Abstract
BackgroundDistant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. As a result of shedding, soluble E-selectin (sE-selectin) from the activated endothelium is present in the serum. In this study, we aimed to understand the role of sE-selectin in tumor progression and metastasis.MethodsWe investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo.ResultsWe found that sE-selectin promoted migration and shear-resistant adhesion of CD44+/high breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to non-activated human microvessel endothelial cells (ES-HMVECs), but not of CD44-/low breast cancer cell lines (MCF-7 and T-47D). This endothelial E-selectin independent, sE-selectin-mediated shear-resistant adhesion was also observed in a leukocyte cell line (HL-60) as well as human peripheral blood mononuclear cells (PBMCs). Additionally, the incubation of MDA-MB-231 cells with sE-selectin triggered FAK phosphorylation and shear-resistant adhesion of sE-selectin-treated cells resulted in increased endothelial permeabilization. However, CD44 knockdown in MDA-MB-231 and HL-60 cells resulted in a significant reduction of sE-selectin-mediated shear-resistant adhesion to non-activated HMVECs, suggesting the involvement of CD44/FAK. Moreover, functional blockade of ICAM-1 in non-activated HMVECs resulted in a marked reduction of sE-selectin-mediated shear-resistant adhesion. Finally, the pre-incubation of CD44+ 4 T1 murine breast cancer cells with sE-selectin augmented infiltration into the lung in E-selectin K/O mice and infusion of human PBMCs pre-incubated with sE-selectin stimulated MDA-MB-231 xenografted breast tumor growth in NSG mice.ConclusionsOur data suggest that circulating sE-selectin stimulates a broad range of circulating cells via CD44 and mediates pleiotropic effects that promote migration and shear-resistant adhesion in an endothelial E-selectin independent fashion, in turn accelerating tissue infiltration of leukocytes and cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2366-2) contains supplementary material, which is available to authorized users.
Highlights
Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer
The adhesion of saline-treated MDA-MB231 and MDA-MB-468 breast cancer cells (BCs) to doxycycline-untreated ESHMVECs was negligible, but increased significantly when E-selectin expression was induced in ES-Human Microvascular Endothelial cells (HMVECs) by doxycycline (1.8 fold and 2.0 fold, respectively, p < 0.001)
Neither sE-selectin nor endothelial E-selectin enhanced the shear-resistant adhesion of estrogen receptor (ER)+/homing cell adhesion molecule (CD44)-/low MCF-7 and T47D BCs
Summary
Distant metastasis resulting from vascular dissemination of cancer cells is the primary cause of mortality from breast cancer. We have previously reported that E-selectin expression on the endothelial cell surface mediates shear-resistant adhesion and migration of circulating cancer cells via interaction with CD44. Tissue infiltration of circulating cells is critical for multiple aspects of tumor progression and metastasis. Tissue infiltration by circulating cells is governed by a multi-step adhesion cascade, mediated by sequential interactions and crosstalk between adhesion molecules expressed on the endothelial cell surface and their counter-receptor ligands expressed on circulating cells [1,2,3,4]. Weak interaction prevents effective attachment of the circulating cells to the endothelial surface. The initial adhesion of circulating cells subsequently leads to firm attachment that opens the endothelial junction enabling transendothelial migration into tissue parenchyma toward cytokine or chemokine stimuli [5, 6]
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