RESUMO
Currently, the optimal sequential use of androgen receptor (AR) axis-targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide-resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane-resistant cells showed no collateral resistance to enzalutamide; taxane-resistant cells expressed comparable protein levels of full-length AR and AR variants. Knockdown of both full-length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full-length AR rendered cells resistant to taxanes. Consistently, the prostate-specific antigen response and progression-free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Taxoides/farmacologia , Idoso , Antagonistas de Receptores de Andrógenos/farmacologia , Antagonistas de Receptores de Andrógenos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Linhagem Celular Tumoral , Intervalo Livre de Doença , Técnicas de Silenciamento de Genes , Humanos , Masculino , Nitrilas , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Feniltioidantoína/uso terapêutico , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , RNA Interferente Pequeno/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Taxoides/uso terapêutico , Resultado do TratamentoRESUMO
PURPOSE: Serum testosterone suppression during androgen deprivation therapy has been reported to affect the efficacy of androgen deprivation therapy. However, the factors impacting hormonal variations during androgen deprivation therapy remain unclear. Therefore, in this study we investigated the significance of missense polymorphisms in the gene encoding GNRH in men treated with primary androgen deprivation therapy for metastatic prostate cancer. MATERIALS AND METHODS: This study included 80 Japanese patients with metastatic prostate cancer with available serum testosterone levels during androgen deprivation therapy. We examined the association of GNRH1 (rs6185, S20W) and GNRH2 (rs6051545, A16V) gene polymorphisms with clinicopathological parameters, including serum testosterone levels during androgen deprivation therapy, as well as prognosis, including progression-free and overall survival. RESULTS: The CT and CT/TT alleles in the GNRH2 gene (rs6051545) were associated with higher serum testosterone during androgen deprivation therapy compared with those of the CC allele. Consequently the CT alleles were associated with a higher risk of progression after adjustment for age and serum testosterone during androgen deprivation therapy (HR 1.73, 95% CI 1.00-3.00, p = 0.049). CONCLUSIONS: Taken together these findings suggest that rs6051545 (GNRH2) genetic variation may result in inadequate suppression of serum testosterone during androgen deprivation therapy. This may lead to detrimental effects of androgen deprivation therapy on prognosis in men with metastatic prostate cancer.
Assuntos
Antagonistas de Androgênios/uso terapêutico , DNA de Neoplasias/genética , Hormônio Liberador de Gonadotropina/análogos & derivados , Polimorfismo Genético , Neoplasias da Próstata/genética , Testosterona/sangue , Idoso , Alelos , Progressão da Doença , Seguimentos , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Masculino , Metástase Neoplásica , Prognóstico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/secundário , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: LIM and SH3 domain protein 1 (LASP1) has been implicated in several human malignancies and has been shown to predict PSA recurrence in prostate cancer. However, the anti-tumor effect of LASP1 knockdown and the association between LASP1 and the androgen receptor (AR) remains unclear. The aim of this study is to clarify the significance of LASP1 as a target for prostate cancer, and to test the effect of silencing LASP1 in vivo using antisense oligonucleotides (ASO). METHODS: A tissue microarray (TMA) was performed to characterize the differences in LASP1 expression in prostate cancer treated after hormone deprivation therapy. Flow cytometry was used to analyze cell cycle. We designed LASP1 ASO for knockdown of LASP1 in vivo studies. RESULTS: The expression of LASP1 in TMA was increased after androgen ablation and persisted in castration resistant prostate cancer (CRPC). Also in TMA, compared with LNCaP cell, LASP1 expression is elevated in CRPC cell lines (C4-2 and VehA cells). Interestingly, suppression of AR elevated LASP1 expression conversely, AR activation decreased LASP1 expression. Silencing of LASP1 reduced cell growth through G1 arrest which was accompanied by a decrease of cyclin D1. Forced overexpression of LASP1 promoted cell cycle and induced cell growth which was accompanied by an increase of cyclin D1. Systemic administration of LASP1 ASO with athymic mice significantly inhibited tumor growth in CRPC xenografts. CONCLUSIONS: These results indicate that LASP1 is negatively regulated by AR at the transcriptional level and promotes tumor growth through induction of cell cycle, ultimately suggesting that LASP1 may be a potential target in prostate cancer treatment. Prostate 77:309-320, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas do Citoesqueleto/antagonistas & inibidores , Proteínas do Citoesqueleto/biossíntese , Progressão da Doença , Proteínas com Domínio LIM/antagonistas & inibidores , Proteínas com Domínio LIM/biossíntese , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Androgênicos/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Antagonistas de Androgênios/farmacologia , Antagonistas de Androgênios/uso terapêutico , Animais , Proteínas do Citoesqueleto/genética , Técnicas de Silenciamento de Genes/métodos , Humanos , Proteínas com Domínio LIM/genética , Masculino , Camundongos , Camundongos Nus , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genéticaRESUMO
PURPOSE: We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia. RESULTS: We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer. CONCLUSIONS: Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis.
Assuntos
Inibidores de 5-alfa Redutase/uso terapêutico , Antagonistas de Androgênios/uso terapêutico , Recidiva Local de Neoplasia/epidemiologia , Neoplasias da Bexiga Urinária/patologia , Inibidores de 5-alfa Redutase/efeitos adversos , Administração Intravesical , Idoso , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos/administração & dosagem , Progressão da Doença , Humanos , Japão , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Hiperplasia Prostática/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológicoRESUMO
PURPOSE: This study aimed to examine the differential impact of body mass index and the feature of metabolic syndrome (MetS; obesity, hypertension, diabetes mellitus, and dyslipidemia) on biochemical recurrence (BCR) following radical prostatectomy (RP) treatment for prostate cancer using different surgical procedures. METHODS: This study included 283 Japanese patients with clinically localized prostate cancer who were treated with RP between 2008 and 2012. The prognostic significance of overweight and the feature of MetS were analyzed according to surgical procedures. RESULTS: BCR occurred in 68/283 (24.0%) men. Overweight and the feature of MetS were predictors of BCR in patients who had undergone open RP (ORP), but not in those treated with laparoscopic surgery. Multivariate analyses incorporating preoperative and postoperative risk factors revealed that overweight and the feature of MetS were independent BCR risk factors when treated with ORP. CONCLUSIONS: In Japanese men, overweight and the feature of MetS were associated with worse outcomes following RP, particularly ORP, compared with those following laparoscopic surgery. These results suggest that laparoscopic surgery can overcome the surgical challenges associated with abdominal obesity.
Assuntos
Índice de Massa Corporal , Síndrome Metabólica/epidemiologia , Recidiva Local de Neoplasia/epidemiologia , Sobrepeso/epidemiologia , Prostatectomia/métodos , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Perda Sanguínea Cirúrgica , Intervalo Livre de Doença , Dislipidemias/epidemiologia , Humanos , Japão/epidemiologia , Laparoscopia , Metástase Linfática , Masculino , Gradação de Tumores , Recidiva Local de Neoplasia/sangue , Duração da Cirurgia , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Fatores de RiscoRESUMO
PURPOSE: Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS: We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS: RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS: T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.
Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Maitansina/análogos & derivados , Receptor ErbB-2/biossíntese , Receptor ErbB-2/efeitos dos fármacos , Trastuzumab/farmacologia , Neoplasias da Bexiga Urinária/metabolismo , Ado-Trastuzumab Emtansina , Animais , Apoptose , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Maitansina/farmacologia , Camundongos , Células Tumorais CultivadasRESUMO
OBJECTIVES: This study aimed to evaluate the efficacy and safety of Vibegron for the treatment of residual overactive bladder (OAB) symptoms after laser vaporization of the prostate (photo-selective vaporization of the prostate, contact laser vaporization of the prostate, and thulium laser vaporization). METHODS: This randomized, open-label, parallel-group, single-center superiority trial with a 12-week observation (jRCTs071190040) enrolled male patients with OAB aged 40 years or older who had undergone laser vaporization of the prostate for not less than 12 weeks and not more than 1 year earlier. Patients were allocated to receive Vibegron 50 mg once daily or follow-up without treatment for 12 weeks. RESULTS: Forty-seven patients were enrolled between January 2020 and March 2023. The median age (interquartile range) was 75.5 (72.5-78.5) years for the Vibegron group and 76.5 (71.0-81.0) years for the control group. The intergroup difference in the mean change (95% confidence interval) in the 24-hour urinary frequency at 12 weeks after randomization was -3.66 (-4.99, -2.33), with a significant decrease for the Vibegron group. The Overactive Bladder Symptom Score, International Prostate Symptom Score, IPSS storage score, and Overactive Bladder Questionnaire score significantly improved for the Vibegron group. Voided volume per micturition also increased for the Vibegron group. CONCLUSIONS: The administration of 50 mg of Vibegron once daily for 12 weeks showed significant improvement compared with follow-up without treatment in bladder storage (OAB) symptoms after laser vaporization of the prostate for symptomatic benign prostatic hyperplasia.
Assuntos
Terapia a Laser , Bexiga Urinária Hiperativa , Humanos , Masculino , Idoso , Bexiga Urinária Hiperativa/etiologia , Bexiga Urinária Hiperativa/tratamento farmacológico , Estudos Prospectivos , Terapia a Laser/métodos , Terapia a Laser/efeitos adversos , Hiperplasia Prostática/cirurgia , Hiperplasia Prostática/complicações , Resultado do Tratamento , Idoso de 80 Anos ou mais , Pirimidinonas , PirrolidinasRESUMO
BACKGROUND: Taxanes, including docetaxel, are currently the only cytotoxic chemotherapeutic agents proven to confer survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the merits of taxanes remain modest, and efforts are needed to improve their therapeutic efficacy. METHODS: We evaluated the sensitivity of prostate cancer cells to various agents using cytotoxicity assays. Gene and protein expression levels were evaluated by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. RESULTS: Hydrogen peroxide-resistant and castration-resistant cells that overexpressed Twist1 and Y-box binding protein-1 (YB-1) were cross-resistant to cytotoxic agents, including docetaxel. Twist1 regulated YB-1 expression in prostate cancer cells, supported by the induction of Twist1 and YB-1 by transforming-growth factor-ß, which is critical for taxane resistance. Twist1 and/or YB-1 were activated in docetaxel-resistant prostate cancer cells, and YB-1 was activated by docetaxel treatment. Conversely, Twist1 and YB-1 knockdown sensitized prostate cancer cells to cytotoxic agents, including docetaxel. In addition, androgen receptor (AR) knockdown increased cellular sensitivity to docetaxel, though AR expression in docetaxel-resistant LNCaP cells was paradoxically lower than in parental cells. Intriguingly, androgen deprivation treatment was more effective in docetaxel-resistant LNCaP cells compared with parental cells. CONCLUSIONS: Twist1/YB-1 and AR signaling promote docetaxel resistance in CRPC cells. However, docetaxel-resistant cells were collaterally sensitive to androgen deprivation because of down-regulation of AR expression, suggesting that the therapeutic effect of initial taxane treatment in hormone-naïve prostate cancer may be superior to that of salvage taxane treatment in CRPC.
Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Taxoides/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Proteína 1 de Ligação a Y-Box/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Docetaxel , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Masculino , Proteínas Nucleares/genética , Orquiectomia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Taxoides/uso terapêutico , Proteína 1 Relacionada a Twist/genética , Proteína 1 de Ligação a Y-Box/genéticaRESUMO
Renal cell carcinoma (RCC) accounts for 80-95 % of kidney tumors, and approximately 30 % of RCC patients have metastatic disease at diagnosis. Conventional chemotherapy is not effective in patients with metastatic RCC (MRCC); therefore, immunotherapy with interferon-α (IFN-α) has been employed to improve survival. However, the response rate of MRCC to IFN-α therapy is low. We previously reported that a signal transducer and activator 3 (STAT3) polymorphism was a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. Therefore, we hypothesized the inhibition of STAT3 in the addition of IFN-α therapy might be useful. Moreover, the blockage of STAT3 itself has been reported to enhance the antitumor effects. However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders. In the present study, we found Y-box binding protein-1 (YB-1) was poorly expressed in T lymphocytes, as compared with cancer tissues. YB-1 was reported to have an important effect on the STAT3 pathway. Suppression of STAT3 by YB-1 inhibition did not seem to enhance the potential risk for autoimmune disorders. Moreover, we found sensitivity to IFN-α was increased by YB-1 suppression, and this suppression did not down-regulate IFN-α activation of T lymphocytes.
Assuntos
Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/terapia , Interferon-alfa/uso terapêutico , Neoplasias Renais/metabolismo , Neoplasias Renais/terapia , Fator de Transcrição STAT3/metabolismo , Proteína 1 de Ligação a Y-Box/antagonistas & inibidores , Animais , Carcinoma de Células Renais/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Interferon-alfa/farmacologia , Neoplasias Renais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteólise , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transplante Heterólogo , Células Tumorais Cultivadas , Proteína 1 de Ligação a Y-Box/farmacologiaRESUMO
Unlike conventional T cells, which are exported from the thymus as naive cells and acquire effector functions upon antigen encounter in the periphery, a subset of γδ T cells differentiates into effectors that produce IL-17 within the fetal thymus. We demonstrate here that intrathymic development of the naturally occurring IL-17-producing γδ T cells is independent of STAT3 and partly dependent on RORγt. Comparative gene-expression analysis identified Hes1, one of the basic helix-loop-helix proteins involved in Notch signaling, as a factor specifically expressed in IL-17-producing γδ T cells. Hes1 is critically involved in the development of IL-17-producing γδ T cells, as evidenced by their severe decrease in the thymi of Hes1-deficient fetal mice. Delta-like 4 (Dll4)-expressing stromal cells support the development of IL-17-producing γδ T cells in vitro. In addition, conditional Hes1 ablation in peripheral γδ T cells decreases their IL-17 production but not their IFN-γ production. These results reveal a unique differentiation pathway of IL-17-producing γδ T cells.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Homeodomínio/metabolismo , Interleucina-17/metabolismo , Transdução de Sinais/imunologia , Células Th17/fisiologia , Timo/citologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Diferenciação Celular/imunologia , Feminino , Proteínas de Homeodomínio/genética , Masculino , Camundongos , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores Notch/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Th17/citologia , Timo/fisiologia , Fatores de Transcrição HES-1RESUMO
Hemorrhagic cystitis often arises after cyclophosphamide (CYP) administration. As yet, however, the mechanism involved in its pathogenesis is unknown. In this study, it was found that the Fc receptor γ chain (FcRγ)- caspase recruitment domain-containing protein 9 (CARD9)-dependent pathway rather than the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway is involved in the pathogenesis of acute CYP-induced cystitis in mice. Rapid and transient production of interleukin (IL)-6 and IL-1ß was detected in the bladder at 4 hr, preceding IL-23 and IL-17A production and an influx of neutrophils, which reached a peak at 24 hr after injection. As assessed by weight, edema and neutrophil infiltration, cystitis was significantly attenuated in CARD9 knockout (KO) and FcRγKO mice, this attenuation being accompanied by impaired production of IL-1ß, IL-6, IL-23 and IL-17A. The major source of IL-17A is the vesical γδ T cell population: IL-17AKO, CδKO and Tyk2KO mice showed little IL-17A production and reduced neutrophil infiltration in the bladder after CYP injection. These results suggest that FcRγ-CARD9-dependent production of proinflammatory cytokines such as IL-1ß, IL-6, and IL-23 and the subsequent activation of IL-17A-producing γδ T cells are at least partly involved in the pathogenesis of acute CYP-induced cystitis in mice.
Assuntos
Ciclofosfamida/toxicidade , Cistite/induzido quimicamente , Lectinas Tipo C/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteínas Adaptadoras de Sinalização CARD , Cistite/patologia , Citocinas/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Linfócitos T/imunologia , Fatores de TempoRESUMO
Intravesical inoculation of Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used for the treatment of bladder cancer. Recent studies implied the requirement of neutrophil infiltration for the antitumor effect. In this study, we found that IL-17 was produced in the bladder after BCG treatment, preceding the infiltration of neutrophils. Neutrophils in the bladder after BCG treatment were reduced in IL-17-deficient mice, in which BCG-induced antitumor effect against intravesically inoculated bladder cancer was abolished. Notably, the level of IL-17 production and the number of neutrophils in BCG-treated bladder was reduced in γδ T-cell-deficient mice but not in CD4-depleted mice. Survival of bladder cancer-inoculated γδ T-cell-deficient mice was not improved by BCG treatment. These results suggest that IL-17-producing γδ T cells play a key role in the BCG-induced recruitment of neutrophils to the bladder, which is essential for the antitumor activity against bladder cancer.
Assuntos
Imunoterapia/métodos , Interleucina-17/imunologia , Mycobacterium bovis/imunologia , Neutrófilos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Neoplasias da Bexiga Urinária/terapia , Animais , Antígenos CD4/imunologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVES: This study aimed to compare the safety and efficacy of three different laser prostate vaporization surgeries, which were photoselective vaporization of the prostate (PVP), diode laser vaporization (DVP), and thulium laser vaporization (ThuVAP), for the treatment of benign prostatic hyperplasia (BPH) in a randomized clinical trial. METHODS: A total of 71 consecutive patients with BPH were included; 23 patients were treated with PVP, 23 with DVP, and 25 with ThuVAP. Patients were evaluated with disease-related symptomatic questionnaires, Quality of Life (QOL) Index, and maximum urinary flow rate (Qmax ) for 12 months. Patients were monitored to record operation/vaporization time, 24-hour hemoglobin/sodium drop, length of catheterization/hospitalization, and perioperative/postoperative complications. RESULTS: In all three groups, patients showed significant and comparable improvements in symptom scores, QOL Index, and Qmax during the 12-month follow-up period. The mean operation/vaporization time was equivalent across all three groups at 69/23 (PVP), 81/34 (DVP), and 76/32 minutes (ThuVAP), while the applied laser energy was lower for PVP at 157 kJ compared to the other two techniques (DVP at 358 kJ, ThuVAP at 240 kJ). The mean vaporization rates per unit energy were significantly different between the three groups (PVP 0.16, DVP 0.09, and ThuVAP 0.09 mL/kJ). There were no significant differences in the main safety profiles between the three groups. CONCLUSIONS: Our study demonstrated that these three types of laser surgeries are similar in terms of complications and outcomes, with excellent hemostasis and high patient satisfaction. It was suggested that sufficient tissue vaporization could be achieved using less energy through PVP surgery.
Assuntos
Terapia a Laser , Hiperplasia Prostática , Ressecção Transuretral da Próstata , Humanos , Terapia a Laser/métodos , Lasers Semicondutores/uso terapêutico , Masculino , Estudos Prospectivos , Hiperplasia Prostática/complicações , Qualidade de Vida , Túlio , Ressecção Transuretral da Próstata/efeitos adversos , Ressecção Transuretral da Próstata/métodos , Resultado do Tratamento , VolatilizaçãoRESUMO
Interleukin-17A (IL-17A)-producing γδ T cells differentiate in the fetal thymus and reside in the peripheral tissues, such as the lungs of naïve adult mice. We show here that naturally occurring γδ T cells play a protective role in the lung at a very early stage after systemic infection with Candida albicans. Selective depletion of neutrophils by in vivo administration of anti-Ly6G monoclonal antibody (MAb) impaired fungal clearance more prominently in the lung than in the kidney 24 h after intravenous infection with C. albicans. Rapid and transient production of IL-23 was detected in the lung at 12 h, preceding IL-17A production and the influx of neutrophils, which reached a peak at 24 h after infection. IL-17A knockout (KO) mice showed reduced infiltration of neutrophils concurrently with impaired fungal clearance in the lung after infection. The major source of IL-17A was the γδ T cell population in the lung, and Cδ KO mice showed little IL-17A production and reduced neutrophil infiltration after infection. Early IL-23 production in a TLR2/MyD88-dependent manner and IL-23-triggered tyrosine kinase 2 (Tyk2) signaling were essential for IL-17A production by γδ T cells. Thus, our study demonstrated a novel role of naturally occurring IL-17A-producing γδ T cells in the first line of host defense against C. albicans infection.
Assuntos
Candidíase/imunologia , Interleucina-17/metabolismo , Pulmão/citologia , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Adaptadoras de Sinalização CARD , Interleucina-17/genética , Interleucina-23/genética , Interleucina-23/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neutrófilos/fisiologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Organismos Livres de Patógenos Específicos , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/metabolismoRESUMO
OBJECTIVES: This study aimed to compare the safety and efficacy of laser vaporization with 532 nm GreenLight High Performance System (HPS) laser 120 W (PVP) and 980 nm diode laser 300 W (CVP) for the treatment of benign prostatic hyperplasia (BPH) in a prospective, single-center, randomized clinical trial. METHODS: A total of 153 consecutive patients with symptomatic BPH were included; 79 patients were treated with PVP and 74 with CVP. Patients were assessed preoperatively and at 3, 6, and 12 months postoperatively using the International Prostate Symptom Score, quality of life index, peak urinary flow rate, and postvoid residual urine volume. All perioperative and postoperative complications were noted. RESULTS: There were significant and comparable improvements in each of the outcome variables over a follow-up period of 12 months in both groups. The mean operation/vaporization duration (minutes) was comparable at 74/38 (PVP) and 76/34 (CVP), whereas the mean applied laser energy was significantly higher with CVP than with PVP at 260 vs 195 (kJ), respectively. The mean vaporization rate (mL/min) was not significantly different between the two groups (0.53 PVP vs 0.56 CVP). Immediately after surgery, the rate of recatheterization for urinary retention was significantly higher with CVP than with PVP (17.6% vs 6.8%; P < 0.05). CONCLUSIONS: Both laser systems provided comparable improvement in the subjective and objective parameters with excellent hemostatic properties. Although our results suggest that both procedures are useful treatment choices, further follow-up is needed to draw definitive conclusions regarding the most ideal laser for treating patients with symptomatic BPH.
Assuntos
Lasers Semicondutores/uso terapêutico , Lasers de Estado Sólido/uso terapêutico , Hiperplasia Prostática/cirurgia , Idoso , Idoso de 80 Anos ou mais , Humanos , Japão , Lasers Semicondutores/efeitos adversos , Lasers de Estado Sólido/efeitos adversos , Masculino , Pessoa de Meia-Idade , Próstata/cirurgia , Resultado do TratamentoRESUMO
Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.
Assuntos
Proteínas do Tecido Nervoso/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Semaforinas/metabolismo , Animais , Proliferação de Células , Humanos , Masculino , Camundongos , Neoplasias de Próstata Resistentes à Castração/patologia , Semaforinas/antagonistas & inibidores , Transdução de Sinais , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The progression of prostate cancer to metastatic and castration-resistant disease represents a critical step. We previously showed that protein kinase C (PKC) activation followed by Twist1 and androgen receptor (AR) induction played a critical role in castration resistance, but the precise molecular mechanism remains unknown. This study aimed to elucidate the relevant molecular mechanism, focusing on NF-κB transcription factor. We examined the activity of NF-κB after PKC inhibition, and the expression of Twist1 and AR after inhibition of NF-κB in human prostate cancer cells. We also investigated the status of PKC/NF-κB after inhibition of AR signaling in cells resistant to hormonal therapy. As a result, inhibition of PKC signaling using knockdown and small-molecule inhibition of PKC suppressed RelA activity, while blocking NF-κB suppressed Twist1 and AR expression. Conversely, inhibition of AR signaling by androgen depletion and the novel antiandrogen enzalutamide induced PKC and RelA activation, resulting in Twist1/AR induction at the transcript level. Moreover, inhibition of NF-κB signaling prevented enzalutamide-induced Twist1 and AR induction. Finally, NF-κB was activated in both castration-resistant and enzalutamide-resistant cells. In conclusion, NF-κB signaling was responsible for Twist1 upregulation by PKC in response to AR inhibition, resulting in aberrant activation of AR. NF-κB signaling thus appears to play a critical role in promoting both castration resistance and enzalutamide resistance in PKC/Twist1 signaling in prostate cancer.
Assuntos
NF-kappa B/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Proteína Quinase C-épsilon/metabolismo , Proteína 1 Relacionada a Twist/metabolismo , Antagonistas de Androgênios/farmacologia , Benzamidas , Linhagem Celular Tumoral , Humanos , Masculino , NF-kappa B/genética , Nitrilas , Proteínas Nucleares/genética , Feniltioidantoína/análogos & derivados , Feniltioidantoína/farmacologia , Neoplasias de Próstata Resistentes à Castração/genética , Proteína Quinase C-épsilon/genética , Receptores Androgênicos/genética , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteína 1 Relacionada a Twist/genéticaRESUMO
BACKGROUND/AIM: Salvage androgen-deprivation therapy (ADT) is standard treatment for recurrent prostate cancer after curative therapy. However, the prognostic impact of different treatment modalities on the time to castration resistance remains unclear. In this study, we investigated the prognosis of men treated with salvage ADT after initial radical prostatectomy or radiotherapy for prostate cancer. PATIENTS AND METHODS: Between 2000 and 2013, 149 Japanese men with recurrent prostate cancer who were initially treated with radical prostatectomy (n=95) or radiotherapy (n=54) and were subsequently treated with salvage ADT after disease recurrence were enrolled in this study. The prognostic significance of the curative treatment modality and clinicopathological findings were analyzed. RESULTS: During a median follow-up period of 4.7 years after recurrence, castration-resistant progression was observed in 22 men. The 5-year progression-free survival, metastasis-free survival, cause-specific survival, and overall survival rates for all patients were 86.3%, 81.4%, 95.7%, and 94.5%, respectively. Multivariate analysis identified the biopsy Gleason score at initial diagnosis and the initial curative treatment modality as significant predictors of castration resistance. CONCLUSION: This study showed that low biopsy Gleason score (≤7) at diagnosis and radical prostatectomy as the curative treatment may be favorable prognostic factors for treatment with salvage ADT.
Assuntos
Adenocarcinoma/terapia , Antagonistas de Androgênios/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Quimiorradioterapia/métodos , Recidiva Local de Neoplasia , Prostatectomia/métodos , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias da Próstata/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Antagonistas de Androgênios/efeitos adversos , Antineoplásicos Hormonais/efeitos adversos , Biópsia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Quimioterapia Adjuvante , Distribuição de Qui-Quadrado , Progressão da Doença , Intervalo Livre de Doença , Humanos , Japão , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Gradação de Tumores , Modelos de Riscos Proporcionais , Prostatectomia/efeitos adversos , Prostatectomia/mortalidade , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is used for the treatment of bladder cancer. The recruitment of neutrophlis to the bladder after BCG instillation exerts anti-tumor activity against bladder tumor. We have recently demonstrated that interleukin (IL)-17A produced by γδ T cells played a role in the recruitment of neutrophlis to the bladder after BCG instillation. IL-15 is known to play an important role in neutrophil migration during inflammation. We previously constructed a recombinant BCG strain expressing the fusion protein of IL-15 and Ag85B (BCG-IL-15) for prevention of Mycobacterium tuberculosis infection. Here we compared the efficacy of the BCG-IL-15 in protection against bladder cancer with that of rBCG-Ag85B (BCG). Six-week-old female C57BL/6 mice were inoculated with MB49 bladder tumor cells in the bladder and subsequently intravesically inoculated with BCG or BCG-IL-15. BCG-IL-15 treatment significantly prolonged survival of mice inoculated with bladder cancer cells compared with BCG treatment. Infiltration of neutrophils was significantly elevated in BCGB-IL-15 treated mice accompanied by increased chemokines (MIP-2 and MIP-1α) in the bladder. Thus, BCG-IL-15 exerted additive effect on Infiltration of neutrophils in the bladder. BCG-IL-15 may be a promising drug for non-muscle invasive bladder cancer.
Assuntos
Imunoterapia/métodos , Interleucina-15/metabolismo , Mycobacterium bovis/imunologia , Neutrófilos/fisiologia , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Aciltransferases/genética , Animais , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Movimento Celular/efeitos dos fármacos , Feminino , Engenharia Genética , Humanos , Imunidade , Interleucina-15/genética , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis/genética , Proteínas Recombinantes de Fusão/genética , Neoplasias da Bexiga Urinária/imunologiaRESUMO
BACKGROUND/AIM: The impact of testosterone or obesity on the pathological grade of prostate cancer remains controversial. Therefore, in this study, we investigated the relationship of serum testosterone and body mass index (BMI) to Gleason score at biopsy. PATIENTS AND METHODS: This study included 128 Japanese patients diagnosed with prostate cancer from 2000 through 2012 whose serum testosterone level and BMI were measured before treatment. Associations between clinical parameters, including pre-treatment serum testosterone level and BMI, and Gleason score at biopsy were examined. RESULTS: The median serum testosterone and BMI were 434 ng/dl (interquartile range=362-542 ng/dl) and 23.5 kg/m(2) (interquartile range=21.7-25.4 kg/m(2)), respectively. Gleason score at biopsy was <7, 7 and >7 for 58 patients (45.3%), 52 patients (40.6%) and 18 patients (14.1%), respectively. On univariate analysis, positive finding at digital rectal examination (DRE), high prostate-specific antigen level at diagnosis and low serum testosterone level, but not BMI, were correlated with high Gleason score at biopsy. Multivariate analysis identified positive finding at DRE and low serum testosterone level as significant predictors of a high Gleason score at prostate biopsy. By combining these parameters, the predictive ability of a high Gleason score was improved. CONCLUSION: This study showed that positive finding at DRE and a low pre-treatment serum testosterone level, but not obesity, may be factors predictive of aggressive prostate cancer, indicating the diagnostic value of serum testosterone, as well as DRE findings, in risk assessment.