雄激素非依赖型前列腺癌相关基因的挖掘及生物信息学分析

目的：从分子水平揭示雄激素非依赖型前列腺癌（AIPC）的发病机制,为临床诊疗提供新思路.方法：在公共基因芯片数据库（GEO）中下载前列腺癌的相关基因芯片数据,使用BRB-ArrayTools软件对其进行数据挖掘分析,筛选AIPC相关基因;并利用GATHER在线分析工具进行深入的生物信息学分析.此外,又利用基因集富集分析（GSEA）软件对上述基因芯片数据集进行了基因富集分析.结果：BRB分析发现在AIPC中有87个差异表达基因,其中上调23个,下调64个.这些差异基因的功能主要集中在细胞信号转导、细胞粘附、粘附斑、细胞外基质（ECM）受体相互作用等功能中.GSEA分析发现AIPC相关基因主要在ECM受体相互作用、SONIC-HEDGEHOG以及HDACI_COLON_TSABUT_DN功能基因集中富集.结论：应用BRB-ArrayTools和GSEA分析发现,ECM受体相互作用、细胞牯附过程及Hedgehog信号通路之间的网络调控系统可能与AIPC的发生密切相关.利用生物信息学的方法能有效分析基因芯片数据并获取生物内在信息,为确定雄激素非依赖型前列腺癌的早期诊断标志与治疗靶点提供新的思路.     

基于文献挖掘的雄激素非依赖型前列腺癌特异表达基因的生物信息学分析

目的:比较雄激素依赖型与非依赖型前列腺癌的基因表达差异,加深对雄激素非依赖型前列腺癌形成的分子机制的认识,为前列腺癌防治找到新的有效手段。方法:通过FACTA工具从PubMed找出前列腺癌的相关基因进行分类,利用GATHER、PANTHER、STRING和ToppGene等在线工具对雄激素非依赖型前列腺癌特异表达基因进行生物信息学分析。结果:筛选雄激素非依赖型前列腺癌特异基因128个,这些特异表达基因在细胞信号转导、凋亡、肿瘤生成、细胞粘附、细胞增殖和分化等生物学过程起着重要作用。结论:通过生物信息学对雄激素非依赖型前列腺癌特异表达基因的挖掘发现,MMP9、EGFR、MMP2、ADM、MIF、IGFBP3、IL2、MET、BAD、RHOA、SPP1、EP300、SMAD3、RAF1、PTK2、TGFB2等基因在雄激素依赖型转变成非依赖型前列腺癌中可能起着重要作用。     

雄激素非依赖型前列腺癌中雄激素受体特征改变的研究进展

前列腺癌在欧美国家高龄男性中发病率较高,在我国的发病率近年来也有明显的上升趋势.雄激素在前列腺癌细胞的生长、转移中起决定性作用,雄激素只有和雄激素受体( androgen receptor,AR)相结合才能发挥作用.在前列腺癌发病前期,肿瘤细胞多为雄激素依赖型,去势治疗有一定疗效.但随着治疗时间延长,部分患者可转变为雄激素非依赖前列腺癌( androgen-independent prostate cancer,AIPC).研究AIPC中AR的相关改变可以帮助我们进一步探索AIPC的成因,为临床治疗提供思路.现就AIPC中与AR相关改变综述如下.     

抗雄激素药物撤退治疗雄激素非依赖性晚期转移性前列腺癌的疗效分析与预测

目的 寻找预测抗雄激素药物撤退治疗雄激素非依赖性晚期转移性前列腺癌有效性的相关因素.方法 晚期转移性前列腺癌患者347例,均接受最大程度雄激素阻断治疗.其中失效进展为雄激素非依赖性前列腺癌(AIPC)237例,接受抗雄激素药物撤退治疗90例.对90例患者进行随访,末次随访时间2009年9月30日.将内分泌治疗前基线血清PSA、Gleason评分(GS)、临床分期、去势方案、抗雄激素药物方案、内分泌治疗过程中血清PSA最低值、达到PSA最低值时间、进展为AIPC时PSA速率(PSAV)、进展为AIPC时PSA倍增时间(PSADT)、内分泌治疗有效时间、进展为AIPC时年龄、抗雄激素药物撤退治疗前PSA作为预测抗雄激素药物撤退治疗是否有效的预测因素,行Logistic单因素及多因素回归分析.结果 90例患者中具有完整随访资料87例,其中有效17例(19.5%),无效70例(80.5%).至末次随访时,失效14例,仍有效3例.抗雄激素药物撤退治疗中位有效时间4个月.单因素分析结果显示,进展为AIPC时PSAV(P=0.033)、进展为AIPC时PSADT(P=0.009)和抗雄激素药物撤退治疗前PSA(P=0.002)为抗雄激素药物撤退治疗有效性的预测因素.多因素分析结果显示:进展为AIPC时PSAV(P=0.042)和PSADT(P=0.036)为抗雄激素药物撤退治疗有效性的独立预测因素.结论 进展为AIPC时PSAV和PSADT为预测抗雄激素药物撤退治疗有效性的独立预测因素.     

前列腺癌雄激素非依赖性相关研究的进展

前列腺癌的雄激素依赖性使得前列腺的内分泌治疗成为可能。但是 ,最终前列腺癌都转化为雄激素非依赖性前列腺癌 (androgen independentprostatecancer,AIPC) ,并因此死亡。如果能够明确前列腺癌的雄激素非依赖性发生机理 ,就能够提出针对性的治疗方法。本文详细综述了AIPC的可能发生机理 ,并对未来AIPC的治疗提出了方向。     

雄激素非依赖性前列腺癌发生的分子机制

雄激素非依赖性前列腺癌（Androgen-independent prostate cancer,AIPC）是前列腺癌进展到一定阶段的表现,是导致前列腺癌恶化的主要原因,当前缺乏有效的治疗方法.因此,研究AIPC的发病机制为全面了解前列腺癌的进程以及在临床上采取有效的治疗手段提供依据.本文就雄激素受体信号途径及神经内分泌分化、凋亡基因异常、隐匿细胞替代等途径,对AIPC的发生机制作一综述.     

雄激素非依赖性前列腺癌发生的分子机制

雄激素非依赖性前列腺癌(Androgen-independent prostate cancer,AIPC)是前列腺癌进展到一定阶段的表现,是导致前列腺癌恶化的主要原因,当前缺乏有效的治疗方法。因此,研究AIPC的发病机制为全面了解前列腺癌的进程以及在临床上采取有效的治疗手段提供依据。本文就雄激素受体信号途径及神经内分泌分化、凋亡基因异常、隐匿细胞替代等途径,对AIPC的发生机制作一综述。     

雄激素受体在雄激素非依赖性前列腺癌的表达

目的探讨雄激素受体(AR)在国人雄激素非依赖性前列腺癌(AIPC)的表达及其临床意义。方法采用免疫组化两步法,检测AR在15例AIPC和20例雄激素依赖性前列腺癌(ADPC)组织标本的表达水平。结果1例AIPC无AR表达,其余14例AIPC及全部ADPC均有AR高表达,AIPC染色的光密值为0.31±0.04较ADPC0.28±0.03升高。结论大多数国人AIPC均高表达AR,AR的异常表达可能在前列腺癌的进展中发挥重要的作用。     

细胞凋亡与晚期前列腺癌的治疗

对晚期前列腺癌，目前尚无十分有效的治疗方法。常规的去势治疗是通过使雄激素依赖型的前列腺癌细胞发生凋亡而起作用，通过时细胞凋亡机制的研究，发现雄激素非依赖型的前列腺癌细胞仍保存着细胞凋亡的能力。因此，探索使雄激素非依赖型的前列腺癌细胞发生凋亡的方法。将为晚期前列腺癌的治疗开辟一条新的途径。     

细胞凋亡与晚期前列腺癌的治疗

对晚期前裂腺癌，目前尚无十分有效的方法。常规的去势治疗是通过使雄激素依赖型的前裂腺癌细胞发生凋亡而起作用，通过对细胞凋亡机制的研究，发现雄激素非依赖型的前列腺癌细胞仍保存着细胞凋亡的能力。因此，探索使雄激素非依赖型的前列腺癌细胞发生凋亡的方法，将为晚期前列腺癌的治疗开辟一条新的途径。     

Bad expression influences time to androgen escape in prostate cancer

OBJECTIVE: To assess the role of selected downstream Bcl-2 family members (Bad, Bax, Bcl-2 and Bcl-xL) in the development of androgen-independent prostate cancer (AIPC), as androgen-deprivation therapy is the treatment of choice in advanced prostate cancer, yet patients generally relapse and progress to an AI state within 18-24 months. PATIENTS, MATERIALS AND METHODS: The patient cohort was established by retrospectively selecting patients with prostate cancer who had an initial response to androgen-deprivation therapy, but subsequently relapsed with AIPC. In all, 58 patients with prostate cancer were included with matched androgen-dependent (AD) and AI prostate tumours available for immunohistochemical analysis; two independent observers using a weighted-histoscore method scored the staining. Changes in Bad, Bax, Bcl-2 and Bcl-xL expression during transition to AIPC were evaluated and then correlated to known clinical variables. RESULTS: High Bad expression in AD tumours was associated with an increased time to biochemical relapse (P = 0.007) and a trend towards improved overall survival (P = 0.053). There were also trends towards a decrease in Bad (P = 0.068) and Bax (P = 0.055) expression with progression to AIPC. There were no significant results for Bcl-2 or Bcl-xL. CONCLUSION: There is evidence to suggest that Bad expression levels at diagnosis influence time to biochemical relapse and overall survival, and that levels of pro-apoptotic proteins Bad and Bax fall during AIPC development. Bad might therefore represent a possible positive prognostic marker and potential therapeutic target for AIPC in the future.     

Hedgehog signalling in androgen independent prostate cancer

Objectives

Androgen-deprivation therapy effectively shrinks hormone-naïve prostate cancer, both in the prostate and at sites of distant metastasis. However prolonged androgen deprivation generally results in relapse and androgen-independent tumour growth, which is inevitably fatal. The molecular events that enable prostate cancer cells to proliferate in reduced androgen conditions are poorly understood. Here we investigate the role of Hedgehog signalling in androgen-independent prostate cancer (AIPC).

Methods

Activity of the Hedgehog signalling pathway was analysed in cultured prostate cancer cells, and circulating prostate tumour cells were isolated from blood samples of patients with AIPC.

Results

AIPC cells were derived through prolonged culture in reduced androgen conditions, modelling hormone therapy in patients, and expressed increased levels of Hedgehog signalling proteins. Exposure of cultured AIPC cells to cyclopamine, which inhibits Hedgehog signalling, resulted in inhibition of cancer cell growth. The expression of the Hedgehog receptor PTCH and the highly prostate cancer–specific gene DD3^PCA3 was significantly higher in circulating prostate cancer cells isolated from patients with AIPC compared with samples prepared from normal individuals. There was an association between PTCH and DD3^PCA3 expression and the length of androgen-ablation therapy.

Conclusions

Our data are consistent with reports implicating overactivity of Hedgehog signalling in prostate cancer and suggest that Hedgehog signalling contributes to the androgen-independent growth of prostate cancer cells. As systemic anti-Hedgehog medicines are developed, the Hedgehog pathway will become a potential new therapeutic target in advanced prostate cancer.     

Changing perspectives of the role of chemotherapy in advanced prostate cancer

The use of cytotoxic chemotherapy in advanced prostate adenocarcinoma has been validated by the recent demonstration of survival benefit in two large randomized phase III trials. Before publication of these landmark trials, SWOG 9916 and TAX 327, no chemotherapeutic regimen had shown survival benefit in the treatment of androgen independent prostate cancer (AIPC). These trials provide new encouragement for the use of chemotherapy in all stages of disease. Improved communication between medical and urologic oncologists and early patient referral for clinical trial participation remains essential for identifying new chemotherapeutic regimens with improved activity in AIPC and for defining the role of chemotherapy in earlier-stage disease. This article discusses the role of chemotherapy as the current standard of care for the treatment of AIPC and provides a historical perspective of the trials that preceded the development of current docetaxel-based regimens.     

Secondary hormonal therapy for advanced prostate cancer

PURPOSE: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer. RESULTS: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents. CONCLUSIONS: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.     

类固醇受体辅活化子-1和核受体辅阻遏子在雄激素非依赖性前列腺癌的表达及临床意义

目的 探讨类固醇受体辅活化子-1（SRC-1）、核受体辅阻遏子（NCoR）在雄激素非依赖性前列腺癌（AIPC）的表达及临床意义。方法 采用免疫组化法检测20例激素依赖性前列腺癌（ADPC）、15例AIPC组织AR、SRC-1及NCoR表达。结果 1例AIPC无AR表达，其余AIPC及ADPC高表达AR。AIPC、ADPC均检测到SRC-1表达。SRC-1在AIPC的阳性率较ADPC组织明显升高（P〈0．01）。NCoR在AIPC、ADPC均有表达，但在AIPC的表达则出现明显降低（P〈0．01）。结论 SRC-1在AIPC表达升高和／或NCoR在AIPC表达降低引起的AR异常活化可能与前列腺癌（Pca）的进展有关。     

Gleason score predicts androgen independent progression after androgen deprivation therapy

OBJECTIVE: The Gleason system is the most widely utilized histologic grading system for prostate cancer and a powerful predictor of cancer behavior. In this study, we evaluated the prognostic value of the Gleason grading system in predicting progression to androgen independent prostate cancer (AIPC). METHODS: Records from 150 patients with advanced or metastatic prostate cancer treated with androgen deprivation therapy (ADT) were retrospectively reviewed. Androgen independent progression was defined as two consecutive elevations of serum prostate specific antigen (PSA) above the nadir value. Kaplan-Meier and the Cox proportional hazards methods were used to assess potential predictors of progression to AIPC. RESULTS: Patients with low and moderate Gleason scores experienced significantly longer remissions compared to those with Gleason score of 8-10 (p=0.0006, Log-Rank test). The cumulative hazard of progressing to AIPC increased by almost 70% for each unit increase in total Gleason score. CONCLUSION: In this patient cohort the Gleason score was the only independent predictor of progression to AIPC.     

雄激素非依赖性前列腺癌的治疗进展

前列腺癌是男性泌尿生殖系常见的恶性肿瘤之一,在我国发病率虽较低,但近年来随着人口老龄化及生活条件的改善,发病率有明显增加的趋势。几乎所有一开始对内分泌治疗敏感的前列腺癌最终都将发展成雄激素非依赖性前列腺癌(AIPC)。AIPC是指对内分泌治疗无反应或内分泌治疗后反而促进疾病进展,导致不可逆的临床进展恶化,直至患者死亡。有关AIPC的发病机制以及治疗策略仍缺乏统一的认识,现就此作一综述。