Faslodex Inhibits Estradiol-Induced Extracellular Matrix Dynamics and Lung Metastasis in a Model of Lymphangioleiomyomatosis
Faslodex Inhibits Estradiol-Induced Extracellular Matrix Dynamics and Lung Metastasis in a Model of Lymphangioleiomyomatosis
复制标题
DOI：
10.1165/rcmb.2012-0476oc
复制
发表时间：
2013-07-01
影响因子：
6.4
通讯作者：
Yu, Jane J.
中科院分区：
文献类型：
--
作者：
Li, Chenggang;Zhou, Xiaobo;Yu, Jane J.
淋巴管平滑肌瘤病（LAM）是一种主要影响女性的破坏性肺部疾病。遗传研究表明，LAM细胞携带灭活结节性硬化症复合体（TSC）-2突变，并转移到肺。我们先前发现雌二醇增加了携带异种移植肿瘤的小鼠中TSC 2缺陷细胞的转移。在此，我们研究了雌二醇诱导TSC 2缺陷细胞肺转移的分子基础，并在LAM临床前模型中检测了芙仕得（一种雌激素受体拮抗剂）的疗效。我们使用了一种异种移植肿瘤模型，其中雌二醇诱导TSC 2缺陷细胞的肺转移。我们分析了芙仕得对肿瘤大小、细胞外基质组织、基质金属蛋白酶（MMP）-2表达和肺转移的影响。我们还在体外研究了雌二醇和芙仕得对结核菌素缺陷细胞中MMP 2表达和活性的影响。与安慰剂治疗的小鼠相比，Eglomerase导致异种移植肿瘤中IV型胶原沉积显著减少，与2倍更高的MMP 2浓度相关。芙仕得使异种移植肿瘤中的IV型胶原蛋白变化正常化，提高小鼠的存活率，并完全阻断肺转移。在体外，雌二醇增强MMP 2的转录，蛋白质的积累，和活动。芙仕得可阻断雌二醇诱导的MMP 2变化。在TSC 2缺陷细胞中，雌二醇增加MMP 2在体外和体内的浓度，并诱导细胞外基质重塑。芙仕得抑制雌激素诱导的TSC 2缺陷细胞肺转移。芙仕得靶向雌激素受体可能有效治疗LAM。
Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.