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 transendothelial 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. Cancer Res; 76(18); 5302-12. ©2016 AACR.
- MeSH
- CD antigeny metabolismus MeSH
- cévní endotel metabolismus MeSH
- E-selektin metabolismus MeSH
- endoteliální buňky metabolismus MeSH
- imunoblotting MeSH
- imunoprecipitace MeSH
- invazivní růst nádoru patologie MeSH
- kadheriny metabolismus MeSH
- modely nemocí na zvířatech MeSH
- monocyty metabolismus MeSH
- mutantní kmeny myší MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- polymerázová řetězová reakce MeSH
- průtoková cytometrie MeSH
- těsný spoj metabolismus patologie MeSH
- transendoteliální a transepiteliální migrace fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
