前列腺癌中雄激素受体的表观遗传学研究进展*

雄激素受体（androgen receptor,AR）作为核内转录因子是前列腺癌中最常见的治疗靶标,在去势抵抗性前列腺癌（castration resistant prostate cancer,CRPC）中雄激素受体也起到了非常重要的作用。去势抵抗性前列腺癌的发生发展机制是当前的研究热点。表观遗传学的改变在前列腺癌的发展中具有重要作用。甲基化、乙酰化及非编码RNA可以通过对雄激素受体信号通路的调控促进或者抑制前列腺癌的发生发展。本文将近期关于前列腺癌雄激素受体信号通路表观遗传学的调节机制进行综述。      

去势抵抗性前列腺癌化疗耐药机制的研究进展

前列腺癌的发病率和死亡率逐年上升,去势治疗是中晚期前列腺癌的最主要治疗方法,但去势抵抗性前列腺癌为临床治疗难点,化疗虽为后续主要治疗手段,但易出现耐药。最新研究表明,去势抵抗性前列腺癌患者化疗后再使用抗雄激素药物能提高总生存率。本文就近年来去势抵抗性前列腺癌化疗耐药相关机制做一综述,探讨雄激素受体、自噬、JAK/STAT3信号通路在去势抵抗性前列腺癌发生化疗耐药过程中所发挥的调控作用。     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标

0 引言 雄激素和雄激素受体(androgen receptor,AR)通路激活在前列腺癌的发生、发展中具有重要作用.因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法(androgen deprivation therapy,ADT)一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80％的患者不可避免的发展为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC),生存期不超过2年[1-2].最近研究表明,前列腺癌细胞自身获得经由胆固醇从头合成雄激素的能力以及肿瘤利用肾上腺来源的激素前体转化为雄激素是前列腺癌进展为CRPC的关键因素[3-6].     

AKR1C3:防治前列腺癌向去势抵抗性前列腺癌进展的新靶标北大核心CSCD

0引言雄激素和雄激素受体（androgen receptor,AR）通路激活在前列腺癌的发生、发展中具有重要作用。因此,以降低血清雄激素水平和拮抗AR为目的的雄激素剥夺疗法（androgen deprivation therapy,ADT）一直是治疗晚期前列腺癌及其转移癌的经典方法,但经过12～18月的ADT后,超过80%的患者不可避免的发展为去势抵抗性前列腺癌.     

去势抵抗性前列腺癌的治疗进展*

去势抵抗性前列腺癌是一种致死性疾病,进展快,常伴随着转移,预后极差,死亡率接近100% ,患者中位生存时间少于20个月,是前列腺癌治疗的热点和难题,其发生发展机制尚不明确。近些年来涌现出许多治疗去势抵抗性前列腺癌的新方法,包括新型雄激素受体拮抗剂、免疫治疗、紫杉烷类化疗药物、抗血管生成药物、放射性核素、骨靶向药物以及各疗法联合应用等,改善了患者的生存期。本文就去势抵抗性前列腺癌的治疗进展进行综述。      

抗雄激素药物治疗去势抵抗型前列腺癌的机制研究进展

去势抵抗型前列腺癌（castration-resistant prostate cancer ,CRPC）是指经内分泌治疗产生耐药并继续发展的致命性前列腺癌,雄激素受体（androgen receptor,AR）激活途径仍是这一阶段前列腺癌发展的驱动机制,因此抗雄激素治疗仍然是重要的治疗手段之一。虽然许多新型抗雄激素治疗药物在临床治疗中显示了显著的疗效,但同时耐药也频繁出现。本文就近年来几种主要抗雄激素治疗药物的作用及相应的耐药机制进行综述。      

雄激素受体在前列腺癌细胞中作用及其靶向治疗的研究进展

雄激素受体(androgen receptor, AR)在前列腺癌的发生发展中扮演重要角色。雄激素剥夺疗法(androgen deprivationtherapy, ADT)早期可成功抑制肿瘤的生长, 但最终导致肿瘤复发并进入激素抵抗阶段。AR对前列腺癌基质细胞起促进肿瘤增殖和转移作用, 是上皮腔样细胞的存活因子, 而对肿瘤干细胞样细胞及上皮基底细胞的增殖起抑制作用, AR在不同类型细胞中的不同作用向当前ADT传统的疗法提出挑战, 为发展新的治疗策略提供理论依据。目前以AR为靶点的靶向治疗药物研发也取得一些进展。本文就AR在前列腺癌不同类型细胞中的作用及靶向治疗方面的进展加以综述。      

前列腺癌干细胞与去势抵抗性前列腺癌放射性耐受的研究进展

前列腺癌经过去势治疗后有进展为去势抵抗性前列腺癌的可能。去势抵抗性前列腺癌对临床医生最大的挑战为其治疗抵抗特性。针对放疗耐受,相关研究认为与前列腺癌干细胞及前列腺癌干细胞相关miRNA相关。下文从去势抵抗性前列腺癌进展机制、前列腺癌干细胞及前列腺癌干细胞相关miRNA等方面介绍去势抵抗性前列腺癌放射性耐受的研究进展。     

人参皂苷抑制去势抵抗性前列腺癌的分子生物学机制

人参皂苷单体Rh2和Rg3具有促进细胞凋亡的作用，研究发现Toll样受体中的TLR4可通过MYD88等下游信号蛋白经由NF-κB反应途径激活白介素6和白介素8的表达，而IL-6和IL-8可以进一步通过JAK-STAT、Src类酪氨酸蛋白激酶、FAK-Ras-MAPK等配体非依赖性的细胞信号传导途径活化雄激素受体，而非配体依赖性AR的激活则进一步促进了前列腺癌肿瘤细胞的增殖，由此推测TLR4、IL-6/IL-8、AR的逐级活化正是去势抵抗性前列腺癌进展的重要机制，研究发现人参皂苷可以下调Toll样受体的表达及活性，由此推测人参皂苷通过下调TLR4，进而抑制IL-6/IL-8和AR受体的表达，最终抑制去势抵抗性前列腺癌的进展。     

去势抵抗性前列腺癌的药物治疗现状

雄激素剥夺疗法(ADT)一直是晚期前列腺癌的代表性疗法。当前列腺癌进展为去势抵抗性前列腺癌(CRPC)时,ADT的抗性也随之出现。目前,多西他赛是首个被美国食品药品监督管理局(FDA)批准用于CRPC的细胞毒性化疗药物。另外,还有阿比特龙、恩杂鲁胺等药物也获得FDA批准,且这些药物都显示出良好的生存获益。本文对这些疗法的临床试验和生存获益进行了回顾,并对这一领域的新兴药物进行了讨论。本综述将对CRPC的药物治疗现状进行陈述,并为临床用药提供参考。     

Androgen receptor: role and novel therapeutic prospects in prostate cancer

Androgen receptor (AR) signaling is necessary for the development of prostate cancer. Androgen-deprivation therapy (ADT) for prostate cancer was described over 50 years ago and ADT remains the mainstay of systemic therapy. AR signaling remains intact as the disease evolves to castration-resistant prostate cancer (CRPC). Through cellular adaptations, CRPC continues to rely on androgens and AR growth signaling, and thus AR remains an important therapeutic target. CRPC cells upregulate enzymes used in androgen synthesis, thus providing an intracellular source of androgen despite systemic castration. Compounds in development, such as antiandrogens, lyase inhibitors, heat-shock protein-90 inhibitors, histone deacetylase inhibitors and others, will provide new tools to more effectively reduce ligand, inhibit AR and/or inhibit costimulatory pathways and result in improved clinical outcomes.     

Androgen receptor: role and novel therapeutic prospects in prostate cancer

Androgen receptor (AR) signaling is necessary for the development of prostate cancer. Androgen-deprivation therapy (ADT) for prostate cancer was described over 50 years ago and ADT remains the mainstay of systemic therapy. AR signaling remains intact as the disease evolves to castration-resistant prostate cancer (CRPC). Through cellular adaptations, CRPC continues to rely on androgens and AR growth signaling, and thus AR remains an important therapeutic target. CRPC cells upregulate enzymes used in androgen synthesis, thus providing an intracellular source of androgen despite systemic castration. Compounds in development, such as antiandrogens, lyase inhibitors, heat-shock protein-90 inhibitors, histone deacetylase inhibitors and others, will provide new tools to more effectively reduce ligand, inhibit AR and/or inhibit costimulatory pathways and result in improved clinical outcomes.     

Platelet-Synthesized Testosterone in Men with Prostate Cancer Induces Androgen Receptor Signaling

Platelets have been long postulated to play a critical role in the pathogenesis of prostate cancer, although relatively little is known regarding the precise mechanisms involved. Androgen deprivation therapy (ADT) for prostate cancer eventually fails with relapse occurring in the form of castration-resistant prostate cancer (CRPC). CRPC tumors typically overexpress androgen receptor (AR), demonstrating continued dependence upon AR signaling. Platelets have been previously demonstrated to contain androgens, and we sought to explore the contribution of platelet-derived androgens in CRPC. In this study, we examined the role of platelet-derived androgens in vitro using platelets from men with CRPC, men with high-risk prostate cancer, and healthy male donors. A series of in vitro assays was performed to elucidate the impact of platelet-derived androgens on androgen-sensitive prostate tumor cells. By examining platelet-derived androgen effects on AR signaling in prostate tumor cells, we found that platelets, from men with CRPC and on ADT, strongly induce AR target genes and tumor cell proliferation. Moreover, we show a fully intact testosterone (T) biosynthetic pathway within platelets from its precursor cholesterol and demonstrate that platelets of CRPC patients with ADT resistance are able to generate T. Overall, our findings reveal an unknown capacity of platelets to synthesize T at functionally relevant levels in patients with lethal prostate cancer. Importantly, it suggests a novel paracrine mechanism of T production that may act to sustain CRPC state and potentiate therapeutic resistance.Abbreviations: ADT, androgen deprivation therapy; AR, androgen receptor; CRPC, castration-resistant prostate cancer; DHT, dihydrotestosterone; HR, high-risk disease; MS, mass spectrometry; T, testosterone     

Androgen Receptor Roles in Benign and Malignant Prostate Disease

Androgen deprivation therapy (ADT), which aims to reduce androgen-androgen receptor (AR) signaling, is the normal method of prostate cancer treatment. Despite its early success in suppressing prostate tumor growth, the therapy eventually fails, leading to recurrent hormone-refractory tumor growth. Recent studies have been carried out with stromal cell-specific or fibroblastspecific AR knockout mice or prostate stromal-specific and epithelial-specific AR knockout transgenic mice prostate cancer models and in vitro and in vivo studies of various human prostate cancer cells with knock-in and knock-out of the AR. These have indicated that the AR in prostatic stroma acts as a proliferation stimulator and survival factor, whereas epithelial AR acts as a survival factor for epithelial luminal cells and stromal smooth muscle cell differentiation, and as a suppressor for epithelial basal intermediate cell proliferation. These two opposite roles of the stromal and epithelial AR pose a major challenge for ADT and should be taken into account when developing new therapies targeting AR in selective cells.     

Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant,AR-V7, in prostate cancer cells

Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.     

前列腺癌雄激素剥夺治疗的新思路——睾酮最大控制临床研究新进展

前列腺癌是常见的男性恶性肿瘤之一,其发病率位居男性恶性肿瘤第二位。前列腺癌的发病率居于所有男性恶性肿瘤首位。中国男性的前列腺癌发病率低于欧美国家,但随着生活方式、饮食习惯的西化以及人均寿命延长,前列腺癌的发病率也呈现逐年升高的趋势。雄激素受体（androgen receptor,AR）在前列腺癌的发生、发展过程中扮演着重要角色,抑制AR信号转导通路是前列腺癌治疗的基础,比如在去势抵抗性前列腺癌（castration-resistant prostate cancer,CRPC）治疗中,使用AR拮抗剂能够竞争性结合AR并阻断内源性雄激素的结合,从而干扰雄激素依赖的细胞下游反应,阻止前列腺癌的进展。雄激素剥夺治疗（androgen deprivation therapy,ADT）是前列腺癌治疗的基石,国内专家共识中前列腺癌去势治疗有效定义的睾酮（testosterone,T）水平为低于50 ng/dL。随着研究的深入,越来越多的研究表明T低于20 ng/dL的患者临床预后更佳：T ＜ 20 ng/dL时可以诱导包括雄激素敏感和部分雄激素不敏感亚群细胞的死亡,在治疗间隙细胞增殖时可以获得雄激素高度敏感的细胞群,从而延长了去势抵抗的时间。如果不能达到T ＜ 20 ng/dL,可能会导致部分雄激素不敏感的亚群持续存在,这些亚群在再次治疗后会快速增殖,加速肿瘤向去势抵抗发展。目前控制T水平的促性腺激素释放激素激动剂（gonadotropin-releasing hormone agonist,GnRHa）的有效性和安全性在研究中和临床上均得到了明确的验证,在药物层面上提供了控制T ＜ 20 ng/dL的临床可行性。通过总结T水平与ADT新进展,探讨最大限度控制T水平与前列腺癌治疗中患者受益、药物疗效及安全性的关系。     

Adaptive responses of androgen receptor signaling in castration-resistant prostate cancer

Prostate Cancer (PCa) is an important age-related disease being the most common cancer malignancy and the second leading cause of cancer mortality in men in Western countries. Initially, PCa progression is androgen receptor (AR)- and androgen-dependent. Eventually advanced PCa reaches the stage of Castration-Resistant Prostate Cancer (CRPC), but remains dependent on AR, which indicates the importance of AR activity also for CRPC. Here, we discuss various pathways that influence the AR activity in CRPC, which indicates an adaptation of the AR signaling in PCa to overcome the treatment of PCa. The adaptation pathways include interferences of the normal regulation of the AR protein level, the expression of AR variants, the crosstalk of the AR with cytokine tyrosine kinases, the Src-Akt-, the MAPK-signaling pathways and AR corepressors. Furthermore, we summarize the current treatment options with regard to the underlying molecular basis of the common adaptation processes of AR signaling that may arise after the treatment with AR antagonists, androgen deprivation therapy (ADT) as well as for CRPC, and point towards novel therapeutic strategies. The understanding of individualized adaptation processes in PCa will lead to individualized treatment options in the future.     

Stem cells in prostate cancer: resolving the castrate-resistant conundrum and implications for hormonal therapy

Androgen deprivation therapy (ADT) is initial systemic therapy for advanced prostate cancer and is used as an adjuvant to local therapy for high-risk disease, but responses in advanced disease are transient. Prostate cancer stem cells are a small fraction of tumor cells that give rise to malignant cells. Initial or acquired stem cell resistance to castration must therefore underlie castrate-resistant prostate cancer. We sought to review the evidence on cancer stem cells and androgen deprivation therapy to determine if prostate cancer stem cell resistance occurs from the outset, or if it is an acquired resistance. Prostate cancer stem cells do not express androgen receptor (AR) and hence should not be directly responsive to androgen deprivation therapy. However, castrate-resistant tumors that are derived from stem cells, have molecular changes such as amplification of the androgen receptor gene, or other genetic changes resulting in gain-of-function changes in AR, implying an acquired resistance to androgen deprivation. The origins of castrate-resistant tumors, with mechanisms such as androgen receptor gene amplification from androgen receptor negative prostate cancer stem cells, is an apparent conundrum. Insight into how this occurs may lead to new treatments that overcome or delay castrate-resistance. Herein, we review the evidence on cancer stem cells, the benefits of ADT, the biological basis of response to ADT, and mechanisms of castrate-resistance. We also explore the apparent conundrum of why AR-negative prostate cancer stem cells can give rise to castrate-resistant prostate cancer. We propose possible explanations that may resolve this conundrum and discuss implications for hormonal therapy.     

Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT.