title: Monocyte Induction of E-Selectin-Mediated Endothelial Activation Releases VE-Cadherin Junctions to Promote Tumor Cell Extravasation in the Metastasis Cascade.
abstract: 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.
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zurich, Switzerland.
authors.forename: Irina
authors.initials: I
authors.lastname: Häuselmann
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zurich, Switzerland.
authors.forename: Marko
authors.initials: M
authors.lastname: Roblek
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zurich, Switzerland.
authors.forename: Darya
authors.initials: D
authors.lastname: Protsyuk
authors.affiliation: Department of Dermatology, Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Huck
authors.affiliation: International Clinical Research Center, Center for Biological and Cellular Engineering, St. Anne's University Hospital and Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Knopfova
authors.affiliation: Department of Dermatology, Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Grässle
authors.affiliation: Department of Dermatology, Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Bauer
authors.affiliation: Department of Dermatology, Experimental Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, Zurich, Switzerland. lborsig@access.uzh.ch.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D016133:Polymerase Chain Reaction; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D019040:E-Selectin; D000099152:Cadherin 5