Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor β signaling
Vascular endothelial cadherin promotes breast cancer progression via transforming growth factor β signaling
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DOI：
10.1158/0008-5472.can-07-2706
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Breier, Georg
中科院分区：
文献类型：
--
作者：
Labelle, Myriam;Schnittler, Hans J.;Breier, Georg
上皮向间充质转化(EMT)是肿瘤进展过程中的一个重要事件，导致肿瘤细胞恶性程度增加。在这里，我们显示血管内皮细胞(VE)-钙粘附素在EMT过程中在乳腺肿瘤细胞中被诱导，并在浸润性乳腺癌中异常表达。Ve-cadherin增强了成纤维细胞样肿瘤细胞的增殖能力，形成了索状侵袭结构，并附着于内皮细胞，这些特性是其恶性程度和转移潜力增加的关键因素。在体内实验中，VE-钙粘附素在恶性成纤维细胞瘤细胞中的表达促进了实验性乳腺癌的生长。对相关信号机制的分析表明，VE-cadherin的表达影响Smad2的磷酸化水平和转化生长因子-β的靶基因表达，转化生长因子-β是晚期肿瘤进展和恶性肿瘤细胞增殖的主要介质。因此，VE-钙粘附素可能不仅通过促进肿瘤再生，而且通过转化生长因子-β信号通路促进肿瘤细胞的增殖，从而促进肿瘤进展。这篇文章为VE-钙粘蛋白在肿瘤进展中的新功能提供了证据，并揭示了以前未知的VE-钙粘蛋白表达与转化生长因子信号之间的分子联系。我们的发现可能对抗VE-钙粘附素策略的临床应用具有重要意义。
Epithelial-to-mesenchymal transition (EMT) is an important event during carcinoma progression and leads to increased tumor cell malignancy. Here, we show that vascular endothelial (VE)-cadherin is induced during EMT in mammary tumor cells and is aberrantly expressed in invasive human breast carcinomas. VE-cadherin enhanced the capacity of fibroblastoid tumor cells to proliferate, form cord-like invasive structures, and adhere to endothelial cells, characteristics that are key contributors to their increased malignancy and metastatic potential. Consistently, VE-cadherin expression in malignant fibroblastoid tumor cells promoted the growth of experimental mammary carcinomas in vivo. Analysis of the signaling mechanisms involved revealed that VE-cadherin expression influences the levels of Smad2 phosphorylation and expression of target genes of transforming growth factor-beta (TGF-beta), a major mediator of advanced tumor progression and malignant tumor cell proliferation. VE-cadherin might thus promote tumor progression not only by contributing to tumor anaiogenesis but also by enhancing tumor cell proliferation via the TGF-beta signaling pathway. This article provides evidence for a novel function of VE-cadherin in tumor progression and reveals a previously unknown molecular link between VE-cadherin expression and TGF- signaling. Our findings may have important implications for the clinical application of anti-VE-cadherin strategies.