Estrogen-Mediated Angiogenesis in Thyroid Tumor Microenvironment Is Mediated Through VEGF Signaling Pathways
Estrogen-Mediated Angiogenesis in Thyroid Tumor Microenvironment Is Mediated Through VEGF Signaling Pathways
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DOI：
10.1001/archoto.2011.194
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发表时间：
2011-11-01
影响因子：
--
通讯作者：
Schantz, Stimson
中科院分区：
文献类型：
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作者：
Kamat, Ameet;Rajoria, Shilpi;Schantz, Stimson
目的：探讨雌激素对甲状腺肿瘤微环境内皮细胞促血管生成表型的诱导作用，以及血管内皮生长因子(VEGF)在这种相互作用中的作用。设计：体外细胞系统分析。对象：甲状腺肿瘤细胞系(bCPAP[乳头状甲状腺癌]和ML-1[滤泡性甲状腺癌])与雌激素受体(ER)抑制剂(Fulvestrant或ICI)加和不加雌激素受体(ER)抑制剂(Fulvestrant或ICI)的雌二醇共培养，并用于处理人脐静脉内皮细胞(HUVECs)。干预：用免疫荧光方法证实bCPAP细胞中ERα和βER的存在。用条件培养液检测HUVEC对小管生成和迁移的诱导。用免疫印迹法检测培养上清液中血管内皮生长因子的分泌。HUVEC裂解产物的Western印迹分析检测促血管生成途径的启动子--磷脂酰肌醇3-激酶(PI3K)的表达。结果：甲状腺癌细胞表达雌激素受体α和ERβ。雌激素刺激的ML-1细胞分泌更多的血管内皮生长因子可能是ER信号的结果。在与这种环境接触时，HUVECs表现出增强的小管生成和迁移。Western印迹分析证实雌激素可上调HUVECs中PI3K的表达。这些影响可被ER抑制剂(fulvestrant/ICI)和中和的VEGF抗体缓解。结论：我们的数据提供了证据，证明雌激素可以通过ER和VEGF信号转导在甲状腺肿瘤微环境中诱导血管生成前内皮细胞表型。我们的研究结果表明，通过抑制血管内皮生长因子可以增强针对肿瘤血管生成的抗雌激素治疗的效果。
Objectives: To explore the induction of a proangiogenic phenotype in endothelial cells in the thyroid tumor microenvironment by estrogen-treated thyroid cancer cells and to define the role of vascular endothelial growth factor (VEGF) in this interaction.Design: Cell-based in vitro systems analysis.Subjects: Thyroid tumor cell lines (BCPAP [papillary thyroid cancer] and ML-1 [follicular thyroid cancer]) were cultured with estradiol with and without an estrogen receptor (ER) inhibitor (fulvestrant or ICI) and used to treat human umbilical vein endothelial cells (HUVECs).Interventions: Immunofluorescence was used to confirm the presence of ER alpha and ER beta in BCPAP cells. Conditioned medium was then used to evaluate the induction of HUVEC tubulogenesis and migration. Secretion of VEGF in this medium was evaluated by Western blot analysis. The expression of phosphoinositide 3-kinase (PI3K), the initiator of a proangiogenic pathway, was evaluated with Western blot analysis of HUVEC lysates. The subsequent effects of an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody were also observed.Results: Estrogen receptor alpha and ER beta are expressed in thyroid cancer cells. Estrogen-stimulated ML-1 cells secreted an increased amount of VEGF likely as a result of ER signaling. In contact with this environment, HUVECs demonstrate enhanced tubulogenesis and migration. Western blot analysis documented estrogen-mediated upregulation of PI3K in HUVECs. These effects were mitigated by an ER inhibitor (fulvestrant/ICI) and a neutralizing VEGF antibody.Conclusions: Our data provide evidence that estrogen can induce a proangiogenic endothelial cell phenotype in the thyroid tumor microenvironment through ER and VEGF signaling. Our findings suggest that the effect of antiestrogenic therapy targeting tumor angiogenesis can be enhanced through VEGF inhibition.