Prostate最新文献

NOTIFICATION: "RhoGDIα Downregulates Androgen Receptor Signaling in Prostate Cancer Cells," by Y. Zhu, C. Liu, R. Tummala, N. Nadiminty, W. Lou, and A. C. Gao, The Prostate 73, no. 15 (2013): 1614-1622, https://doi.org/10.1002/pros.22615. This Notification is for the above article, published online on 06 August 2013 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Dr. Samuel Denmeade; and Wiley Periodicals LLC. A third party reported that the cytoplasmic Pol II band and nuclear tubulin bands in Figure 4C had been duplicated. An investigation by the publisher also found that the RhoGDIα and Tubulin bands were duplicated between Figure 2D and Figure 2E. The authors responded to an inquiry by the publisher and reported that the authors used the same images in Figure 2D and 2E to show that RhoGDIa expression was knocked down by shGDI, as the same materials were used for Fig. 2E and 2D. The editors agreed with this statement and confirmed that the Pol II and tubulin bands in Figure 4C were intentionally marked with blank images and that the same blank image had been used to illustrate that Pol II and tubulin were used as loading controls for nuclear and cytoplasmic proteins, respectively. As such, the journal's investigation has determined that there are no concerns regarding the duplicated bands in Figures 2 and 4. This Notification has been agreed to in order to inform and alert readers of the investigation.

Purpose: Genetic testing is recommended but underutilized in advanced prostate cancer. Given known disparities affecting Black patients, we assessed genetic testing completion rates by race.

Methods: Henry Ford Health's electronic medical record was queried for new prostate cancer diagnoses (1/1/2017-6/30/2022). The primary outcome was completion of somatic and/or germline testing in stage IV cases. Secondary outcomes included genetic counseling referrals and attendance. Multivariable logistic regression assessed associations with baseline variables. Kaplan-Meier analysis was used for exploratory survival comparisons.

Results: Among 452 stage IV patients (150 Black, 302 White), Black patients had higher somatic (30.7% vs. 18.9%, p = 0.00489) and comparable germline testing rates (16.7% vs. 21.2%, p = 0.255). In M1 cases (N = 297), germline testing was lower among Black patients (14.8% vs. 25.4%, p = 0.0329) despite higher referral rates (32.0% vs 22.2%, p = 0.0241) and similar counseling attendance (45.8% and 43.3%, p = 0.786). No significant racial differences were seen in germline testing for N1 cases (N = 155, 21.4% vs 14.2%, p = 0.274), or somatic testing for M1 (36.1% vs 25.9%, p = 0.0644) or N1 (16.7% vs 7.1%, p = 0.0728) subgroups. M1 patients that completed testing had improved survival (p = 0.0352), while no survival difference by testing in N1 disease or race was observed.

Conclusions: Genetic testing uptake in this advanced prostate cancer cohort was low overall. Notably, Black patients had higher rates of somatic testing, an equitable finding given historically higher prostate cancer-specific mortality. Germline testing was comparable overall but remained lower among Black patients with metastatic disease, indicating that additional decisional and systemic barriers persist beyond access to care and referrals to genetic counseling. Insurance disparities and lower census tract-estimated income represent the largest structural differences between cohorts, with observed equity likely supported by broad coverage of commercial testing. Together, these results indicate that equitable testing utilization is achievable through consistent access frameworks, while residual disparities in germline testing warrant targeted intervention at both the patient and healthcare delivery levels.

Background: Megalin (LRP2) is a multifunctional endocytic receptor whose role in prostate cancer (PCa), particularly in cancer stem cells (CSCs) and metastatic progression, remains largely unexplored.

Methods: We analyzed LRP2 mRNA and protein expression in DU-145, PC-3, and RWPE1 cells and their CD133^high/CD44^high CSCs via qRT-PCR and immunofluorescence, in both 2D and 3D cultures. Public RNA-seq data (TCGA, WCDT-MCRPC) were used to assess LRP2, CD133, and CD44 across normal, primary, and metastatic tumors. Gene Set Enrichment Analysis (GSEA) and correlation with AR, VDR, and stemness genes were performed.

Result: LRP2 was significantly upregulated in DU-145 cells and CSCs in the 3D culture system. In contrast, PC-3 CSCs showed reduced LRP2 expression. In clinical datasets, LRP2 was highest in metastatic tumors (log2FC = 3.58), with bone (M1B) and other parts of the body (M1C) subtypes exhibiting elevated levels compared to primary tumors. CD133 was consistently downregulated in metastases. GSEA highlighted LRP2 involvement in lipid, retinoid, and steroid metabolism. LRP2 correlated positively with VDR and negatively with AR in M1C tumors.

Conclusion: LRP2 shows subtype-specific expression patterns in PCa, with elevated levels in DU-145 CSCs and metastatic tumors. Its link to metabolic pathways and inverse relationship with AR suggest a potential role in therapy resistance and metastasis.

Background: Metastatic prostate cancers are primarily treated by therapies targeting the androgen/androgen receptor (AR) signaling pathways. Despite the initial success, treatment resistance is almost universal, leading to disease progression and patient mortality. Currently, the molecular mechanism and vulnerability of treatment-resistant prostate cancers are poorly understood. These knowledge gaps are major obstacles in improving treatment and patient survival. Recently, we used the single-cell approach to establish a new anti-androgen/AR resistant cell model, in which tumor cells had an AR-low phenotype, expressing low levels of AR and AR-target genes, and were resistant to androgen-deprivation (ADT) and enzalutamide in vitro and in vivo.

Methods: We determined the transcriptome of the treatment-resistant AR-low cells with bulk RNA-Seq, qRT-PCR, and chromatin immunoprecipitation (ChIP)-qPCR. We identified a metabolic vulnerability of the resistant cells with siRNA, plasmid-based overexpression and metabolic assays. We next determined whether the vulnerability can be exploited by small molecule inhibitors to enhance enzalutamide with proliferation and colony formation assays and Incucyte-based live cell imaging. We also determined the clinical relevance of the vulnerability with the prostate cancer TCGA data set.

Results: The AR-low treatment resistant tumor cells had significantly different transcriptomes from the treatment-sensitive counterparts, notably represented by the EMT-high expression phenotype. The resistant cells were deficient in the expression of NAPRT, a rate determining enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis, causing the resistant cells to be vulnerable to NAD+ biosynthesis inhibitors. Importantly, this vulnerability can be exploited to enhance enzalutamide efficacy in the castration sensitive setting as NAPRT-low was phenotypically associated with EMT-high and AR-low in subpopulations of tumor cells and patient samples.

Conclusion: Our newly established treatment-resistant cell model has the AR-low/EMT-high phenotype, which is clinically associated with enzalutamide resistance in patients. NAPRT-deficiency (NAPRT-low) can be a novel vulnerability associated with the AR-low/EMT-high phenotype and thus can be targeted by NAD+ inhibitors to improve enzalutamide efficacy.

Retraction: R. Tummala, N. Nadiminty, W. Lou, C. P. Evans, and A. C. Gao, "Lin28 Induces Resistance to Anti-Androgens via Promotion of AR Splice Variant Generation," The Prostate 76, no. 5 (2016): 445-455, https://doi.org/10.1002/pros.23134. The above article, published online on 30 December 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Dr. Samuel Denmeade; and Wiley Periodicals LLC. A third party reported that the Lin28 band in Figure 4D had been duplicated and resized as the AR-V7 band in Figure 4E and that one of the AR-V7 images in Figure 4A had been duplicated in one of the hnRNPA1 images in Figure 5C. Further investigation by the publisher confirmed these duplications and also found that bands had been duplicated between Figures 1A and 5A and between Figures 1B and 5C. The investigation also found evidence of image splicing in Figures 3A, 3C, 5B, and 5D. The authors responded to an inquiry by the publisher and provided explanations for some instances of duplicated western blot images. The authors further stated that evidence of image splicing in the mentioned bands could be due to artifacts from image editing software. The authors stated that original data were no longer available. The editors determined that the re-use of experimental data between Figures 1A and 5C and between Figures 1B and 5C may have been appropriate. However, the re-use of data between Figures 4D and 4E as well as between Figures 4A and 5C, in which the data were used for different experimental conditions, was not considered acceptable. Additionally, the evidence of splicing in Figures 3A, 5B, and 5D added further concerns about the veracity of the data. The retraction has been agreed to because the multiple instances of duplication and potential splicing in some images compromise the editors' confidence in the conclusions presented in the article. The authors did not respond to our notice regarding the retraction.

Background: Molecular heterogeneity in prostate cancer is defined by distinct gene fusions and expression profiles involving ERG, SPINK1, ETV1, and ETV4. These markers are typically mutually exclusive and represent biologically distinct molecular subtypes with clinical and therapeutic relevance. Conventional methods assess these markers independently, limiting the ability to study their spatial relationships within the same tumor focus.

Methods: We developed a combined dual immunohistochemistry (IHC) and dual RNA in situ hybridization (RNA-ISH) assay for simultaneous detection of ERG, SPINK1, ETV1, and ETV4 in formalin-fixed paraffin-embedded (FFPE) prostate cancer tissues. Validated antibodies were used for ERG and SPINK1 protein detection, while RNAscope probes were employed for ETV1 and ETV4 mRNA visualization. The assay was optimized for sequential staining compatibility, chromogen contrast, and morphological preservation, and subsequently applied to prostate cancer cores representing various molecular subtypes.

Results: The combined assay enabled clear, concurrent visualization of ERG and SPINK1 protein expression together with ETV1 and ETV4 transcripts in a single tissue section. Expression patterns were mutually exclusive across tumor foci, consistent with known molecular subtypes of prostate cancer. The method maintained histological integrity and signal specificity, providing high-resolution spatial information that could not be obtained by separate assays. This approach allowed detailed assessment of intra- and inter-tumoral heterogeneity within the same histological context.

Conclusions: This dual IHC and dual RNA-ISH approach represents a novel and reliable platform for multiplex detection of key prostate cancer biomarkers on a single slide. The method offers significant advantages for molecular classification, tissue-based biomarker validation, and comprehensive evaluation of tumor heterogeneity in translational and diagnostic research.

Introduction: The 12th Annual 2025 Coffey-Holden Prostate Cancer Academy (CHPCA) Meeting, "Deciphering Resistance: Beyond the Androgen Paradigm," was held at the University of California, Los Angeles (UCLA), Luskin Conference Center, in Los Angeles, CA, from June 19 to 22, 2025.

Methods: The CHPCA Meeting is a discussion-focused conference held annually by the Prostate Cancer Foundation (PCF), for in-depth academic analysis of emerging research with the greatest potential to drive new understandings and treatments for prostate cancer. The 2025 CHPCA Meeting included attendance by 79 academic investigators and 39 talks over 8 sessions.

Results: The session topics included: drug discovery in academia, non-apoptotic cell death mechanisms, understanding and overcoming treatment resistance, chromosomal instability (CIN) as a driver of metastasis and treatment resistance, targeting metastatic sites, immunotherapy sensitizers, and optimizing therapy delivery and biomedical engineering.

Discussion: This meeting report summarizes the presentations from the 2025 CHPCA Meeting. We hope that disseminating this information will directly contribute to novel research efforts and improved treatment strategies for patients with prostate cancer.

Background: To evaluate the diagnostic accuracy, procedural feasibility, and clinical outcomes of a novel cystoscopic-guided indocyanine green (ICG) injection technique followed by fluorescence-guided sentinel lymph node dissection (SLND) during robotic-assisted radical prostatectomy (RaRP), hereafter referred to as CysICG-SLND.

Methods: We prospectively enrolled patients with clinically localized prostate cancer (cT1-cT3, cN0) scheduled for RaRP between November 2019 and May 2020. Each patient received cystoscopic-guided intraprostatic injections of ICG, with injection volumes tailored according to prostate size. SLND was performed using the da Vinci Xi Surgical System equipped with near-infrared imaging and followed by a routine extended pelvic lymph node dissection (ePLND). Diagnostic accuracy, procedural complications, and medium-term oncological outcomes were analyzed.

Results: A total of 34 patients were included (risk category: low = 2, intermediate = 11, high = 21). Cystoscopic ICG injection was technically successful in all cases. The overall fluorescence detection rate was 97.1%, with excellent per-patient sensitivity (100%) and negative predictive value (NPV) (100%) across all patients. However, per-node diagnostic performance was moderate (sensitivity 66.7%, specificity 47.8%). Notably, in the high-risk group, per-node performance was modest, with sensitivity, specificity, positive predictive value (PPV), and NPV of 66.7%, 55.2%, 20.5%, and 90.7%, respectively. No metastatic nodes were identified in low-risk and intermediate-risk groups, demonstrating a reliable 100% NPV in these subpopulations. High-risk patients had significantly higher biochemical recurrence (BCR) rates compared to lower-risk groups (p = 0.017). There were no allergic reactions or postoperative complications attributable to ICG.

Conclusions: CysICG-SLND is a feasible, accurate approach for nodal staging in prostate cancer, particularly beneficial in low- to intermediate-risk groups, achieving excellent sensitivity and NPV. Although diagnostic performance is limited in high-risk patients, high per-patient accuracy still supports clinical utility. Larger prospective studies are warranted to validate these results and further elucidate the technique's clinical role.

Background: Several studies have suggested that biopsy-free radical prostatectomy reduces burdens for selected prostate cancer (PCa) patients pre-screened by clinical indicators and PSMA-PET/CT. However, the absence of pre-operative pathology precludes high-risk PCa (HRPCa) identification, crucial for determining the need for extended pelvic lymph node dissection (ePLND). We evaluated whether combining pre-operative clinical indicators and ¹⁸F-PSMA-1007 PET/CT could non-invasively stratify HRPCa risk.

Methods: This retrospective diagnostic study included a development cohort of 93 patients from USTC center, as well as two external validation cohorts: one cohort of 83 patients from XYH Hospital and another cohort of 117 patients from XJH Hospital. All enrolled patients met the USTC model value ≥ 0.6 criteria (assessed using a nomogram composed of PSAD and PI-RADS grade) and obtained definitive pathological results within 4 weeks after ¹⁸F-PSMA-1007 PET/CT examination. Patients were stratified as HRPCa (D'Amico criteria: tPSA> 20 ng/mL, GS ≥ 8, or ≥ cT2c) or non-high-risk (NHR). Maximum standardized uptake value (SUVmax) and target-to-background ratios (TBRs) of PSMA-PET/CT were quantified. Diagnostic performance for HRPCa was evaluated using ROC analysis. Multivariate logistic regression analysis identified independent predictors.

Results: In the development cohort (n = 93), SUVmax (AUC = 0.807) and tPSA (AUC = 0.777) demonstrated good discriminatory performance for identifying HRPCa (both p < 0.05). The dual-threshold criterion (SUVmax> 20.9 and tPSA> 15.09 ng/mL) achieved a consistently high PPV (up to 100% in the development cohort and > 91% in external validation) and specificity, significantly outperforming single parameters (p < 0.001). In two external validation cohorts, similar diagnostic performance was observed.

Conclusion: A dual-threshold non-invasive strategy is established for predicting HRPCa in biopsy-free radical prostatectomy candidates pre-screened by the USTC model, while its applicability to unscreened or low to intermediate-risk populations remains unproven.