-
Cell Death & Disease Jan 2024Prostate cancer (PCa) is one of the most common malignancy in men. However, the molecular mechanism of its pathogenesis has not yet been elucidated. In this study, we...
Prostate cancer (PCa) is one of the most common malignancy in men. However, the molecular mechanism of its pathogenesis has not yet been elucidated. In this study, we demonstrated that CYLD, a novel deubiquitinating enzyme, impeded PCa development and progression via tumor suppression. First, we found that CYLD was downregulated in PCa tissues, and its expression was inversely correlated with pathological grade and clinical stage. Moreover, we discovered that CYLD inhibited tumor cell proliferation and enhanced the sensitivity to cell ferroptosis in PCa in vitro and in vivo, respectively. Mechanistically, we demonstrated that CYLD suppressed the ubiquitination of YAP protein, then promoted ACSL4 and TFRC mRNA transcription. Then, we demonstrated that CYLD could enhance the sensitivity of PCa xenografts to ferroptosis in vivo. Furthermore, we discovered for the first time that there was a positive correlation between CYLD expression and ACSL4 or TFRC expression in human PCa specimens. The results of this study suggested that CYLD acted as a tumor suppressor gene in PCa and promoted cell ferroptosis through Hippo/YAP signaling.
Topics: Humans; Male; Cell Proliferation; Deubiquitinating Enzyme CYLD; Ferroptosis; Heterografts; Prostate; Prostatic Neoplasms
PubMed: 38246916
DOI: 10.1038/s41419-024-06464-5 -
Frontiers in Endocrinology 2023Surgical treatment is important for male lower urinary tract symptom (LUTS) management, but there are few reviews of the risks of reoperation. (Meta-Analysis)
Meta-Analysis
CONTEXT
Surgical treatment is important for male lower urinary tract symptom (LUTS) management, but there are few reviews of the risks of reoperation.
OBJECTIVE
To systematically evaluate the current evidence regarding the reoperation rates of surgical treatment for LUTS in accordance with current recommendations and guidelines.
EVIDENCE ACQUISITION
Eligible studies published up to July 2023, were searched for in the PubMed (National Library of Medicine, Bethesda, MD, USA), Embase (Elsevier, Amsterdam, the Netherlands), and Web of Science™ (Clarivate™, Philadelphia, PA, USA) databases. STATA (StataCorp LP, College Station, TX, USA) software was used to conduct the meta-analysis. Random-effects models were used to calculate the pooled incidences (PIs) of reoperation and the 95% confidence intervals (CIs).
EVIDENCE SYNTHESIS
A total of 119 studies with 130,106 patients were included. The reoperation rate of transurethral resection of the prostate (TURP) at 1, 2, 3, and 5 years was 4.0%, 5.0%, 6.0%, and 7.7%, respectively. The reoperation rate of plasma kinetic loop resection of the prostate (PKRP) at 1, 2, 3, and 5 years was 3.5%, 3.6%, 5.7%, and 6.6%, respectively. The reoperation rate of holmium laser enucleation of the prostate (HoLEP) at 1, 2, 3, and 5 years was 2.4%, 3.3%, 5.4%, and 6.6%, respectively. The reoperation rate of photoselective vaporization of the prostate (PVP) at 1, 2, 3, and 5 years was 3.3%, 4.1%, 6.7%, and 7.1%, respectively. The reoperation rate of surgery with AquaBeam at 1, 2, 3, and 5 years was 2.6%, 3.1%, 3.0%, and 4.1%, respectively. The reoperation rate of prostatic artery embolization (PAE) at 1, 2, 3, and 5 years was 12.2%, 20.0%, 26.4%, and 23.8%, respectively. The reoperation rate of transurethral microwave thermotherapy (TUMT) at 1, 2, 3, and 5 years was 9.9%, 19.9%, 23.3%, and 31.2%, respectively. The reoperation rate of transurethral incision of the prostate (TUIP) at 5 years was 13.4%. The reoperation rate of open prostatectomy (OP) at 1 and 5 years was 1.3% and 4.4%, respectively. The reoperation rate of thulium laser enucleation of the prostate (ThuLEP) at 1, 2, and 5 years was 3.7%, 7.7%, and 8.4%, respectively.
CONCLUSION
Our results summarized the reoperation rates of 10 surgical procedures over follow-up durations of 1, 2, 3, and 5 years, which could provide reference for urologists and LUTS patients.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023445780.
Topics: United States; Humans; Male; Prostatic Hyperplasia; Transurethral Resection of Prostate; Prostate; Reoperation; Embolization, Therapeutic; Lower Urinary Tract Symptoms
PubMed: 38027158
DOI: 10.3389/fendo.2023.1287212 -
European Urology Oct 2023Radiohybrid (rh) F-rhPSMA-7.3 is a novel high-affinity prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for prostate cancer (PCa) imaging.
Diagnostic Performance and Safety of Positron Emission Tomography with F-rhPSMA-7.3 in Patients with Newly Diagnosed Unfavourable Intermediate- to Very-high-risk Prostate Cancer: Results from a Phase 3, Prospective, Multicentre Study (LIGHTHOUSE).
BACKGROUND
Radiohybrid (rh) F-rhPSMA-7.3 is a novel high-affinity prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for prostate cancer (PCa) imaging.
OBJECTIVE
To evaluate the diagnostic performance and safety of F-rhPSMA-7.3 in newly diagnosed PCa patients planned for prostatectomy.
DESIGN, SETTING, AND PARTICIPANTS
Data on F-rhPSMA-7.3 were reported from the phase 3 prospective, multicentre LIGHTHOUSE study (NCT04186819).
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Patients underwent positron emission tomography/computed tomography (PET/CT) 50-70 min after an injection of 296 MBq F-rhPSMA-7.3. Images were interpreted locally and by three blinded independent readers. The coprimary endpoints were patient-level sensitivity and specificity for the detection of pelvic lymph node (PLN) metastases, validated using histopathology at PLN dissection. Prespecified statistical thresholds (lower bounds of 95% confidence interval [CI]) were set at 22.5% for sensitivity and 82.5% for specificity.
RESULTS AND LIMITATIONS
Of 372 patients screened, 352 had evaluable F-rhPSMA-7.3-PET/CT and 296 (99 [33%] with unfavourable intermediate-risk [UIR] and 197 [67%] with high-/very-high-risk [VHR] PCa) subsequently underwent surgery. As per the independent reads, 23-37 (7.8-13%) patients had F-rhPSMA-7.3-positive PLN. Seventy (24%) patients had one or more positive PLNs on histopathology. The sensitivity for PLN detection was 30% (95% CI, 19.6-42.1%) for reader 1, 27% (95% CI, 17.2-39.1%) for reader 2, and 23% (95% CI, 13.7-34.4%) for reader 3, not meeting the prespecified threshold. Specificity was 93% (95% CI, 88.8-95.9%), 94% (95% CI, 89.8-96.6%), and 97% (95% CI, 93.7-98.7%), respectively, exceeding the threshold for all readers. Specificity was high (≥92%) across both risk stratifications. Sensitivity was higher among high-risk/VHR (24-33%) than among UIR (16-21%) patients. Extrapelvic (M1) lesions were reported for 56-98/352 (16-28%) patients who underwent F-rhPSMA-7.3-PET/CT irrespective of surgery. Verification of these (predominantly by conventional imaging) gave a verified detection rate of 9.9-14% (positive predictive value, 51-63%). No serious adverse events were observed.
CONCLUSIONS
Across all risk stratifications, F-rhPSMA-7.3-PET/CT had high specificity, meeting the specificity endpoint. The sensitivity endpoint was not met, although higher sensitivity was noted among high-risk/VHR than among UIR patients. Overall, F-rhPSMA-7.3-PET/CT was well tolerated, and identified N1 and M1 disease prior to surgery in newly diagnosed PCa patients.
PATIENT SUMMARY
In order to select the most appropriate treatment for patients with prostate cancer, it is critical to diagnose the disease burden accurately at initial diagnosis. In this study, we investigated a new diagnostic imaging agent in a large population of men with primary prostate cancer. We found it to have an excellent safety profile and to provide clinically useful information regarding the presence of disease beyond the prostate.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Prospective Studies; Positron-Emission Tomography; Prostatic Neoplasms; Prostate; Gallium Radioisotopes
PubMed: 37414702
DOI: 10.1016/j.eururo.2023.06.018 -
The Journal of Clinical Investigation Dec 2023Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA...
Strategies for patient stratification and early intervention are required to improve clinical benefits for patients with prostate cancer. Here, we found that active DHEA utilization in the prostate gland correlated with tumor aggressiveness at early disease stages, and 3βHSD1 inhibitors were promising for early intervention. [3H]-labeled DHEA consumption was traced in fresh prostatic biopsies ex vivo. Active DHEA utilization was more frequently found in patients with metastatic disease or therapy-resistant disease. Genetic and transcriptomic features associated with the potency of prostatic DHEA utilization were analyzed to generate clinically accessible approaches for patient stratification. UBE3D, by regulating 3βHSD1 homeostasis, was discovered to be a regulator of patient metabolic heterogeneity. Equilin suppressed DHEA utilization and inhibited tumor growth as a potent 3βHSD1 antagonist, providing a promising strategy for the early treatment of aggressive prostate cancer. Overall, our findings indicate that patients with active prostatic DHEA utilization might benefit from 3βHSD1 inhibitors as early intervention.
Topics: Male; Humans; Prostate; Dehydroepiandrosterone; Prostatic Neoplasms
PubMed: 38099500
DOI: 10.1172/JCI171199 -
Archives of Pathology & Laboratory... Sep 2023It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and...
CONTEXT.—
It is important to recognize high-grade foamy gland prostatic adenocarcinoma with desmoplastic stroma given its aggressive clinical course with frequent metastases and death.
OBJECTIVE.—
To review the morphology, immunohistochemistry, and prognosis for this rare subtype of prostate adenocarcinoma.
DESIGN.—
Twenty-four cases received for consultation from 2010 to 2021 were analyzed including needle biopsy (n = 21), transurethral resection (n = 2), and a cystoprostatectomy (n = 1).
RESULTS.—
Patients ranged in age from 40 to 89 years (mean, 67 years). On average, 8 cores per case were involved (mean 67% core involvement). Extraprostatic extension and seminal vesicle invasion were observed in 6 of 21 (29%) and 3 of 21 (14%) needle biopsy cases, respectively. Twenty of the 24 cases (83%) were Grade Group (GG) 5 with 4 of 24 (17%) being GG4. Tumor necrosis as a component of Gleason pattern 5 was observed in 21 of 24 cases (88%). Associated intraductal adenocarcinoma (IDC) was observed in 22 of 24 cases (92%), with 4 of 24 cases (17%) demonstrating extensive IDC. Diagnostic challenges were as follows: (1) sparse isolated cancer glands embedded in the dense desmoplastic stroma; (2) fragmented glands; and (3) aberrant staining for high-molecular-weight cytokeratin in a nonbasal cell pattern in all cases. PTEN loss was observed in 9 cases, and p53 nuclear accumulation was observed in 8 cases. Three patients were lost to follow-up. Overall, of the 16 patients with meaningful follow-up, 12 (75%) either had metastases or died from prostate cancer.
CONCLUSIONS.—
High-grade desmoplastic foamy gland adenocarcinoma is difficult to diagnose and grade and has a poor prognosis.
Topics: Male; Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Prostate; Prostatic Neoplasms; Adenocarcinoma; Prostatectomy; Biopsy, Needle
PubMed: 36399606
DOI: 10.5858/arpa.2022-0165-OA -
Cancer Research Dec 2023Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells...
UNLABELLED
Prostate cancer remains the second leading cause of cancer death in men in Western cultures. A deeper understanding of the mechanisms by which prostate cancer cells divide to support tumor growth could help devise strategies to overcome treatment resistance and improve survival. Here, we identified that the mitotic AGC family protein kinase citron kinase (CIT) is a pivotal regulator of prostate cancer growth that mediates prostate cancer cell interphase progression. Increased CIT expression correlated with prostate cancer growth induction and aggressive prostate cancer progression, and CIT was overexpressed in prostate cancer compared with benign prostate tissue. CIT overexpression was controlled by an E2F2-Skp2-p27 signaling axis and conferred resistance to androgen-targeted treatment strategies. The effects of CIT relied entirely on its kinase activity. Conversely, CIT silencing inhibited the growth of cell lines and xenografts representing different stages of prostate cancer progression and treatment resistance but did not affect benign epithelial prostate cells or nonprostatic normal cells, indicating a potential therapeutic window for CIT inhibition. CIT kinase activity was identified as druggable and was potently inhibited by the multikinase inhibitor OTS-167, which decreased the proliferation of treatment-resistant prostate cancer cells and patient-derived organoids. Isolation of the in vivo CIT substrates identified proteins involved in diverse cellular functions ranging from proliferation to alternative splicing events that are enriched in treatment-resistant prostate cancer. These findings provide insights into the regulation of aggressive prostate cancer cell behavior by CIT and identify CIT as a functionally diverse and druggable driver of prostate cancer progression.
SIGNIFICANCE
The poorly characterized protein kinase citron kinase is a therapeutic target in prostate cancer that drives tumor growth by regulating diverse substrates, which control several hallmarks of aggressive prostate cancer progression. See related commentary by Mishra et al., p. 4008.
Topics: Humans; Male; Cell Line, Tumor; Cell Proliferation; Prostate; Prostatic Neoplasms; Protein Kinases; Signal Transduction
PubMed: 37801613
DOI: 10.1158/0008-5472.CAN-23-0883 -
Annual Review of Medicine Jan 2024Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or... (Review)
Review
Prostate-specific membrane antigen (PSMA) as a transmembrane protein is overexpressed by prostate cancer (PC) cells and is accessible for binding antibodies or low-molecular-weight radioligands due to its extracellular portion. Successful targeting of PSMA began with the development of humanized J591 antibody. Due to their faster clearance compared to antibodies, small-molecule radioligands for targeted imaging and therapy of PC have been favored in recent development efforts. PSMA positron emission tomography (PET) imaging has higher diagnostic performance than conventional imaging for initial staging of high-risk PC and biochemical recurrence detection/localization. However, it remains to be demonstrated how to integrate PSMA PET imaging for therapy response assessment and as an outcome endpoint measure in clinical trials. With the recent approval of Lu-PSMA-617 by the US Food and Drug Administration for metastatic castration-resistant PC progressing after chemotherapy, the high value of PSMA-targeted therapy was confirmed. Compared to standard of care, PSMA-based radioligand therapy led to a better outcome and a higher quality of life. This review, focusing on the advanced PC setting, provides an overview of different approved and nonapproved PSMA-targeted imaging and therapeutic modalities and discusses the future of PSMA-targeted theranostics, also with an outlook on non-radiopharmaceutical-based PSMA-targeted therapies.
Topics: United States; Male; Humans; Quality of Life; Prostate; Prostatic Neoplasms; Positron-Emission Tomography; Precision Medicine
PubMed: 38285513
DOI: 10.1146/annurev-med-081522-031439 -
British Journal of Cancer Nov 2023A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational.
BACKGROUND
A rapid, low-cost blood test that can be applied to reliably detect multiple different cancer types would be transformational.
METHODS
In this large-scale discovery study (n = 2092 patients) we applied the Dxcover® Cancer Liquid Biopsy to examine eight different cancers. The test uses Fourier transform infrared (FTIR) spectroscopy and machine-learning algorithms to detect cancer.
RESULTS
Area under the receiver operating characteristic curve (ROC) values were calculated for eight cancer types versus symptomatic non-cancer controls: brain (0.90), breast (0.76), colorectal (0.91), kidney (0.91), lung (0.91), ovarian (0.86), pancreatic (0.84) and prostate (0.86). We assessed the test performance when all eight cancer types were pooled to classify 'any cancer' against non-cancer patients. The cancer versus asymptomatic non-cancer classification detected 64% of Stage I cancers when specificity was 99% (overall sensitivity 57%). When tuned for higher sensitivity, this model identified 99% of Stage I cancers (with specificity 59%).
CONCLUSIONS
This spectroscopic blood test can effectively detect early-stage disease and can be fine-tuned to maximise either sensitivity or specificity depending on the requirements from different healthcare systems and cancer diagnostic pathways. This low-cost strategy could facilitate the requisite earlier diagnosis, when cancer treatment can be more effective, or less toxic.
STATEMENT OF TRANSLATIONAL RELEVANCE
The earlier diagnosis of cancer is of paramount importance to improve patient survival. Current liquid biopsies are mainly focused on single tumour-derived biomarkers, which limits test sensitivity, especially for early-stage cancers that do not shed enough genetic material. This pan-omic liquid biopsy analyses the full complement of tumour and immune-derived markers present within blood derivatives and could facilitate the earlier detection of multiple cancer types. There is a low barrier to integrating this blood test into existing diagnostic pathways since the technology is rapid, simple to use, only minute sample volumes are required, and sample preparation is minimal. In addition, the spectroscopic liquid biopsy described in this study has the potential to be combined with other orthogonal tests, such as cell-free DNA, which could provide an efficient route to diagnosis. Cancer treatment can be more effective when given earlier, and this low-cost strategy has the potential to improve patient prognosis.
Topics: Male; Female; Humans; Prostatic Neoplasms; ROC Curve; Prostate; Biomarkers, Tumor; Spectrum Analysis; Liquid Biopsy
PubMed: 37717120
DOI: 10.1038/s41416-023-02423-7 -
Journal For Immunotherapy of Cancer Sep 2023Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been...
BACKGROUND
Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.
METHODS
Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.
RESULTS
Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.
CONCLUSION
NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.
Topics: Male; Humans; Fulvestrant; Prostatic Neoplasms, Castration-Resistant; Receptors, Estrogen; Prostate
PubMed: 37678915
DOI: 10.1136/jitc-2023-007386 -
Advanced Science (Weinheim,... Mar 2024The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a... (Meta-Analysis)
Meta-Analysis
The extracellular matrix (ECM) undergoes substantial changes during prostate cancer (PCa) progression, thereby regulating PCa growth and invasion. Herein, a meta-analysis of multiple PCa cohorts is performed which revealed that downregulation or genomic loss of ITGA1 and ITGA2 integrin genes is associated with tumor progression and worse prognosis. Genomic deletion of both ITGA1 and ITGA2 activated epithelial-to-mesenchymal transition (EMT) in benign prostate epithelial cells, thereby enhancing their invasive potential in vitro and converting them into tumorigenic cells in vivo. Mechanistically, EMT is induced by enhanced secretion and autocrine activation of TGFβ1 and nuclear targeting of YAP1. An unbiased genome-wide co-expression analysis of large PCa cohort datasets identified the transcription factor TEAD1 as a key regulator of ITGA1 and ITGA2 expression in PCa cells while TEAD1 loss phenocopied the dual loss of α1- and α2-integrins in vitro and in vivo. Remarkably, clinical data analysis revealed that TEAD1 downregulation or genomic loss is associated with aggressive PCa and together with low ITGA1 and ITGA2 expression synergistically impacted PCa prognosis and progression. This study thus demonstrated that loss of α1- and α2-integrins, either via deletion/inactivation of the ITGA1/ITGA2 locus or via loss of TEAD1, contributes to PCa progression by inducing TGFβ1-driven EMT.
Topics: Male; Humans; Prostate; Cell Line, Tumor; Prostatic Neoplasms; Signal Transduction; Integrin alpha2; TEA Domain Transcription Factors
PubMed: 38169150
DOI: 10.1002/advs.202305547