VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells.
VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells.
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DOI：
10.1038/srep45835
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发表时间：
2017-04-10
影响因子：
4.6
通讯作者：
Dong C
中科院分区：
文献类型：
--
作者：
Aragon-Sanabria V;Pohler SE;Eswar VJ;Bierowski M;Gomez EW;Dong C
在转移过程中，内皮屏障的破坏对于肿瘤细胞通过血管壁外渗是至关重要的，并且由肿瘤分泌的可溶性因子和受体-配体相互作用的组合介导。然而，肿瘤细胞跨内皮迁移的完整机制尚不清楚。在这里，我们研究肿瘤相关信号在调节内皮细胞收缩性和粘附连接解体导致内皮屏障破坏中的作用。我们表明，Src介导VE-钙粘蛋白分解在转移性黑色素瘤细胞。通过使用药理学抑制剂的细胞骨架收缩，我们发现，内皮细胞的收缩是响应与转移性癌细胞的相互作用，并减少内皮细胞收缩废除迁移的黑色素瘤细胞通过内皮单层。此外，我们发现肿瘤分泌的可溶性因子和受体-配体相互作用的组合介导内皮细胞内Src的活化，这是VE-钙粘蛋白磷酸化和内皮屏障破坏所必需的。总之，这些结果提供了对肿瘤细胞信号如何协同作用以调节外渗期间细胞骨架收缩性和粘附连接解体的见解，并可能有助于鉴定阻断转移的治疗靶点。
During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis.