RESUMO
Extracellular vesicles (EVs) contain various types of molecules including micro-RNAs, so isolating EVs can be an effective way to analyze and diagnose diseases. A lot of micro-RNAs have been known in relation to prostate cancer (PCa), and we evaluate miR-21, miR-141, and miR-221 in EVs and compare them with prostate-specific antigen (PSA). EVs were isolated from plasma of 38 patients with prostate cancer and 8 patients with benign prostatic hyperplasia (BPH), using a method that showed the highest recovery of RNA. Isolation of EVs concentrated micro-RNAs, reducing the cycle threshold (Ct) value of RT-qPCR amplification of micro-RNA such as miR-16 by 5.12 and miR-191 by 4.65, compared to the values before EV isolation. Normalization of target micro-RNAs was done using miR-191. For miR-221, the mean expression level of patients with localized PCa was significantly higher than that of the control group, having 33.45 times higher expression than the control group (p < 0.01). Area under curve (AUC) between BPH and PCa for miR-221 was 0.98 (p < 0.0001), which was better than AUC for prostate-specific antigen (PSA) level in serum for the same patients. The levels of miR-21 and miR-141 in EVs did not show significant changes in patients with PCa compared to the control group in this study. This study suggests isolating EVs can be a helpful approach in analyzing micro-RNAs with regard to disease.
Assuntos
Vesículas Extracelulares/metabolismo , MicroRNAs/sangue , MicroRNAs/metabolismo , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Área Sob a Curva , Linhagem Celular Tumoral , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Metástase Neoplásica , Antígeno Prostático Específico/biossíntese , Hiperplasia Prostática/sangueRESUMO
To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high-risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of biochemical recurrence (BCR) with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8+ cell) and CD204-positive M2-like macrophage (CD204+ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan-Meier analysis and competing risks regression. A higher CD8+ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204+ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8+ and CD204+ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8+ and CD204+ cell infiltration is useful to predict the prognosis.
Assuntos
Linfócitos T CD8-Positivos/citologia , Macrófagos/metabolismo , Receptores Depuradores Classe A/metabolismo , Idoso , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Próstata/patologia , Antígeno Prostático Específico/biossíntese , Prostatectomia , Neoplasias da Próstata , Análise de Regressão , Estudos Retrospectivos , Risco , Glândulas Seminais/patologia , Microambiente TumoralRESUMO
Diabetic men have decreased risk for prostate cancer (PCa) overall and lower PSA compared to non-diabetics. This may affect the outcomes of PSA-based screening. We investigated the effect of PSA-based screening at 4-year intervals on PCa incidence and mortality separately among users and non-users of antidiabetic medication with the hypothesis that screening would detect less low-grade cancer and more high-grade cancer in diabetic men. A cohort of 80,458 men from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC) were linked to national prescription database to obtain information on antidiabetic medication purchases. PCa risk and mortality were compared between the FinRSPC screening arm (SA) and the control arm (CA) separately among users and non-users of antidiabetic medication. Among antidiabetic medication users median PSA was lower than in non-users (0.93 and 1.09 ng/ml, respectively, P for difference = 0.001). Screening increased overall PCa incidence compared to CA after the first screen both among medication users and non-users (HR 1.31, 95% CI 1.08-1.60 and HR 1.55, 95% CI 1.44-1.66, respectively). On the second and third screen the difference between SA and CA attenuated only among medication users. Detection of Gleason 6 tumors was lower among medication users, whereas no difference was observed in detection of Gleason 8-10 cancers. Concordantly, screening affected PCa mortality similarly regardless of antidiabetic medication use (HR 0.38, 95% CI 0.14-1.07 and HR 0.19, 95% CI 0.11-0.33 among users and non-users after three screens, respectively. P for difference = 0.18). Median PSA is lower in men using antidiabetic drugs than among non-users. Systematic PSA screening detects less low-risk tumors among medication users, whereas detection of high-risk tumors and mortality effects are similar regardless of medication use. This suggests that antidiabetic medication users may form a suitable target group for PCa screening, with less screening-related overdiagnosis of indolent tumors.
Assuntos
Detecção Precoce de Câncer/estatística & dados numéricos , Hipoglicemiantes/uso terapêutico , Neoplasias da Próstata/diagnóstico , Idoso , Bases de Dados Factuais , Complicações do Diabetes/diagnóstico , Progressão da Doença , Finlândia , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/complicações , Neoplasias da Próstata/epidemiologia , Risco , Resultado do TratamentoRESUMO
Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Acetilação , Antagonistas de Androgênios/farmacocinética , Antagonistas de Receptores de Andrógenos/uso terapêutico , Animais , Antineoplásicos/farmacocinética , Morte Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular , Progressão da Doença , Docetaxel/farmacocinética , Interações Medicamentosas , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Nus , Proteínas de Neoplasias/metabolismo , Transplante de Neoplasias , Antígeno Prostático Específico/biossíntese , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Testosterona/administração & dosagem , Testosterona/antagonistas & inibidores , Testosterona/metabolismo , Tubulina (Proteína)/efeitos dos fármacos , Tubulina (Proteína)/metabolismoRESUMO
The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53-74) years, 0.28 (0.20-0.79) ng/ml and 7.7 (2.3-38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30-100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule.
Assuntos
Fracionamento da Dose de Radiação , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/sangue , Neoplasias da Próstata/radioterapia , Terapia de Salvação/métodos , Idoso , Androgênios/metabolismo , Intervalo Livre de Doença , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Cinética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Próstata/efeitos da radiação , Prostatectomia , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Hipofracionamento da Dose de Radiação , Radioterapia Adjuvante , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. METHODS: To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. RESULTS: Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). CONCLUSIONS: Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.
Assuntos
Calicreínas/biossíntese , Neoplasias da Próstata/enzimologia , Idoso , Humanos , Imuno-Histoquímica , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Fenótipo , Prognóstico , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genética , Regulador Transcricional ERG/biossíntese , Regulador Transcricional ERG/genética , Regulador Transcricional ERG/metabolismoRESUMO
Purpose of this study was to evaluate the diagnostic performance of T1 relaxation time (T1) for differentiating prostate cancer (PCa) from benign tissue as well as high- from low-grade PCa. Twenty-three patients with suspicion for PCa were included in this prospective study. 3 T MRI including a Modified Look-Locker inversion recovery sequence was acquired. Subsequent targeted and systematic prostate biopsy served as a reference standard. T1 and apparent diffusion coefficient (ADC) value in PCa and reference regions without malignancy as well as high- and low-grade PCa were compared using the Mann-Whitney U test. The performance of T1, ADC value, and a combination of both to differentiate PCa and reference regions was assessed by receiver operating characteristic (ROC) analysis. T1 and ADC value were lower in PCa compared to reference regions in the peripheral and transition zone (p < 0.001). ROC analysis revealed high AUCs for T1 (0.92; 95%-CI, 0.87-0.98) and ADC value (0.97; 95%-CI, 0.94 to 1.0) when differentiating PCa and reference regions. A combination of T1 and ADC value yielded an even higher AUC. The difference was statistically significant comparing it to the AUC for ADC value alone (p = 0.02). No significant differences were found between high- and low-grade PCa for T1 (p = 0.31) and ADC value (p = 0.8). T1 relaxation time differs significantly between PCa and benign prostate tissue with lower T1 in PCa. It could represent an imaging biomarker for PCa.
Assuntos
Processamento de Imagem Assistida por Computador/métodos , Próstata/diagnóstico por imagem , Neoplasias da Próstata/diagnóstico por imagem , Idoso , Área Sob a Curva , Biópsia , Imagem de Difusão por Ressonância Magnética , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/biossíntese , Curva ROC , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC). METHODS: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC. RESULTS: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036). CONCLUSIONS: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC.
Assuntos
Calicreínas/biossíntese , Antígeno Prostático Específico/biossíntese , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Análise de SobrevidaRESUMO
Prostate cancer (PC) commonly metastasizes to the bone, resulting in pathologic fractures and poor prognosis. CCN3/nephroblastoma overexpressed is a secreted protein with a known role in promoting breast cancer metastasis to bone. However, in PC, CCN3 has been ascribed conflicting roles; some studies suggest that CCN3 promotes PC metastasis, whereas others argue a tumor suppressor role for CCN3 in this disease. Indeed, in the latter context, CCN3 has been shown to sequester the androgen receptor (AR) and suppress AR signaling. In the present study, we demonstrate that CCN3 functions as a bone-metastatic mediator, which is dependent on its C-terminal domain for this function. Analysis of tissue microarrays comprising >1500 primary PC patient radical prostatectomy specimens reveals that CCN3 expression correlates with aggressive disease and is negatively correlated with the expression of prostate-specific antigen, a marker of AR signaling. Together, these findings point to CCN3 as a biomarker to predict PC aggressiveness while providing clarity on its role as a functional mediator of PC bone metastasis.
Assuntos
Neoplasias Ósseas/metabolismo , Proteína Sobre-Expressa em Nefroblastoma/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Neoplasias Ósseas/secundário , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Calicreínas/biossíntese , Calicreínas/genética , Masculino , Metástase Neoplásica , Proteínas de Neoplasias , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais/genéticaRESUMO
BACKGROUND: The tyrosine kinase inhibitors (TKI), imatinib and nilotinib, are used to treat chronic myelogenous leukemia (CML). In three CML patients being monitored for urologic diseases, we observed that switching of TKI therapy affected prostate-specific antigen (PSA) titers. Urologists and other medical professionals need to be aware of the potential side-effects of drugs that patients may be receiving for other indications to modify this important prostate diseases indicator. TKIs may affect PSA titers independent of prostate growth or volume. MATERIALS AND METHODS: We followed PSA levels in urology patients who were also undergoing TKI treatment for CML. We determined the effects of nilotinib and imatinib on proliferation, AR and PSA expression in the LNCaP and 22Rv1 prostate cancer (PCa) cell lines using real-time PCR and Western blotting. RESULTS: Clinically, nilotinib and dasatinib reversibly reduced PSA titers compared to imatinib. At high doses nilotinib and imatinib both demonstrated antiproliferative effects in the PCa cells. At low doses expression of AR and PSA was decreased by both drugs, at mRNA and protein levels. Nilotinib exerted greater effects at lower doses than imatinib. CONCLUSIONS: Nilotinib down-regulates serum PSA in patients being treated for non-urological indications, potentially masking a clinical useful marker, we cannot exclude a similar but smaller effect of imatinib. Nilotinib and imatinib both decreased AR and PSA expression in PCa cell lines with the nilotinib effect evident at lower doses. Urologists must appreciate the effects of drugs provided for other diseases on PSA titers and be aware that sudden changes may not reflect underlying prostatic disease.
Assuntos
Mesilato de Imatinib/administração & dosagem , Calicreínas/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Mesilato de Imatinib/efeitos adversos , Calicreínas/biossíntese , Calicreínas/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Hiperplasia Prostática/sangue , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/biossíntese , Receptores Androgênicos/genéticaRESUMO
PURPOSE: A prostate-specific antigen (PSA) nadir <0.2 ng/mL is generally considered as tissue ablative and at low risk for recurrence. After attaining such a low PSA nadir, we analyzed risk factors for recurrence. METHODS AND MATERIALS: We identified patients from our institutionalized database with either D'Amico low- or intermediate-risk prostate cancer that was treated with either low-dose-rate prostate brachytherapy or external beam radiotherapy as monotherapy. We compared patients who attained a nadir <0.2 ng/mL and subsequently developed biochemical failure to patients who did not experience biochemical failure by using χ2 test and Student t test. Survival analysis was performed using the Kaplan-Meier method (log-rank test). RESULTS: Of 892 patients, 560 (63%) achieved a nadir <0.2 ng/mL. Only 23 (4.1%) later developed a biochemical recurrence. The 7-year Kaplan-Meier biochemical recurrence-free survival after a PSA nadir of <0.2 ng/mL was 96%. Patients who later experienced biochemical recurrence were more likely to have Cancer of the Prostate Risk Assessment Score intermediate- or high-risk cancer: (74% vs. 40%, p < 0.001). Patients were more likely to have a diagnostic PSA >6.0 ng/mL: (66% vs. 43% p < 0.001) and have a Gleason score ≥ 3 + 4: (52% vs. 34%, p = 0.005). They were also more likely to be older (p = 0.003): mean (SD) 70.3 (6.4) vs. 66.2 (6.5) and have a time to PSA nadir that was significantly shorter (p = 0.013): mean (SD) 51.8 (29.6) vs. 65.2 (25.1). CONCLUSIONS: Biochemical recurrence after attaining a PSA nadir <0.2 ng/mL is rare and more frequent in patients with intermediate risk cancer and older patients. These patients can benefit from a prolonged followup with specialized physicians.
Assuntos
Braquiterapia/métodos , Recidiva Local de Neoplasia/sangue , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/radioterapia , Medição de Risco/métodos , Idoso , Canadá/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/sangue , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos , Fatores de RiscoRESUMO
INTRODUCTION: The prostate-specific antigen (PSA) based prostate cancer (PC) screening is currently being debated. The current assessment is to understand the variability of detecting high-risk PC in a NZ cohort in comparison to a US cohort with better PSA screening facilities. Aldo-keto reductase 1C3 (AKR1C3) is known for multiple functions with a potential to regulate subsequent PSA levels. Therefore, we wish to understand the influence of tobacco smoking and the AKR1C3 rs12529 gene polymorphism in this variability. METHOD: NZ cohort (n = 376) consisted of 94% Caucasians while the US cohort consisted of African Americans (AA), n = 202, and European Americans (EA), n = 232. PSA level, PC grade and stage at diagnosis were collected from hospital databases for assigning high-risk PC status. Tobacco smoking status and the AKR1C3 rs12529 SNP genotype were considered as confounding variables. Variation of the cumulative % high-risk PC (outcome variable) with increasing PSA intervals (exposure factor) was compared between the cohorts using the Kolmogorov-Smirnov test. Comparisons were carried out with and without stratifications made using confounding variables. RESULTS: NZ cohort has been diagnosed at a significantly higher mean age (66.67± (8.08) y) compared to both AA (62.65±8.17y) and EA (64.83+8.56y); median PSA (NZ 8.90ng/ml compared to AA 6.86ng/ml and EA 5.80ng/ml); and Gleason sum (NZ (7) compared EA (6)) (p<0.05). The cumulative % high-risk PC detection shows NZ cohort with a significantly lower diagnosis rates at PSA levels between >6 - <10ng/ml compared to both US groups (p<0.05). These were further compounded significantly by smoking status and genetics. CONCLUSIONS: High-risk PCs recorded at higher PSA levels in NZ could be due to factors including lower levels of PSA screening and subsequent specialist referrals for biopsies. These consequences could be pronounced among NZ ever smokers carrying the AKR1C3 rs12529 G alleles making them a group that requires increased PSA screening attention.
Assuntos
Adenocarcinoma/genética , Membro C3 da Família 1 de alfa-Ceto Redutase/genética , Detecção Precoce de Câncer , Variação Genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Fumar/metabolismo , Ativação Metabólica/genética , Adenocarcinoma/sangue , Adenocarcinoma/enzimologia , Adenocarcinoma/etnologia , Negro ou Afro-Americano , Idoso , Diagnóstico Tardio , Europa (Continente)/etnologia , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/sangue , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/etnologia , Risco , Fumar/epidemiologia , Fumar/genética , Determinantes Sociais da Saúde , Estados Unidos , População BrancaRESUMO
BACKGROUND Bladder cancer caused by exposure to aniline dyes, chronic cystitis, and smoking is detected in approximately 70 000 new cases annually. In the USA alone, it leads to 15 000 deaths every year. In the present study, we investigated the role of 3-((4'-amino-[1,1'-biphenyl]-4-yl)amino)-4-bromo-5-oxo-2,5-dihydrofuran-2-yl acetate (ABDHFA) in the inhibition of bladder cancer cell viability. MATERIAL AND METHODS Viability of cells was examined using MTT assay and distribution of cell cycle was assessed by flow cytometry. Expression of cyclin D1, androgen, prostate-specific antigen (PSA), and miR-449a was analyzed using Western blot and quantitative real-time polymerase chain reaction assays. RESULTS The results demonstrated that ABDHFA treatment inhibited viability of UMUC3 and TCCSUP AR-positive bladder cancer cells. ABDHFA treatment led to break-down of AR in UMUC3 and TCCSUP cells after 48 h in a dose-dependent manner. Up-regulation of miR-449a by lentivirus transfection down-regulated the AR signalling pathway. In UMUC3 and TCCSUP cells, ABDHFA treatment led to inhibition of mRNA and protein expression corresponding to AR. CONCLUSIONS In summary, the present study demonstrates that proliferation of AR-positive bladder carcinoma cells is markedly reduced by ABDHFA treatment through arrest of cell cycle and degradation of AR protein. Thus, ABDHFA, a novel compound, can be used for the treatment of bladder cancer.
Assuntos
Glucosamina/farmacologia , MicroRNAs/biossíntese , Receptores Androgênicos/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/metabolismo , Acetatos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/biossíntese , Ciclina D1/genética , Furanos/farmacologia , Humanos , Calicreínas/biossíntese , Calicreínas/genética , MicroRNAs/genética , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Androgênicos/genética , Transdução de Sinais , Regulação para Cima , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Antimony is a widely used heavier pnictogens in industry, and its toxicity has been a matter of concern. Although previous studies have suggested that antimony may have the function as either a tumor suppressor or an oncogene in several cancers, the molecular basis underlying antimony-mediated transformation is still unclear. In the current study, we attempt to elucidate the potential role of antimony in the development of prostate cancer. Our results showed that the concentration of antimony was much higher in serum of prostate cancer patients, and was closely associated with poor outcome of patients who underwent radical prostatectomy. Additionally, low dose of antimony could promote proliferation and invasion of androgen-dependent prostate cancer cell line LNCaP cells in vitro and in vivo. The mechanistic studies demonstrated that exposure to antimony triggered the phosphorylation of androgen receptor (AR), which transcriptionally regulates the expression of androgen-related targets, including PSA and NKX3.1. Overall, our results unearthed that antimony could promote tumor growth by mimicking androgen activity in androgen-dependent prostate cancer cells. Therefore, these findings expanded our understanding on the molecular mechanism of antimony in tumorigenesis and tumor progression of prostate cancer, and it appears to be an inspiring strategy to restrain prostate cancer by inhibiting antimony-induced androgen-like effects.
Assuntos
Androgênios/farmacologia , Antimônio/farmacologia , Neoplasias da Próstata/patologia , Antagonistas de Androgênios/farmacologia , Animais , Antimônio/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosforilação , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/efeitos dos fármacos , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/cirurgia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores Androgênicos/efeitos dos fármacos , Fatores de Transcrição/biossíntese , Fatores de Transcrição/efeitos dos fármacos , Resultado do TratamentoRESUMO
Apalutamide (ARN-509) is an antiandrogen that binds selectively to androgen receptors (AR) and does not show antagonist-to-agonist switch like bicalutamide. We compared the activity of ARN versus bicalutamide on prostate cancer cell lines. The 22Rv1, PC3, and DU145 cell lines were used to study the effect of ARN and bicalutamide on the expression cytoplasmic/nuclear kinetics of AR, AR-V7 variant, phosphorylated AR, as well as the levels of the AR downstream proteins prostate-specific antigen and TMPRSS2, under exposure to testosterone and/or hypoxia. The effects on autophagic flux (LC3A, p62, TFEB, LAMP2a, cathepsin D) and cell metabolism-related enzymes (hypoxia-inducible factor 1α/2α, BNIP3, carbonic anhydrase 9, LDHA, PDH, PDH-kinase) were also studied. The 22Rv1 cell line responded to testosterone by increasing the nuclear entry of AR, AR-V7, and phosphorylated AR and by increasing the levels of prostate-specific antigen and TMPRSS2. This effect was strongly abrogated by ARN and to a clearly lower extent by bicalutamide at 10 µmol/l, both in normoxia and in hypoxia. ARN had a stronger antiproliferative effect than bicalutamide, which was prominent in the 22Rv1 hormone-responsive cell line, and completely repressed cell proliferation at a concentration of 100 µmol/l. No effect of testosterone or of antiandrogens on autophagy flux, hypoxia-related proteins, or metabolism enzyme levels was noted. The PC3 and DU145 cell lines showed poor expression of the proteins and were not responsive to testosterone. On the basis of in-vitro studies, evidence has been reported that ARN is more potent than bicalutamide in blocking the AR pathway in normoxia and in hypoxia. This reflects a more robust, dose-dependent, repressive effect on cell proliferation.
Assuntos
Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Nitrilas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Receptores Androgênicos/efeitos dos fármacos , Tioidantoínas/farmacologia , Compostos de Tosil/farmacologia , Antagonistas de Androgênios/uso terapêutico , Anilidas/uso terapêutico , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Masculino , Nitrilas/uso terapêutico , Antígeno Prostático Específico/biossíntese , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Testosterona/uso terapêutico , Tioidantoínas/uso terapêutico , Compostos de Tosil/uso terapêuticoRESUMO
BACKGROUND: Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. OBJECTIVE: To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml. OUTCOME MEASUREMENTS AND STATISITICAL ANALYSIS: Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. RESULTS AND LIMITATIONS: The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02-19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16-21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46-70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48-22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. CONCLUSIONS: Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. PATIENT SUMMARY: Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.
Assuntos
Neoplasias da Próstata/genética , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/sangue , Genoma , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/genética , Valor Preditivo dos Testes , Prognóstico , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/secundário , Medição de RiscoRESUMO
OBJECTIVE: This study sought to evaluate the protective effect of ethanolic leaf extract of Moringa oleifera on testosterone-induced benign prostatic hyperplasia (BPH) in male Sprague-Dawley rats. MATERIALS AND METHODS: BPH was induced in rats by the administration of testosterone propionate (3 mg/kg, s.c., in olive oil) for 4 weeks. M. oleifera (50, 100, or 200 mg/kg), celecoxib (20 mg/kg), or M. oleifera (50 mg/kg) + celecoxib (20 mg/kg) were orally administered daily 15 min before testosterone. On day 29, blood was collected to measure the levels of serum testosterone and prostate-specific antigen before the animals were sacrificed. The prostates were weighed, assayed, and histologically examined. RESULTS: M. oleifera significantly reduced the testosterone-induced increase in prostate weight (20.16%), prostate index (65.85%), serum testosterone (72.86%), and prostate-specific antigen (48.49%). Testosterone caused a significant increase in malondialdehyde (73%) as well as a reduction in glutathione (62.5%), superoxide dismutase (50%), and catalase (64%) activities which were attenuated by M. oleifera with a peak effect obtained at 100 mg/kg. The disruption of prostate histoarchitecture by testosterone was also ameliorated by M. oleifera. CONCLUSION: M. oleifera prevented testosterone-induced BPH through enhancement of antioxidant defence mechanisms, and hence could be used as an adjunct in the treatment of BPH.
Assuntos
Antioxidantes/farmacologia , Moringa oleifera , Extratos Vegetais/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Animais , Catalase/biossíntese , Relação Dose-Resposta a Droga , Glutationa/biossíntese , Masculino , Malondialdeído/metabolismo , Folhas de Planta , Antígeno Prostático Específico/biossíntese , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/biossíntese , Testosterona/farmacologiaRESUMO
BACKGROUND: In the COU-AA-302 study (NCT00887198), abiraterone acetate plus prednisone (AAP) significantly improved outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) versus prednisone alone. Baseline clinical parameters predicting that treatment response could help inform clinical decisions were explored. OBJECTIVE: To identify patients who derive the greatest clinical benefit from AAP treatment. DESIGN, SETTING, AND PARTICIPANTS: A total of 1088 mCRPC patients treated with either AAP or prednisone in the first-line setting in COU-AA-302 were included in this post hoc analysis. INTERVENTION: Abiraterone acetate1000mg daily versus placebo, both plus prednisone 10mg daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariate and multivariable Cox regression analyses were performed, including clinical and pathological parameters for the primary end points overall survival (OS) and radiographic progression-free survival (rPFS), and secondary study end points. Tumor-associated baseline parameters independently impacting OS were applied to stratify patients according to possible treatment effects. RESULTS AND LIMITATIONS: Baseline prostate-specific antigen (PSA), tumor-related pain as assessed by the Brief Pain Inventory-Short Form (BPI-SF), and Gleason score (GS) at primary diagnosis were identified as tumor-associated variables that independently impacted OS. AAP significantly improved outcomes versus prednisone in both group 1 (BPI-SF 0-1 and PSA <80 ng/ml and GS <8; p=0.006; hazard ratio [HR]: 0.61) and group 2 (BPI-SF 2-3 and/or PSA ≥80 ng/ml and/or GS ≥8; p=0.03; HR: 0.84). The differences observed for treatment effects between groups 1 and 2 for OS (HR: 0.61 vs 0.84), rPFS (HR: 0.41 vs 0.59), and time to chemotherapy (HR: 0.64 vs 0.71) were not statistically significant. CONCLUSIONS: AAP significantly improved outcomes in mCRPC patients compared with prednisone alone regardless of baseline pain and PSA level, and GS at primary diagnosis with no significant differences between observed treatment effects in groups 1 and 2. PATIENT SUMMARY: Treatment with abiraterone acetate and prednisone (compared with treatment with prednisone only) for metastatic castration-resistant prostate cancer increased survival in all patients in the study regardless of pain, prostate-specific antigen levels at the start of treatment, and Gleason score at primary diagnosis.
Assuntos
Acetato de Abiraterona/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Prednisona/administração & dosagem , Antígeno Prostático Específico/biossíntese , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Método Duplo-Cego , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Dor/etiologia , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Análise de SobrevidaRESUMO
Positron emission tomography/computed tomography (PET/CT) with 68Ga-PSMA is a non-invasive diagnostic technique to image prostate cancer with increased prostate-specific membrane antigen (PSMA) expression. PSMA is a transmembrane protein present in all prostatic tissues. Increased PSMA expression is seen in several malignancies, although prostate cancer is the tumour where it presents higher concentrations. Almost all prostate adenocarcinomas show PSMA expression in most of lesions, primary and metastatic. Immunohistochemistry has demonstrated that the expression of PSMA increases in patients with de-differentiated, metastatic or hormone-refractory tumours. Moreover, the expression level of PSMA has a prognostic value for disease outcome. PET measures the three-dimensional distribution of 68Ga-PSMA, producing semi-quantitative images that allow for non-invasive assessment of PSMA expression.
Assuntos
Adenocarcinoma/diagnóstico por imagem , Ácido Edético/análogos & derivados , Radioisótopos de Gálio/farmacocinética , Oligopeptídeos/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética , Adenocarcinoma/química , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Ácido Edético/síntese química , Ácido Edético/farmacocinética , Seguimentos , Isótopos de Gálio , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oligopeptídeos/síntese química , Prognóstico , Antígeno Prostático Específico/análise , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Radiometria , Compostos Radiofarmacêuticos/síntese química , Recidiva , Sensibilidade e Especificidade , Distribuição Tecidual , Carga TumoralRESUMO
Mantle cell lymphoma (MCL) affects approximately 4500 patients/year in the US and demonstrates a male to female ratio of approximately 4:1. While the pathobiology underlying this ratio is unknown, the hematopoietic system is characterized by sex-related differences in androgen receptor (AR) expression, leading us to hypothesize that the male-biased incidence of MCL may reflect sex-related differences in AR signaling during MCL lymphomagenesis. To explore the AR axis in MCL, we evaluated AR expression in MCL cell lines and human tumors, and tested the impact of androgen pathway inhibition on MCL proliferation. AR transcript levels ranged up to ~26 fold higher in MCL lines vs non-MCL NHL lines (p = 0.006) and were correlated with expression of the canonical AR-regulated gene, prostate-specific antigen (PSA; r = 0.715, p = 0.001), consistent with functional AR activity. Patient-derived MCL samples demonstrated a range of AR expression. Treatment of four different MCL lines with the potent AR antagonist enzalutamide demonstrated suppression of proliferation across both male and female-derived cell lines. These data suggest androgen-axis blockade may represent a novel therapeutic modality in MCL. This novel treatment approach is currently under investigation in a phase II clinical trial of AR inhibition in patients with relapsed/refractory MCL.