Blockade of Estrogen Receptor Signaling Inhibits Growth and Migration of Medulloblastoma
Blockade of Estrogen Receptor Signaling Inhibits Growth and Migration of Medulloblastoma
复制标题
DOI：
10.1210/en.2008-1363
复制
发表时间：
2009-03-01
期刊：
影响因子：
4.8
通讯作者：
Le, Hoa H.
中科院分区：
文献类型：
--
作者：
Belcher, Scott M.;Ma, Xiaolan;Le, Hoa H.
髓母细胞瘤是儿童最常见的恶性脑肿瘤。这些侵袭性神经外胚层肿瘤起源于小脑颗粒细胞样前体。在发育中的小脑中，雌激素影响颗粒细胞前体细胞的生长和活力，颗粒细胞前体细胞在分化期间瞬时表达升高水平的雌激素受体β（ER β）。免疫分析显示，ER β在成熟的人小脑中表达，在分析的所有22个原发性MD肿瘤中，以及在两个MD衍生的细胞系（D283 Med和Daoy）中。在每个细胞系和41%的肿瘤样品中检测到非常低水平的ER α样蛋白。生理浓度的17 β-雌二醇或ER β-选择性激动剂2，3-双（4-羟基苯基）-丙腈二芳基丙腈剂量依赖性地增加MD生长和细胞迁移。相比之下，ER α选择性激动剂（4-丙基-[1H]吡唑-1，3，5-三基）三酚不影响MD生长。与以前在正常小脑颗粒细胞前体中的研究类似，这些研究表明，雌激素在MD中的生理作用是由ER β介导的。进行了评估抗雌激素化疗剂治疗人MD的疗效的临床前研究。研究发现，ER拮抗剂药物芙仕得（ICI 182，780）对ER介导的信号传导的药理学抑制可阻断人MD细胞培养和异种移植模型中所有雌激素介导的效应。这些研究表明，功能性ER β表达是MD生物学的一个基本方面，并将抗雌激素治疗定义为改善MD患者长期结局的潜在有效临床方法。（内分泌学150：1112-1121，2009）
Medulloblastoma ( MD) is the most common malignant brain tumor in children. These invasive neuroectodermal tumors arise from cerebellar granule cell-like precursors. In the developing cerebellum, estrogen influences growth and viability of granule cell precursors that transiently express elevated levels estrogen receptor-beta (ER beta) during differentiation. Immunoanalysis revealed that ER beta was expressed in the maturing human cerebellum, in all 22 primary MD tumors analyzed, and in two MD-derived cell lines (D283Med and Daoy). Very low levels of ER alpha-like proteins were detected in each cell line and 41% of tumor samples. Physiological concentrations of the 17 beta-estradiol- or the ER beta-selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile diarylpropionitrile dose-dependently increased MD growth and cellular migration. In contrast, the ER alpha-selective agonist (4-propyl-[1H]pyrazole-1,3,5-triyl) trisphenol did not influence MD growth. Similar to previous studies in normal cerebellar granule cell precursors, these studies demonstrate that the physiological actions of estrogens in MD are mediated by ER beta. Preclinical studies assessing the therapeutic efficacy of antiestrogen chemotherapeutics for treating human MD were performed. It was found that pharmacological inhibition of ER-mediated signaling with the ER antagonist drug Faslodex (ICI182,780) blocked all estrogen-mediated effects in both cell culture and xenograft models of human MD. These studies have revealed that functional ER beta expression is a fundamental aspect of MD biology and has defined antiestrogen therapy as a potentially efficacious clinical approach to improve the long-term outcomes for MD patients. ( Endocrinology 150: 1112-1121, 2009)