the failure of targeted therapies in various cancers. However, the driver and actionable drug targets in promoting cancer cell lineage plasticity are scarcely identified. Here, we found that a G protein-coupled receptor, ADORA2A, is specifically upregulated during neuroendocrine differentiation, a common form of lineage plasticity in prostate cancer and lung cancer following targeted therapies. Activation of the ADORA2A signaling rewires the proline metabolism via an ERK/MYC/PYCR cascade. Increased proline synthesis promotes deacetylases SIRT6/7-mediated deacetylation of histone H3 at lysine 27 (H3K27), and thereby biases a global transcriptional output toward a neuroendocrine lineage profile. Ablation of Adora2a in genetically engineered mouse models inhibits the development and progression of neuroendocrine prostate and lung cancers, and, intriguingly, prevents the adenocarcinoma-to-neuroendocrine phenotypic transition. Importantly, pharmacological blockade of ADORA2A profoundly represses neuroendocrine prostate and lung cancer growth in vivo. Therefore, we believe that ADORA2A can be used as a promising therapeutic target to govern the epigenetic reprogramming in neuroendocrine malignancies.
Topics: Animals; Humans; Male; Mice; Cell Line, Tumor; Epigenesis, Genetic; Lung Neoplasms; Proline; Prostate; Prostatic Neoplasms; Sirtuins
PubMed: 38099497
DOI: 10.1172/JCI168670 -
Medicina (Kaunas, Lithuania) Sep 2023Image-guided focal therapy has increased in popularity as a treatment option for patients with primary and locally recurrent prostate cancer. This review will cover the... (Review)
Review
Image-guided focal therapy has increased in popularity as a treatment option for patients with primary and locally recurrent prostate cancer. This review will cover the basic indications, evaluation, treatment algorithm, and follow-up for patients undergoing image-guided ablation of the prostate. Additionally, this paper will serve as an overview of some technical approaches to cases so that physicians can familiarize themselves with working in this space. While the focus of this paper is prostate cryoablation, readers will obtain a basic literature overview of some of the additional available image-guided treatment modalities for focal prostate therapy.
Topics: Male; Humans; Cryosurgery; Prostate; Algorithms; Pelvis; Physicians
PubMed: 37763708
DOI: 10.3390/medicina59091589 -
World Journal of Urology Apr 2024To provide a comprehensive update on the different techniques and outcomes of contemporary Single-Port (SP) Robotic Radical Prostatectomy (RARP) approaches. (Review)
Review
PURPOSE
To provide a comprehensive update on the different techniques and outcomes of contemporary Single-Port (SP) Robotic Radical Prostatectomy (RARP) approaches.
METHODS
A literature review was performed to identify cohort studies that have utilized the purpose-built SP robotic platform (Intuitive Surgical Inc., Sunnyvale, California) for RARP. All published approaches of SP-RARP were included in our review. Baseline clinical, perioperative, and postoperative oncological and functional outcomes were collected from the included studies.
RESULTS
A total of 16 studies involving 1159 patients were identified. To date, five approaches of SP-RARP have been described, namely Transperitoneal, Extraperitoneal, Retzius-Sparing, Transperineal, and Transvesical. The surgical steps and clinical outcomes of the aforementioned approaches were discussed. While operating times were still faster in the Transperitoneal and Extraperitoneal cohorts, the novel and more regionalized Transvesical approach allowed for radical prostatectomy to be pursued in more patients with previous abdominal surgeries and contributed to significantly improved postoperative outcomes, including the earlier return of urinary continence and with most patients being discharged on the same day without any opioids.
CONCLUSION
Based on the existing literature, the introduction of SP-RARP not only enriched the repertoire of minimally-invasive surgical treatment options for prostate cancer but also provided the opportunity for urologists to develop new techniques that can improve perioperative outcomes and postoperative quality of life. Given the limited number of patients and heterogeneity in the patient selection and reporting of postoperative outcomes, further research remains necessary to better understand the different benefits and improve patient selection algorithms for the different techniques.
Topics: Male; Humans; Robotic Surgical Procedures; Robotics; Quality of Life; Prostate; Prostatectomy; Prostatic Neoplasms; Treatment Outcome
PubMed: 38643347
DOI: 10.1007/s00345-024-04914-5 -
Revista Internacional de Andrologia Mar 2024It is estimated that microorganisms colonize 90% of the body surface. In some tracts, such as the genitourinary tract, the microbiota varies throughout life, influenced...
It is estimated that microorganisms colonize 90% of the body surface. In some tracts, such as the genitourinary tract, the microbiota varies throughout life, influenced by hormonal stimulation and sexual practices. This study evaluated the semen differences and presence of , , and in semen samples from patients with symptoms of chronic prostatitis and men asymptomatic for urogenital infections. Fifty-three semen samples were included: 22 samples from men with symptoms of chronic prostatitis and 31 asymptomatic men (control group). In addition to the presence of , , and , semen parameters, total antioxidant capacity of seminal plasma, prostatic antigen and some proinflammatory cytokines were evaluated in each semen sample. Volunteers with symptoms of chronic prostatitis presented a lower percentage of sperm morphology (4.3% control group 6.0%, = 0.004); in the semen samples of volunteers in the group asymptomatic for urogenital infections, microorganisms associated with the vaginal microbiota were detected more frequently. The presence of bacteria in the vaginal microbiota can also benefit male reproductive health, which undergoes various modifications related to lifestyle habits that are susceptible to modification. Microorganisms associated with the vaginal microbiota, such as , , and , may have a protective role against the development of male genitourinary diseases such as prostatitis.
Topics: Humans; Male; Prostatitis; Semen; Adult; Microbiota; Coitus; Gardnerella vaginalis; Lactobacillus; Vagina; Middle Aged; Actinobacteria; Female; Young Adult; Chronic Disease; Case-Control Studies; Semen Analysis; Cytokines
PubMed: 38735876
DOI: 10.22514/j.androl.2024.006 -
Scientific Reports Feb 2024According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut...
According to previous observational researches and clinical trials, the gut microbiota is related to prostate diseases. However, the potential association between gut microbiota and prostate disorders is still uncertain. We first identified groups of gut microbiota based on the phylum, class, order, family, and genus levels from consortium MiBioGen. And we acquired prostate diseases statistics from the FINNGEN study and PRACTICAL consortium. Next, two-sample Mendelian randomization was used to investigate the potential associations between three prevalent prostate disease and gut microbiota. In addition, we performed a reverse MR analysis and Benjamini-Hochberg (BH) test for further research. We investigated the connection between 196 gut microbiota and three prevalent prostate diseases. We identified 42 nominally significant associations and 2 robust causative links. Upon correction for multiple comparisons using the Benjamini-Hochberg procedure, our analysis revealed a positive correlation between the risk of prostatitis and the presence of the taxonomic order Gastranaerophilales. Conversely, the risk of prostate cancer exhibited an inverse correlation with the presence of the taxonomic class Alphaproteobacteria. Our study revealed the potential association between gut microbiota and prostate diseases. The results may be useful in providing new insights for further mechanistic and clinical studies of prostate diseases.
Topics: Male; Humans; Gastrointestinal Microbiome; Mendelian Randomization Analysis; Prostate; Prostatic Diseases; Prostatic Neoplasms; Alphaproteobacteria; Genome-Wide Association Study
PubMed: 38369514
DOI: 10.1038/s41598-024-54293-5 -
International Journal of Molecular... Sep 2023Extracellular vesicles (EVs)-including apoptotic bodies, microvesicles, and exosomes-are released by almost all cell types and contain molecular footprints from their... (Review)
Review
Extracellular vesicles (EVs)-including apoptotic bodies, microvesicles, and exosomes-are released by almost all cell types and contain molecular footprints from their cell of origin, including lipids, proteins, metabolites, RNA, and DNA. They have been successfully isolated from blood, urine, semen, and other body fluids. In this review, we discuss the current understanding of the predictive value of EVs in prostate and renal cancer. We also describe the findings supporting the use of EVs from liquid biopsies in stratifying high-risk prostate/kidney cancer and advanced disease, such as castration-resistant (CRPC) and neuroendocrine prostate cancer (NEPC) as well as metastatic renal cell carcinoma (RCC). Assays based on EVs isolated from urine and blood have the potential to serve as highly sensitive diagnostic studies as well as predictive measures of tumor recurrence in patients with prostate and renal cancers. Overall, we discuss the biogenesis, isolation, liquid-biopsy, and therapeutic applications of EVs in CRPC, NEPC, and RCC.
Topics: Male; Humans; Carcinoma, Renal Cell; Prostate; Prostatic Neoplasms, Castration-Resistant; Clinical Relevance; Kidney Neoplasms; Neoplasm Recurrence, Local; Extracellular Vesicles; Exosomes
PubMed: 37834162
DOI: 10.3390/ijms241914713 -
Frontiers in Endocrinology 2023Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary... (Review)
Review
Androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, and the development of castrate-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-related mortality. While CRPC typically develops through a gain in androgen receptor (AR) signaling, a subset of CRPC will lose reliance on the AR. This process involves genetic, epigenetic, and hormonal changes that promote cellular plasticity, leading to AR-indifferent disease, with neuroendocrine prostate cancer (NEPC) being the quintessential example. NEPC is enriched following treatment with second-generation anti-androgens and exhibits resistance to endocrine therapy. Loss of , , and expression and and amplification appear to be key drivers for NEPC differentiation. Epigenetic modifications also play an important role in the transition to a neuroendocrine phenotype. DNA methylation of specific gene promoters can regulate lineage commitment and differentiation. Histone methylation can suppress AR expression and promote neuroendocrine-specific gene expression. Emerging data suggest that EZH2 is a key regulator of this epigenetic rewiring. Several mechanisms drive AR-dependent castration resistance, notably AR splice variant expression, expression of the adrenal-permissive 3βHSD1 allele, and glucocorticoid receptor expression. Aberrant epigenetic regulation also promotes radioresistance by altering the expression of DNA repair- and cell cycle-related genes. Novel therapies are currently being developed to target these diverse genetic, epigenetic, and hormonal mechanisms promoting lineage plasticity-driven NEPC.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Epigenesis, Genetic; Androgen Antagonists; Prostate
PubMed: 37455903
DOI: 10.3389/fendo.2023.1191311 -
Radiology Oct 2023Background High variability in prostate MRI quality might reduce accuracy in prostate cancer detection. Purpose To prospectively evaluate the quality of MRI scanners... (Clinical Trial)
Clinical Trial
Background High variability in prostate MRI quality might reduce accuracy in prostate cancer detection. Purpose To prospectively evaluate the quality of MRI scanners taking part in the quality control phase of the global PRIME (Prostate Imaging Using MRI ± Contrast Enhancement) trial using the Prostate Imaging Quality (PI-QUAL) standardized scoring system, give recommendations on how to improve the MRI protocols, and establish whether MRI quality could be improved by these recommendations. Materials and Methods In the prospective clinical trial (PRIME), for each scanner, centers performing prostate MRI submitted five consecutive studies and the MRI protocols (phase I). Submitted data were evaluated in consensus by two expert genitourinary radiologists using the PI-QUAL scoring system that evaluates MRI diagnostic quality using five points (1 and 2 = nondiagnostic; 3 = sufficient; 4 = adequate, 5 = optimal) between September 2021 and August 2022. Feedback was provided for scanners not achieving a PI-QUAL 5 score, and centers were invited to resubmit new imaging data using the modified protocol (phase II). Descriptive comparison of outcomes was made between the MRI scanners, feedback provided, and overall PI-QUAL scores. Results In phase I, 41 centers from 18 countries submitted a total of 355 multiparametric MRI studies from 71 scanners, with nine (13%) scanners achieving a PI-QUAL score of 3, 39 (55%) achieving a score of 4, and 23 (32%) achieving a score of 5. Of the 48 ( = 71 [68%]) scanners that received feedback to improve, the dynamic contrast-enhanced sequences were those that least adhered to the Prostate Imaging Reporting and Data System, version 2.1, criteria (44 of 48 [92%]), followed by diffusion-weighted imaging (20 of 48 [42%]) and T2-weighted imaging (19 of 48 [40%]). In phase II, 36 centers from 17 countries resubmitted revised studies, resulting in a total of 62 ( = 64 [97%]) scanners with a final PI-QUAL score of 5. Conclusion Substantial variation in global prostate MRI acquisition parameters as a measure of quality was observed, particularly with DCE sequences. Basic evaluation and modifications to MRI protocols using PI-QUAL can lead to substantial improvements in quality. Clinical trial registration no. NCT04571840 Published under a CC BY 4.0 license. See also the editorial by Almansour and Chernyak in this issue.
Topics: Humans; Male; Diffusion Magnetic Resonance Imaging; Magnetic Resonance Imaging; Pelvis; Prospective Studies; Prostate
PubMed: 37815448
DOI: 10.1148/radiol.231130