RESUMO
The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.
Assuntos
PTEN Fosfo-Hidrolase , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Homeostase , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismoRESUMO
Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.
Assuntos
Antagonistas de Receptores de Andrógenos , Antineoplásicos , Quimiotaxia , Resistencia a Medicamentos Antineoplásicos , Células Mieloides , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Quimiotaxia/efeitos dos fármacos , Progressão da Doença , Inflamação/tratamento farmacológico , Inflamação/patologia , Antígenos CD15/metabolismo , Células Mieloides/efeitos dos fármacos , Células Mieloides/patologia , Metástase Neoplásica , Próstata/efeitos dos fármacos , Próstata/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Defining the transition from benign to malignant tissue is fundamental to improving early diagnosis of cancer1. Here we use a systematic approach to study spatial genome integrity in situ and describe previously unidentified clonal relationships. We used spatially resolved transcriptomics2 to infer spatial copy number variations in >120,000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.
Assuntos
Células Clonais , Variações do Número de Cópias de DNA , Instabilidade Genômica , Neoplasias , Análise Espacial , Células Clonais/metabolismo , Células Clonais/patologia , Variações do Número de Cópias de DNA/genética , Detecção Precoce de Câncer , Genoma Humano , Instabilidade Genômica/genética , Genômica , Humanos , Masculino , Modelos Biológicos , Neoplasias/genética , Neoplasias/patologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transcriptoma/genéticaRESUMO
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 177Lu-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.
Assuntos
Neoplasias da Próstata , Qualidade de Vida , Estados Unidos , Masculino , Humanos , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia , Tomografia por Emissão de Pósitrons , Medicina de PrecisãoRESUMO
Chromosomal rearrangements resulting in the fusion of TMPRSS2, an androgen-regulated gene, and the ETS family transcription factor ERG occur in over half of prostate cancers. However, the mechanism by which ERG promotes oncogenic gene expression and proliferation remains incompletely understood. Here, we identify a binding interaction between ERG and the mammalian SWI/SNF (BAF) ATP-dependent chromatin remodeling complex, which is conserved among other oncogenic ETS factors, including ETV1, ETV4, and ETV5. We find that ERG drives genome-wide retargeting of BAF complexes in a manner dependent on binding of ERG to the ETS DNA motif. Moreover, ERG requires intact BAF complexes for chromatin occupancy and BAF complex ATPase activity for target gene regulation. In a prostate organoid model, BAF complexes are required for ERG-mediated basal-to-luminal transition, a hallmark of ERG activity in prostate cancer. These observations suggest a fundamental interdependence between ETS transcription factors and BAF chromatin remodeling complexes in cancer.
Assuntos
Carcinogênese/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/genética , Serina Endopeptidases/genética , Proteínas E1A de Adenovirus/genética , Proteínas E1A de Adenovirus/metabolismo , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Cromatina/química , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Organoides/metabolismo , Organoides/patologia , Próstata/metabolismo , Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-ets , Serina Endopeptidases/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismoRESUMO
The bromodomain and extra-terminal domain (BET) protein BRD4 is emerging as a promising anticancer therapeutic target. However, resistance to BET inhibitors often occurs, and it has been linked to aberrant degradation of BRD4 protein in cancer. Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization. Expression of DUB3 is transcriptionally repressed by the NCOR2-HDAC10 complex. The NCOR2 gene is frequently deleted in castration-resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells. DUB3-proficient prostate cancer cells are resistant to the BET inhibitor JQ1 in vitro and in mice, but this effect is diminished by DUB3 inhibitory agents such as CDK4/6 inhibitor in a RB-independent manner. Our findings identify a previously unrecognized mechanism causing BRD4 upregulation and drug resistance, suggesting that DUB3 is a viable therapeutic target to overcome BET inhibitor resistance in cancer.
Assuntos
Quinase 4 Dependente de Ciclina/genética , Quinase 6 Dependente de Ciclina/genética , Endopeptidases/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Neoplasias de Próstata Resistentes à Castração/genética , Fatores de Transcrição/genética , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Endopeptidases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Masculino , Camundongos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Correpressor 2 de Receptor Nuclear/deficiência , Correpressor 2 de Receptor Nuclear/genética , Piperazinas/farmacologia , Próstata/efeitos dos fármacos , Próstata/enzimologia , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/enzimologia , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteólise , Piridinas/farmacologia , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Transcrição Gênica , Triazóis/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
While radical prostatectomy remains the mainstay of prostate cancer (PCa) treatment, 20 to 40% of patients develop postsurgical biochemical recurrence (BCR). A particularly challenging clinical cohort includes patients with intermediate-risk disease whose risk stratification would benefit from advanced approaches that complement standard-of-care diagnostic tools. Here, we show that imaging tumor lactate using hyperpolarized 13C MRI and spatial metabolomics identifies BCR-positive patients in two prospective intermediate-risk surgical cohorts. Supported by spatially resolved tissue analysis of established glycolytic biomarkers, this study provides the rationale for multicenter trials of tumor metabolic imaging as an auxiliary tool to support PCa treatment decision-making.
Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Antígeno Prostático Específico/análise , Ácido Láctico , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , Próstata/patologia , Prostatectomia/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/patologia , Estudos RetrospectivosRESUMO
In prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.
Assuntos
Proteínas de Drosophila , Neoplasias de Próstata Resistentes à Castração , Humanos , Animais , Feminino , Masculino , Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Endorreduplicação , Ecdisona/genética , Ecdisona/metabolismo , Fator de Transcrição E2F1/genética , Fatores de Transcrição/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismoRESUMO
Benign prostate hyperplasia (BPH) is caused by the nonmalignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms. Although current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. Herein, these alterations parallel urodynamic disturbance reminiscent of lower urinary tract symptoms. Single-cell RNA-sequencing analysis of Pb-PRL mouse prostates revealed that their epithelium mainly includes low-androgen signaling cell populations analogous to Club/Hillock cells enriched in the aged human prostate. These intermediate cells are predicted to result from the reprogramming of androgen-dependent luminal cells. Pb-PRL mouse prostates exhibited increased vulnerability to oxidative stress due to reduction of antioxidant enzyme expression. One-month treatment of Pb-PRL mice with anethole trithione (ATT), a specific inhibitor of mitochondrial ROS production, reduced prostate weight and voiding frequency. In human BPH-1 epithelial cells, ATT decreased mitochondrial metabolism, cell proliferation, and stemness features. ATT prevented the growth of organoids generated by sorted Pb-PRL basal and LSCmed cells, the two major BPH-associated, androgen-independent epithelial cell compartments. Taken together, these results support cell plasticity as a driver of BPH progression and therapeutic resistance to androgen signaling inhibition, and identify antioxidant therapy as a promising treatment of BPH.
Assuntos
Sintomas do Trato Urinário Inferior , Hiperplasia Prostática , Masculino , Humanos , Camundongos , Animais , Idoso , Androgênios/farmacologia , Androgênios/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Antioxidantes/farmacologia , Plasticidade Celular , Hiperplasia/patologia , Chumbo/metabolismo , Chumbo/uso terapêutico , Camundongos Transgênicos , Prolactina/metabolismo , Prolactina/uso terapêutico , Células Epiteliais/metabolismo , Sintomas do Trato Urinário Inferior/metabolismo , Sintomas do Trato Urinário Inferior/patologiaRESUMO
BACKGROUND: Given the high prevalence of BPH among elderly men, pinpointing those at elevated risk can aid in early intervention and effective management. This study aimed to explore that polygenic risk score (PRS) is effective in predicting benign prostatic hyperplasia (BPH) incidence, prognosis and risk of operation in Han Chinese. METHODS: A retrospective cohort study included 12,474 male participants (6,237 with BPH and 6,237 non-BPH controls) from the Taiwan Precision Medicine Initiative (TPMI). Genotyping was performed using the Affymetrix Genome-Wide TWB 2.0 SNP Array. PRS was calculated using PGS001865, comprising 1,712 single nucleotide polymorphisms. Logistic regression models assessed the association between PRS and BPH incidence, adjusting for age and prostate-specific antigen (PSA) levels. The study also examined the relationship between PSA, prostate volume, and response to 5-α-reductase inhibitor (5ARI) treatment, as well as the association between PRS and the risk of TURP. RESULTS: Individuals in the highest PRS quartile (Q4) had a significantly higher risk of BPH compared to the lowest quartile (Q1) (OR = 1.51, 95% CI = 1.274-1.783, p < 0.0001), after adjusting for PSA level. The Q4 group exhibited larger prostate volumes and a smaller volume reduction after 5ARI treatment. The Q1 group had a lower cumulative TURP probability at 3, 5, and 10 years compared to the Q4 group. PRS Q4 was an independent risk factor for TURP. CONCLUSIONS: In this Han Chinese cohort, higher PRS was associated with an increased susceptibility to BPH, larger prostate volumes, poorer response to 5ARI treatment, and a higher risk of TURP. Larger prospective studies with longer follow-up are warranted to further validate these findings.
Assuntos
Predisposição Genética para Doença , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Hiperplasia Prostática , Humanos , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Idoso , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos , Herança Multifatorial/genética , Povo Asiático/genética , Fatores de Risco , Inibidores de 5-alfa Redutase/uso terapêutico , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/genética , Taiwan/epidemiologia , Prognóstico , Próstata/patologia , Estratificação de Risco Genético , População do Leste AsiáticoRESUMO
Despite evidence of genetic signatures in normal tissue correlating with disease risk, prospectively identifying genetic drivers and cell types that underlie subsequent pathologies has historically been challenging. The human prostate is an ideal model to investigate this phenomenon because it is anatomically segregated into three glandular zones (central, peripheral, and transition) that develop differential pathologies: prostate cancer in the peripheral zone (PZ) and benign prostatic hyperplasia (BPH) in the transition zone (TZ), with the central zone (CZ) rarely developing disease. More specifically, prostatic basal cells have been implicated in differentiation and proliferation during prostate development and regeneration; however, the contribution of zonal variation and the critical role of basal cells in prostatic disease etiology are not well understood. Using single-cell RNA sequencing of primary prostate epithelial cultures, we elucidated organ-specific, zone-specific, and cluster-specific gene expression differences in basal cells isolated from human prostate and seminal vesicle (SV). Aggregated analysis identified ten distinct basal clusters by Uniform Manifold Approximation and Projection. Organ specificity compared gene expression in SV with the prostate. As expected, SV cells were distinct from prostate cells by clustering, gene expression, and pathway analysis. For prostate zone specificity, we identified two CZ-specific clusters, while the TZ and PZ populations clustered together. Despite these similarities, differential gene expression was identified between PZ and TZ samples that correlated with gene expression profiles in prostate cancer and BPH, respectively. Zone-specific profiles and cell type-specific markers were validated using immunostaining and bioinformatic analyses of publicly available RNA-seq datasets. Understanding the baseline differences at the organ, zonal, and cellular level provides important insight into the potential drivers of prostatic disease and guides the investigation of novel preventive or curative treatments. Importantly, this study identifies multiple prostate basal cell populations and cell type-specific gene signatures within prostate basal epithelial cells that have potential critical roles in driving prostatic diseases. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Hiperplasia Prostática , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Transcriptoma , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Células Epiteliais/patologia , Análise de Sequência de RNARESUMO
HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration-resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher-grade tumors, although no significant association between HOXB13 expression and recurrence or disease-specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor-negative castration-resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non-prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration-resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Animais , Humanos , Masculino , Camundongos , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Próstata/patologia , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Reino UnidoRESUMO
Prostate cancer is one of the most prevalent and, upon metastasis, deadliest cancers in men. Timely identification is essential for effective treatment. Furthermore, accurate determination of prostatic origin is crucial for personalized therapy once the cancer has spread. However, current prostate cancer screening methods are lacking. A recent article in The Journal of Pathology addresses this issue by utilizing an improved antibody to reevaluate HOXB13 as a lineage marker for prostate cancer. The study's findings support the concept that, despite decreased expression in advanced prostate cancer, HOXB13 remains highly suitable for determining prostatic origin due to its androgen receptor independence, high specificity, and sensitivity. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Detecção Precoce de Câncer , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Próstata/patologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , ImunoglobulinasRESUMO
Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a Srd5a2-/- mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)+ LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase , Células Epiteliais , Receptor alfa de Estrogênio , Proteínas de Membrana , Camundongos Knockout , Próstata , Hiperplasia Prostática , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Masculino , Animais , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Próstata/patologia , Próstata/metabolismo , Humanos , Hiperplasia Prostática/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Inibidores de 5-alfa Redutase/farmacologia , Proliferação de Células , Modelos Animais de Doenças , Diferenciação Celular , Sintomas do Trato Urinário Inferior/patologia , Sintomas do Trato Urinário Inferior/metabolismoRESUMO
Biofluids contain molecules in circulation and from nearby organs that can be indicative of disease states. Characterizing the proteome of biofluids with DIA-MS is an emerging area of interest for biomarker discovery; yet, there is limited consensus on DIA-MS data analysis approaches for analyzing large numbers of biofluids. To evaluate various DIA-MS workflows, we collected urine from a clinically heterogeneous cohort of prostate cancer patients and acquired data in DDA and DIA scan modes. We then searched the DIA data against urine spectral libraries generated using common library generation approaches or a library-free method. We show that DIA-MS doubles the sample throughput compared to standard DDA-MS with minimal losses to peptide detection. We further demonstrate that using a sample-specific spectral library generated from individual urines maximizes peptide detection compared to a library-free approach, a pan-human library, or libraries generated from pooled, fractionated urines. Adding urine subproteomes, such as the urinary extracellular vesicular proteome, to the urine spectral library further improves the detection of prostate proteins in unfractionated urine. Altogether, we present an optimized DIA-MS workflow and provide several high-quality, comprehensive prostate cancer urine spectral libraries that can streamline future biomarker discovery studies of prostate cancer using DIA-MS.
Assuntos
Neoplasias da Próstata , Proteoma , Proteômica , Humanos , Masculino , Neoplasias da Próstata/urina , Neoplasias da Próstata/diagnóstico , Proteoma/análise , Proteômica/métodos , Próstata/metabolismo , Próstata/patologia , Biblioteca de Peptídeos , Biomarcadores Tumorais/urina , Espectrometria de Massas em Tandem/métodos , Fluxo de TrabalhoRESUMO
Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.
Assuntos
Doenças Autoimunes , Quimiocina CCL20 , Quimiotaxia , Interleucina-17 , Prostatite , Células Th17 , Masculino , Prostatite/imunologia , Prostatite/patologia , Prostatite/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Animais , Interleucina-17/metabolismo , Interleucina-17/imunologia , Camundongos , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Macrófagos/metabolismo , Macrófagos/imunologia , Modelos Animais de Doenças , NF-kappa B/metabolismo , Transdução de Sinais , Humanos , Camundongos Endogâmicos C57BL , Próstata/patologia , Próstata/metabolismo , Próstata/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , AutoimunidadeRESUMO
Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17ß-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.
Assuntos
Estrogênios/metabolismo , Genitália Masculina/metabolismo , Receptores de Estrogênio/metabolismo , Reprodução , Animais , Aromatase/genética , Aromatase/metabolismo , Genitália Masculina/patologia , Genitália Masculina/fisiopatologia , Genótipo , Humanos , Masculino , Camundongos Knockout , Mutação , Fenótipo , Próstata/metabolismo , Próstata/patologia , Próstata/fisiopatologia , Doenças Prostáticas/metabolismo , Doenças Prostáticas/patologia , Doenças Prostáticas/fisiopatologia , Receptores de Estrogênio/deficiência , Receptores de Estrogênio/genética , Transdução de SinaisRESUMO
Magnetic resonance imaging (MRI) is increasingly used to triage patients for prostate biopsy. However, 9% to 24% of clinically significant (cs) prostate cancers (PCas) are not visible in MRI. We aimed to identify histomic and transcriptomic determinants of MRI visibility and their association to metastasis, and PCa-specific death (PCSD). We studied 45 radical prostatectomy-treated patients with csPCa (grade group [GG]2-3), including 30 with MRI-visible and 15 with MRI-invisible lesions, and 18 men without PCa. First, histological composition was quantified. Next, transcriptomic profiling was performed using NanoString technology. MRI visibility-associated differentially expressed genes (DEGs) and Reactome pathways were identified. MRI visibility was classified using publicly available genes in MSK-IMPACT and Decipher, Oncotype DX, and Prolaris. Finally, DEGs and clinical parameters were used to classify metastasis and PCSD in an external cohort, which included 76 patients with metastatic GG2-4 PCa, and 84 baseline-matched controls without progression. Luminal area was lower in MRI-visible than invisible lesions and low luminal area was associated with short metastasis-free and PCa-specific survival. We identified 67 DEGs, eight of which were associated with survival. Cell division, inflammation and transcriptional regulation pathways were upregulated in MRI-visible csPCas. Genes in Decipher, Oncotype DX and MSK-IMPACT performed well in classifying MRI visibility (AUC = 0.86-0.94). DEGs improved classification of metastasis (AUC = 0.69) and PCSD (AUC = 0.68) over clinical parameters. Our data reveals that MRI-visible csPCas harbor more aggressive histomic and transcriptomic features than MRI-invisible csPCas. Thus, targeted biopsy of visible lesions may be sufficient for risk stratification in patients with a positive MRI.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/genética , Neoplasias da Próstata/cirurgia , Prognóstico , Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Perfilação da Expressão Gênica , Estudos RetrospectivosRESUMO
The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.
Assuntos
COVID-19 , Neoplasias da Próstata , Idoso , Masculino , Humanos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Antígeno Prostático Específico , Próstata/patologia , Análise de Séries Temporais Interrompida , Pandemias , Antagonistas de Androgênios , Prostatectomia , Austrália/epidemiologia , COVID-19/epidemiologia , Programas Nacionais de SaúdeRESUMO
INTRODUCTION: In this study we used nuclear magnetic resonance spectroscopy in prostate tissue to provide new data on potential biomarkers of prostate cancer in patients eligible for prostate biopsy. MATERIAL AND METHODS: Core needle prostate tissue samples were obtained. After acquiring all the spectra using a Bruker Avance III DRX 600 spectrometer, tissue samples were subjected to routine histology to confirm presence or absence of prostate cancer. Univariate and multivariate analyses with metabolic and clinical variables were performed to predict the occurrence of prostate cancer. RESULTS: A total of 201 patients, were included in the study. Of all cores subjected to high-resolution magic angle spinning (HR-MAS) followed by standard histological study, 56 (27.8%) tested positive for carcinoma. According to HR-MAS probe analysis, metabolic pathways such as glycolysis, the Krebs cycle, and the metabolism of different amino acids were associated with presence of prostate cancer. Metabolites detected in tissue such as citrate or glycerol-3-phosphocholine, together with prostate volume and suspicious rectal examination, formed a predictive model for prostate cancer in tissue with an area under the curve of 0.87, a specificity of 94%, a positive predictive value of 80% and a negative predictive value of 84%. CONCLUSIONS: Metabolomics using HR-MAS analysis can uncover a specific metabolic fingerprint of prostate cancer in prostate tissue, using a tissue core obtained by transrectal biopsy. This specific fingerprint is based on levels of citrate, glycerol-3-phosphocholine, glycine, carnitine, and 0-phosphocholine. Several clinical variables, such as suspicious digital rectal examination and prostate volume, combined with these metabolites, form a predictive model to diagnose prostate cancer that has shown encouraging results.