RESUMO
PURPOSE: Benefits of docetaxel-based neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP) remain largely unknown. We explored whether docetaxel-based NCHT would bring pathological benefits and improve biochemical progression-free survival (bPFS) over neoadjuvant hormonal therapy (NHT) in locally advanced prostate cancer. MATERIALS AND METHODS: A randomized trial was designed recruiting 141 locally advanced, high-risk prostate cancer patients who were randomly assigned at the ratio of 2:1 to the NCHT group (75 mg/m2 body surface area every 3 weeks plus androgen deprivation therapy for 6 cycles) and the NHT group (androgen deprivation therapy for 24 weeks). The primary end point was 3-year bPFS. Secondary end points were pathological response including pathological downstaging and minimal residual disease rates. RESULTS: The NCHT group showed significant benefits in 3-year bPFS compared to the NHT group (29% vs 9.5%, P = .002). At a median follow-up of 53 months, the NCHT group achieved a significantly longer median bPFS time than the NHT group (17 months vs 14 months). No significant differences were found between the 2 groups in pathological downstaging and minimal residual disease rates. CONCLUSIONS: NCHT plus RP achieved significant bPFS benefits when compared with NHT plus RP in high-risk, locally advanced prostate cancer. A larger cohort with longer follow-up duration is essential in further investigation.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/cirurgia , Docetaxel , Terapia Neoadjuvante , Antagonistas de Androgênios/uso terapêutico , Estudos Prospectivos , Androgênios , Neoplasia Residual/cirurgia , Prostatectomia , Antígeno Prostático EspecíficoRESUMO
BACKGROUND: The precise staging and proper management of high-risk prostate cancer (PCa) continues to be a challenge. We aimed to demonstrate the prognostic value of baseline prostate-specific membrane antigen-ligand positron emission tomography/computed tomography (PSMA-PET/CT) in high-risk, nonmetastatic PCa patients who received neoadjuvant hormonal or chemohormonal treatment followed by radical prostatectomy (RP). METHODS: We performed retrospective analyses of 70 patients with high-risk, nonmetastatic PCa confirmed by biopsy between 2018 and 2021. All patients underwent neoadjuvant therapy followed by RP and pelvic lymph node dissection (PLND); PSMA-PET/CT was performed before initiation of neoadjuvant therapy. Acquired image information and clinical characteristics/outcomes were examined for possible associations. RESULTS: Among 70 high-risk PCa patients, median age was 69 years old and median prostate specific antigen (PSA) at presentation was 58.5 ng/mL. Thirty (42.9%) patients had uptake of the PSMA tracer only in the primary PCa lesions and 40 (57.1%) patients had PSMA-positive lesions in regional or distant sites. Sixteen (32%) localized PCa patients defined by pre-PET magnetic resonance imaging were found to have locally advanced PCa based on PSMA-PET/CT. Fifteen (30%) localized PCa patients and 7 (35%) locally advanced PCa patients were upstaged to metastatic PCa. The sensitivity and specificity of PSMA-PET/CT for the detection of lymph node involvement were 90.9% and 69.5%, respectively, with a positive prediction value of 35.7% and negative prediction value of 97.6%. The diagnostic accuracy was 72.9%. Univariate analysis showed upstaging, tumor stage, and metastasis location based on PSMA-PET/CT are predictors to PSA persistence after surgery, while multivariate logistic regression analysis showed only the tumor stage based on PSMA-PET/CT remained an independent predictor of the outcome. CONCLUSIONS: This study further highlights the accuracy and necessity of PSMA-PET/CT in newly diagnosed, high-risk, nonmetastatic PCa patients.
Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Idoso , Próstata/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Terapia Neoadjuvante , Estudos Retrospectivos , Radioisótopos de Gálio , Metástase Linfática/patologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/cirurgia , ProstatectomiaRESUMO
AIMS: To propose a novel S.I.S technique during the robotic-assisted radical prostatectomy (RARP), encompassing pubourethral suspension, posterior wall intensification, and bladder neck stripping, and to present functional and oncological outcomes with a special focus on long-term continence. METHODS: From January 1, 2018, to December 31, 2019, consecutive patients who underwent RARP were retrospectively investigated and separated into the S.I.S group and the conventional group. Preoperative patient characteristics, tumor status, and perioperative parameters were collected, followed by the assessment of self-reported status on continence, using an International Consultation on Incontinence Modular Questionnaire-urinary incontinence short form (ICIQ-UI-SF). Statistical comparisons were performed on variables between the two surgery groups, and multivariate logistic regression analysis was used to determine predictive factors for postoperative incontinence severity. RESULTS: A total of 602 subjects were analyzed with a median follow-up of 24 months. There was no significant difference regarding baseline characteristics and perioperative parameters, except for a more advanced tumor stage in the S.I.S group. The application of the S.I.S technique did not jeopardize the positive surgical margin rate at the bladder neck or long-term tumor control. Notably, the patient-reported degree of incontinence was significantly reduced with the assistance of S.I.S technique, as evidenced by the diminished severe-to-very severe cases. On multivariate analysis, both preoperative body mass index and use of S.I.S modification were independent predictive factors for the long-term incontinence severity. CONCLUSIONS: The application of S.I.S technique during RARP is feasible and superior compare with the conventional approach, with a significantly alleviated long-term incontinence severity, without compromising cancer control.
Assuntos
Procedimentos Cirúrgicos Robóticos , Incontinência Urinária , Masculino , Humanos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/métodos , Estudos Retrospectivos , Resultado do Tratamento , Bexiga Urinária/cirurgia , Prostatectomia/efeitos adversos , Prostatectomia/métodosRESUMO
BACKGROUND: Prostate cancer (PCa) is the second most prevalent cancer in males worldwide, yet detecting PCa and its metastases remains a major challenging task in clinical research setups. The present study aimed to characterize the metabolic changes underlying the PCa progression and investigate the efficacy of related metabolic panels for an accurate PCa assessment. METHODS: In the present study, 75 PCa subjects, 62 PCa patients with bone metastasis (PCaB), and 50 benign prostatic hyperplasia (BPH) patients were enrolled, and we performed a cross-sectional metabolomics analysis of serum samples collected from these subjects using a 1H nuclear magnetic resonance (NMR)-based metabolomics approach. RESULTS: Multivariate analysis revealed that BPH, PCa, and PCaB groups showed distinct metabolic divisions, while univariate statistics integrated with variable importance in the projection (VIP) scores identified a differential metabolite series, which included energy, amino acid, and ketone body metabolism. Herein, we identified a series of characteristic serum metabolic changes, including decreased trends of 3-HB and acetone as well as elevated trends of alanine in PCa patients compared with BPH subjects, while increased levels of 3-HB and acetone as well as decreased levels of alanine in PCaB patients compared with PCa. Additionally, our results also revealed the metabolic panels of discriminant metabolites coupled with the clinical parameters (age and body mass index) for discrimination between PCa and BPH, PCaB and BPH, PCaB and PCa achieved the AUC values of 0.828, 0.917, and 0.872, respectively. CONCLUSIONS: Overall, our study gave successful discrimination of BPH, PCa and PCaB, and we characterized the potential metabolic alterations involved in the PCa progression and its metastases, including 3-HB, acetone and alanine. The defined biomarker panels could be employed to aid in the diagnosis and classification of PCa in clinical practice.
Assuntos
Hiperplasia Prostática , Neoplasias da Próstata , Acetona , Alanina , Estudos Transversais , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Metabolômica/métodos , Hiperplasia Prostática/diagnóstico , Neoplasias da Próstata/patologia , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
OBJECTIVES: TP53 loss-of-function is commonly found in aggressive prostate cancer. However, a highly-efficient therapy for this tumor subtype is still lacking. In this study, we investigated the relationship between TP53 mutation status and autophagy in prostate cancer and assessed the efficacy of autophagy inhibitors on TP53-deficient tumors. METHODS: We first evaluated the expression patterns of p53 and autophagy-related proteins, namely LC3B, ULK1 and BECLIN1, as well as their relationship in treatment-naïve and castration-resistant prostate cancer specimens through immunohistochemistry. Subsequently, we generated a Trp53-deleted genetically-engineered mouse model, established prostate tumor organoid lines from the mice and assessed the efficacy of autophagy inhibitors in overcoming Enzalutamide resistance in the tumor organoid model. We also investigated the impact of TP53 re-expression in modulating responses to autophagy inhibitors using LNCaP cell line, which harbored a TP53 missense mutation. Lastly, we attempted to identify potential autophagy-related genes that were crucial for TP53-deficient tumor maintenance. RESULTS: TP53 loss-of-function was associated with increased levels of autophagy-related proteins in aggressive prostate cancers and Trp53-deleted genetically-engineered mouse-derived tumors. Moreover, the generated androgen receptor-independent tumor organoids were highly vulnerable to autophagy inhibition. Upon TP53 re-expression, not only did the surviving LNCaP cells demonstrate resistance, but they also showed growth advantage in response to autophagy inhibition. Lastly, PEX14, an important peroxisomal regulator was differentially upregulated in aggressive tumors with TP53 loss-of-function mutations, thus implying the importance of peroxisome turnover in this tumor subtype. CONCLUSION: Our results support the potential use of autophagy inhibitors in prostate cancers that contain TP53 loss-of-function mutations.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Proteína Supressora de Tumor p53 , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular Tumoral , Humanos , Imuno-Histoquímica , Mutação com Perda de Função , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/patologia , Proteína Supressora de Tumor p53/genéticaRESUMO
Advances in bioimaging technologies have led to unprecedented findings of novel biological processes at the nanoscale. However, there remains an ever-lasting demand for the improvement of spatiotemporal resolution, multiplexity, and smart responsiveness of bioimaging in living systems. In recent decades, self-assembled DNA nanostructures with highly programmable shape, nanometer addressability, and structural responsiveness have shown great promise in developing nanoscale probes and labels for high-performance bioimaging. Here, we briefly review the recent progress in structural DNA nanotechnology and the development of DNA frameworks, and summarize the bioimaging strategies empowered by DNA nanotechnology. We highlight the advantages of DNA nanostructures in overcoming the bottlenecks in bioimaging and discuss the challenges and opportunities in this field.
Assuntos
DNA/química , Diagnóstico por Imagem , Nanoestruturas/química , Nanotecnologia , Animais , HumanosRESUMO
The HOX genes are a group of highly conserved Homeobox-containing genes that control the body plan organization during development. However, their contributions to tumorigenesis and tumor progression remain uncertain and controversial. Here we provided evidence of tumor-suppressive activity of HOXD13 in prostate cancer. HOXD13 depletion contributes to more aggressiveness of prostate cancer cells in vitro and in vivo. These effects were corroborated in a metastatic mice model, where we observed more bone metastatic lesions formed by prostate cancer cells with HOXD13 ablation. Mechanistically, HOXD13 prevents BMP4-induced epithelial-mesenchymal transition (EMT) by inhibiting mothers against decapentaplegic homolog 1 (SMAD1) transcription. Both bioinformation and our tissue microarray cohort data show that HOXD13 expression inversely correlated in advanced prostate cancer patient specimens. Our findings establish HOXD13 as a negative regulator of prostate cancer progression and metastasis by preventing BMP4/SMAD1 signaling, and potentially suggest new strategies for targeting metastatic prostate cancer.
Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias da Próstata/patologia , Proteína Smad1/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismoRESUMO
DNA aptamers and framework DNA nanostructures are emerging DNA materials with many appealing biological applications including biosensing, bioimaging, drug delivery, and so forth. When placed in physiological fluids, they inevitably encounter biomolecules (majorly proteins) and form complexes that largely affect their biological fate. Nevertheless, little is known regarding the quantitative profile of proteins that adsorb to DNA aptamers and DNA nanostructures in biological environments, and there are no potent strategies to regulate protein profiles. Herein, we performed a proteomic analysis to profile proteins that bind to DNA aptamers (Sgc8c and SYLC3) and nanostructures (a tetrahedral DNA nanostructure and a DNA origami rod) in human serum using liquid chromatography-mass spectrometry (LC-MS). Dozens to hundreds of proteins were identified with each DNA material exhibiting highly distinctive profiles. It was also revealed that the origin of serum (from healthy donor vs from prostate cancer patients) causes significant differences in profiles of bound proteins. Furthermore, we demonstrated that the protein profile may be regulated by tethering a layer of single-stranded DNA (polythymine) onto the DNA origami rod to alleviate the adsorption of complement-associated proteins, which significantly reduced its sequestration by macrophages. Taken together, this study has provided qualitative and quantitative proteomic profiles regarding serum proteins that adsorb to various DNA materials and have demonstrated that the composition of interacted proteins may be regulated toward better biological performances.
Assuntos
Aptâmeros de Nucleotídeos , Nanoestruturas , DNA , Humanos , Proteínas , ProteômicaRESUMO
PURPOSE: We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing. MATERIALS AND METHODS: A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers. RESULTS: We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence of PTEN alteration was found in viscerally metastatic prostate cancer compared with bone-only metastatic prostate cancer (PTEN, 9.09% vs 2.08%, p=0.105). When comparing viscerally metastatic prostate cancer according to the metastatic sites, AR alteration rarely occurs in hepatically metastatic prostate cancer, which stood in great contrast to the high alteration frequency in hepatically metastatic prostate cancer (0.0% vs 42.1%, p=0.01). For overall DNA damage response alteration, the highest frequency was found in hepatically metastatic prostate cancer (63.2%). CONCLUSIONS: Through genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of AR alterations in pulmonarily metastatic prostate cancer without liver involvement, high prevalence of DNA damage response pathway deficiency in hepatically metastatic prostate cancer and high PTEN alteration rates in viscerally metastatic prostate cancer. We discovered the genomic diversity among bone-only metastatic prostate cancer, hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint at potential therapeutic targets in both hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement.
Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Proteína BRCA2/genética , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Quinases Ciclina-Dependentes/genética , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , PTEN Fosfo-Hidrolase/genética , Receptores Androgênicos/genética , Proteínas de Ligação a Retinoblastoma/genética , Estudos Retrospectivos , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
PURPOSE: To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. MATERIALS AND METHODS: A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, TP53 and RB1. RESULTS: We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of CDK12 (27.2% vs 6.4%, p <0.001) and FOXA1 (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. CONCLUSIONS: Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of CDK12 and FOXA1 were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.
Assuntos
DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Análise de Sequência de DNA , Idoso , Antagonistas de Androgênios/uso terapêutico , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Estudos RetrospectivosRESUMO
PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA2/genética , Biópsia , Carboplatina/farmacologia , Cisplatino/farmacologia , Quinases Ciclina-Dependentes/genética , Análise Mutacional de DNA , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Recombinação Homóloga/genética , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/secundário , Estudos RetrospectivosRESUMO
BACKGROUND: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. PATIENTS AND METHODS: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. RESULTS: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%-7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. CONCLUSIONS: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients' response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.
Assuntos
DNA Tumoral Circulante , Neoplasias de Próstata Resistentes à Castração , Povo Asiático/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Dano ao DNA , Reparo do DNA , Docetaxel/uso terapêutico , Genômica , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo.
Assuntos
Caderinas/fisiologia , Polaridade Celular , Próstata/citologia , Fuso Acromático/fisiologia , Animais , Caderinas/genética , Carcinogênese , Divisão Celular , Linhagem Celular , Proliferação de Células , Modelos Animais de Doenças , Epitélio , Deleção de Genes , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos Knockout , Neoplasias da Próstata/patologiaRESUMO
Tumor metabolic characteristics have been associated with the progression of prostate cancer (PCa), but little information is available regarding the metabolic alterations from hormone-sensitive (HSPC) to castration-resistant PCa (CRPC). In this study, therefore, we investigated the metabolic profiles in prostate tissues from patients with benign prostatic hyperplasia (BPH), HSPC, and CRPC using a 1H NMR-based metabolomics approach. The results show that clear separations in metabolic patterns were obtained in prostate tissues among BPH, HSPC, and CRPC; however, CRPC may induce a metabolic shift toward BPH, mainly involving amino acid metabolism, choline metabolism, and the Warburg effect. Based on these metabolic changes, we identified potential biomarker panels for the discrimination between BPH vs HSPC, BPH vs CRPC, and HSPC vs CRPC with the AUC values of 0.995, 0.972, and 0.937, respectively. Collectively, tissue-based metabolomics analysis not only identifies the altered metabolic pathways during PCa progression but also has the potential to help the classification and diagnosis of PCa in clinical practice.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Biópsia , Hormônios , Humanos , Masculino , Metabolômica , Neoplasias da Próstata/diagnóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Castration-resistant prostate cancer (CRPC) causes most of the deaths in patients with prostate cancer (PCa). The androgen receptor (AR) axis plays an important role in castration resistance. Emerging studies showed that the lysine demethylase KDM4B is a key molecule in AR signaling and turnover, and autophagy plays an important role in CRPC. However, little is known about whether KDM4B promotes CRPC progression by regulating autophagy. Here we used an androgen-independent LNCaP (LNCaP-AI) cell line to assay aberrant KDM4B expression using qPCR and western blot analysis and investigated the function of KDM4B in regulating cell proliferation. We found that KDM4B was markedly increased in LNCaP-AI cells compared with LNCaP cells. KDM4B level was significantly correlated with the Gleason score in PCa tissues. In vitro, KDM4B overexpression in CRPC cells promoted cell proliferation, whereas knockdown of KDM4B significantly inhibited cell proliferation. Upregulated KDM4B contributed to activate Wnt/ß-catenin signaling and autophagy. Moreover, KDM4B activated autophagy by regulating the Wnt/ß-catenin signaling. Finally, we demonstrated that autophagy inhibition attenuated KDM4B-induced CRPC cell proliferation. Our results provided novel insights into the function of KDM4B-driven CRPC development and indicated that KDM4B may be served as a potential target for CRPC therapy.
Assuntos
Autofagia/genética , Proliferação de Células/genética , Histona Desmetilases com o Domínio Jumonji/genética , Neoplasias de Próstata Resistentes à Castração/genética , Regulação para Cima/genética , Idoso , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Células PC-3 , Receptores Androgênicos/genética , Ativação Transcricional/genética , Via de Sinalização Wnt/genéticaRESUMO
Intratumoral heterogeneity remains as a major challenge in the treatment resistance of prostate cancer. Understanding the mechanism of prostate cancer heterogeneity is essential for developing effective therapies. In this study, we reported the heterogeneous activation of Wnt/ß-catenin signaling in prostate cancer. We developed a Wnt/ß-catenin signaling reporting system to directly characterize the differences between Wnt/ß-catenin signaling active (GFP+) and inactive (GFP-) cells. Compared to GFP- cells, GFP+ cells demonstrated cancer stem cell properties with higher colony formation efficiency, slower cell cycle, higher resistance to docetaxel and higher expression of cancer stem cell markers. In addition, we found that Wnt/ß-catenin signaling is negatively correlated with H3K27me3 levels. Further studies demonstrated that Wnt/ß-catenin signaling affected H3K27me3 levels by regulating the expression of KDM6A, one of the H3K27me3 demethylases. H3K27me3 suppressed Wnt/ß-catenin signaling by directly silencing LEF1 promoter. Together, our studies suggest that Wnt/ß-catenin signaling makes a major contribution to prostate cancer heterogeneity and targeting both Wnt/ß-catenin signaling active and inactive populations is essential for developing more effective therapies.
Assuntos
Neoplasias da Próstata/metabolismo , Via de Sinalização Wnt , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Metilação/efeitos dos fármacos , Células PC-3 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Relação Estrutura-Atividade , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Prostate cancer most frequently metastasizes to bone, resulting in abnormal bone metabolism and the release of components into the blood stream. Here, we evaluated the capacity of convolutional neural networks (CNNs) to use Raman data for screening of prostate cancer bone metastases. We used label-free surface-enhanced Raman spectroscopy (SERS) to collect 1281 serum Raman spectra from 427 patients with prostate cancer, and then we constructed a CNN based on LetNet-5 to recognize prostate cancer patients with bone metastases. We then used 5-fold cross-validation method to train and test the CNN model and evaluated its actual performance. Our CNN model for bone metastases detection revealed a mean training accuracy of 99.51% ± 0.23%, mean testing accuracy of 81.70% ± 2.83%, mean testing sensitivity of 80.63% ± 5.07%, and mean testing specificity of 82.82% ± 2.94%.
Assuntos
Neoplasias Ósseas/sangue , Detecção Precoce de Câncer , Proteínas de Neoplasias/sangue , Neoplasias da Próstata/sangue , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Humanos , Masculino , Nanopartículas/química , Proteínas de Neoplasias/isolamento & purificação , Redes Neurais de Computação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Análise Espectral RamanRESUMO
BACKGROUND: To evaluate the value of the serum neuroendocrine differentiation (NED) markers in helping to select the best treatment sequence of abiraterone acetate (AA) and docetaxel-prednisone (DP) in mCRPC. METHODS: Eighty-eight mCRPC patients were identified (42 in the DP-to-AA group and 46 in the AA-to-DP group). The serum levels of NED markers were measured before the first-line treatment in 88 patients and also before and after DP therapy in 38 patients. We determined their impact on OS, radiographic progression-free survival (rPFS), and PSA-PFS. RESULTS: In men with an elevation of at least one NED marker (n = 46) before the first-line treatment, those who received AA and then DP had significantly better worse OS (21.7 months [95% CI 21.0-22.4] vs 19.9 months (95% CI 15.3-24.5); P = 0.023. In a multivariate Cox regression analysis, treatment sequencing selection (selecting DP-AA rather than AA-DP) independently predicted OS (HR 0.4, 95% CI 0.2-0.9, P = 0.035) in patients with an elevation of at least one NED marker. However, in the subgroup without NED marker elevation, there was no significant difference in clinical outcomes between AA-DP and DP-AA groups (all P > 0.05). In the group with continued NED marker evaluation during DP treatment, patients with higher baseline NED markers and obtaining PSA response to DP were more inclined to experience NED markers decline. CONCLUSIONS: Elevated pretreatment serum NED markers might indicate mCRPC patients would get better clinical outcomes from DP-AA than AA-DP. In contrast, those without NED marker elevation had similar outcomes regardless of which agent was chosen first. mCRPC patients with elevated NED markers and chemotherapy response were more inclined to obtain NED markers decline during DP therapy, which could account for this phenomenon.
Assuntos
Acetato de Abiraterona/administração & dosagem , Antígenos de Diferenciação/sangue , Docetaxel/administração & dosagem , Prednisona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração , Idoso , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Monitoramento de Medicamentos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Seleção de Pacientes , Intervalo Livre de Progressão , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
BACKGROUND: Chronic lymphocytic leukemia is a malignancy with good prognosis. However, the incidence of secondary tumors increases every year after the diagnosis of chronic lymphotcytic leukemia. One of the induced secondary tumors is prostate cancer. For high-risk prostate cancer in particular, the standard therapy is radical prostatectomy and extended lymphadenectomy, which carries high risks of lymphatic leakage and reduced quality of life. Currently, there has been no study reporting the necessity of extended lymphadenectomy for high-risk prostate cancer in patients with chronic lymphocytic leukemia. CASE PRESENTATION: We reported two cases with concomitant high-risk prostate cancer and chronic lymphocytic leukemia. The first patient was a 60-year-old male diagnosed with synchronous prostate cancer and chronic lymphocytic leukemia. The second patient was a 70-year-old male initially presented with chronic lymphocytic leukemia alone but was then diagnosed with high-risk prostate cancer nine years later. Both patients received neoadjuvant androgen deprivation therapy and robot-assisted radical prostatectomy. The first patient underwent extended lymphadenectomy and developed prolonged postoperative lymphatic cyst. Histology showed chronic lymphocytic leukemia infiltration in resected lymph nodes. Serum prostate-specific antigen levels at one and 13 months post-operation were both 0.01 ng/ml. The second patient received positron emission tomography/computed tomography before androgen deprivation therapy, which showed mild fluorodeoxyglucose-avidity in lymph nodes across the entire body. Lymph node biopsy showed only chronic lymphocytic leukemia. The patient experienced no postoperative complication. Serum prostate-specific antigen levels at one and nine months post-operation were both 0.02 ng/ml. CONCLUSIONS: Extended lymphadenectomy may not be necessary for patients with concomitant high-risk prostate cancer and chronic lymphocytic leukemia, but such patients must undergo thorough preoperative assessment and mindful postoperative follow-up. Positron emission tomography/computed tomography may be valuable in detecting nodal metastases. A lymph node biopsy is necessary for patients with an ambiguous positron emission tomography/computed tomography in the metastatic involvement of lymph node.