Prostate cancer: androgen deprivation causes EMT in the prostate.
Prostate cancer: androgen deprivation causes EMT in the prostate.
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DOI：
10.1038/nrurol.2011.208
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发表时间：
2011-12-27
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影响因子：
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通讯作者：
Clyne, Melanie
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作者：
Clyne, Melanie
根据美国旧金山弗朗西斯科的一组研究人员的研究，雄激素缺乏会导致健康和癌变前列腺组织的上皮-间质转化（EMT）。这一过程被认为是由雄激素受体和Zeb 1之间的负反馈回路介导的。在第一组实验中，Sun等人评估了完整和去势小鼠前列腺的基因表达谱。去势后3天，N-cadherin，Twist 1和Slug表达水平上调。这些增加在睾酮补充后被逆转。在患者的肿瘤活检中观察到类似的变化，并且SLUG是化学去势后14天表达状态的顶级基因之一。在进一步的工作中，将LuCaP 35的异种移植物-来自前列腺癌的淋巴结转移-移植到小鼠身上。那些建立了移植物的人被阉割，4周后分离出消退的肿瘤。基因表达谱分析显示，在消退的癌症中激活了TGFβ信号传导，以及几种EMT诱导基因和两种“干性”标志物（WNT 5a和WNT 5 b）的表达增加。体外去势-通过剥夺LNCaP细胞的细胞产生生长缓慢的细胞，这些细胞形成球体并粘附在平板上。在所有研究中，雄激素剥夺导致ZEB 1表达增加，表明该基因在EMT中起关键作用。雄激素受体和Zeb 1的表达是相互排斥的，该小组确定了一个双向负反馈回路，介导去势诱导的EMT。这些发现可能对前列腺癌治疗产生重大影响，因为EMT与治疗耐药性和预后不良有关。因此，接受雄激素剥夺治疗的患者可能受益于EMT抑制剂的伴随治疗。为了支持这一理论，一种靶向N-钙粘蛋白的新型药物已被证明可以延迟去势抵抗的发生。“靶向N-钙粘蛋白的单克隆抗体是令人鼓舞的，尽管毒性可能最终限制它们的效用，”
Androgen deprivation causes epithelial–mesenchymal transition (EMT) in both healthy and cancerous prostate tissue, according to a team of researchers from San Francisco, USA. This process is thought to be mediated by a negative feedback loop between the androgen receptor and Zeb1. In the first set of experiments, Sun et al. evaluated the gene expression profiles of intact and castrated mouse prostates. 3 days postcastration, N-cadherin, Twist1 and Slug expression levels were upregulated. These increases were reversed upon testosterone replenishment. Similar changes were observed in tumor biopsies from patients and SLUG was one of the top-ranking genes for expression status 14 days after chemical castration. In further work, xenografts of LuCaP35—derived from a lymph node metastasis of prostate cancer—were transplanted onto mice. Those with established grafts were castrated, and regressed tumors were isolated 4 weeks later. Gene expression profiling revealed activated TGFβ signaling in regressed cancers, as well as increased expression of several EMT-inducing genes and two ‘stemness’ markers (WNT5a and WNT5b).‘In vitro castration’—achieved by depriving LNCaP cells of hormones—produced slow-growing cells that formed spheres and adhered poorly to plates. In all studies, androgen deprivation resulted in increased ZEB1 expression, suggesting a key role for this gene in EMT. Androgen receptor and Zeb1 expression are mutually exclusive of each other and the group identified a bidirectional negative feedback loop that mediates castration-induced EMT. These findings could have significant implications for prostate cancer therapy as EMT has been linked to therapeutic resistance and a poor prognosis. Thus, patients receiving androgen deprivation therapy might benefit from concomitant treatment with an EMT inhibitor. In support of this theory, a novel drug targeting N-cadherin has been shown to delay the onset of castration resistance.“The monoclonal antibodies targeting N-cadherin are encouraging, though toxicity may ultimately limit their utility,”