Mechanisms of HER2-Induced endothelial cell retraction
Mechanisms of HER2-Induced endothelial cell retraction
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DOI：
10.1245/s10434-007-9442-4
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发表时间：
2007-10-01
影响因子：
3.7
通讯作者：
Muffly, Barbara J.
中科院分区：
文献类型：
--
作者：
Carter, W. Bradford;Niu, Guilian;Muffly, Barbara J.
背景：HER2过表达在乳腺癌中具有转移优势。我们已经证明，乳腺癌细胞中的HER2信号诱导邻近内皮细胞（EC）缩回，破坏内皮细胞的完整性。由于内皮的完整性依赖于粘附体的连接，我们假设肿瘤细胞诱导的EC收缩机制涉及血管内皮（VE）钙粘蛋白的连环蛋白解离。在这项研究中，我们报道了肿瘤相关EC中ve -钙粘蛋白的缺失。我们还通过操纵肿瘤细胞中的HER2信号，测试了catenin与VE-cadherin分离的变化。方法：在暴露于乳腺癌细胞或条件培养基后，我们检测了人EC的融合单层对VE钙粘蛋白的下调和VE钙粘蛋白的分离。通过免疫沉淀，我们定量分析了不同处理后肿瘤相关EC中剩余的复合连环蛋白为ve -钙粘蛋白，以操纵HER2信号传导。结果：用表达HER2的MCF-7细胞的条件培养基处理EC诱导VE-cadherin表达缺失，以及VE-cadherin中连环蛋白的时间依赖性解离。Heregulin β 1刺激可增强Catenin与VE-cadherin的分离（P < 0.05），而曲妥珠单抗阻断癌细胞中HER2信号传导可降低Catenin与VE-cadherin的分离（P < 0.05）。8小时后发现EC phosphoSrc （Tyr 416）升高。结论：我们的数据表明HER2诱导EC收缩涉及VE-cadherin的下调和连环蛋白的解离。HER2信号似乎调节了这种潜在的转移机制。此外，Src磷酸化表明该途径可能参与了这一机制。
Background: HER2 overexpression imparts a metastatic advantage in breast cancer. We have shown that HER2 signaling in breast cancer cells induces adjacent endothelial cell (EC) retraction, disrupting endothelial integrity. Because endothelial integrity is dependent on the adherens junctions, we postulated that the mechanism of tumor cell-induced EC retraction involves dissociation of catenin proteins from vascular endothelial (VE) cadherin. In this study, we report a loss of VE-cadherin in tumor-associated EC. We also tested for a change of catenin dissociation from VE-cadherin by manipulating HER2 signaling in tumor cells.Methods: We tested confluent monolayers of human EC for downregulation of VE cadherin and dissociation of catenins from VE cadherin after exposure to breast cancer cells or conditioned media. Using immunoprecipitation, we quantitated the remaining complexed catenins to VE-cadherin in tumor-associated EC after different treatments to manipulate HER2 signaling.Results: Treatment of EC with conditioned media from MCF-7 cells expressing HER2 induced a loss of VE-cadherin expression, and time-dependent dissociation of catenins from VE cadherin. Catenin dissociation from VE-cadherin was enhanced by Heregulin beta 1 (P < .05) stimulation and decreased by trastuzumab (P < .05) blockade of HER2 signaling in cancer cells. An increase in EC phosphoSrc (Tyr 416) was seen by 8 hours.Conclusions: Our data suggest that HER2 induction of EC retraction involves both down-regulation of VE-cadherin and dissociation of catenins. HER2 signaling appears to regulate this potential metastatic mechanism. Further, Src phosphorylation suggests that this pathway may be involved in this mechanism.