Monocyte Induction of E-Selectin-Mediated Endothelial Activation Releases VE-Cadherin Junctions to Promote Tumor Cell Extravasation in the Metastasis Cascade.
Monocyte Induction of E-Selectin-Mediated Endothelial Activation Releases VE-Cadherin Junctions to Promote Tumor Cell Extravasation in the Metastasis Cascade.
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DOI：
10.1158/0008-5472.can-16-0784
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发表时间：
2016-09-15
期刊：
影响因子：
11.2
通讯作者：
Borsig L
中科院分区：
文献类型：
--
作者：
Häuselmann I;Roblek M;Protsyuk D;Huck V;Knopfova L;Grässle S;Bauer AT;Schneider SW;Borsig L
肿瘤细胞与血液成分相互作用，这些相互作用促进转移。选择素是促进肿瘤细胞与血小板、白细胞和内皮相互作用的血管受体，但内皮E-选择素的作用仍不清楚。在这里，我们证明 E-选择素是单核细胞募集到肿瘤细胞激活的内皮细胞的主要受体。使用小鼠肿瘤细胞（没有 E-选择素配体）进行的实验性和自发性肺转移在 E-选择素缺陷小鼠中得到减弱。肿瘤细胞来源的 CCL2 促进内皮激活，导致内皮 E-选择素表达增强。炎症单核细胞向转移性肿瘤细胞的募集依赖于局部内皮激活和 E-选择素的存在。单核细胞通过诱导 E-选择素依赖性内皮回缩以及随后通过 VE-钙粘蛋白去磷酸化调节紧密连接来促进肿瘤细胞的跨内皮迁移。因此，内皮E-选择素通过单核细胞的募集、粘附和激活来塑造肿瘤微环境，从而促进肿瘤细胞外渗并从而转移。这些发现提供了证据，证明内皮E-选择素是促进有效肺转移所需的内皮回缩的新因素。
Tumor cells interact with blood constituents and these interactions promote metastasis. Selectins are vascular receptors facilitating interactions of tumor cells with platelets, leukocytes and endothelium but the role of endothelial E-selectin remains unclear. Here we show that E-selectin is a major receptor for monocyte recruitment to tumor cell-activated endothelium. Experimental and spontaneous lung metastasis using murine tumor cells, without E-selectin ligands, were attenuated in E-selectin-deficient mice. Tumor cell-derived CCL2 promoted endothelial activation resulting in enhanced endothelial E-selectin expression. The recruitment of inflammatory monocytes to metastasizing tumor cells was dependent on the local endothelial activation and the presence of E-selectin. Monocytes promoted trans-endothelial migration of tumor cells through the induction of E-selectin-dependent endothelial retractions and a subsequent modulation of tight junctions through dephosphorylation of VE-cadherin. Thus, endothelial E-selectin shapes the tumor microenvironment through the recruitment, adhesion and activation of monocytes that facilitate tumor cell extravasation and thereby metastasis. These findings provide evidence that endothelial E-selectin is a novel factor contributing to endothelial retraction required for efficient lung metastasis.