title: The effect of soluble E-selectin on tumor progression and metastasis.
abstract: 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. 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.
  
  
  
  We investigated the effect of sE-selectin on shear-resistant adhesion and migration of metastatic breast cancer cells and leukocytes in vitro and in vivo.
  
  
  
  We 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.
  
  
  
  Our 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.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Shin-Ae
authors.initials: SA
authors.lastname: Kang
authors.affiliation: Thomas Jefferson University, Pharmaceutical Sciences, 1020 Locust St, Philadelphia, PA, 19107, USA.
authors.forename: Celine A
authors.initials: CA
authors.lastname: Blache
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bajana
authors.affiliation: Thomas Jefferson University, Pharmaceutical Sciences, 1020 Locust St, Philadelphia, PA, 19107, USA.
authors.forename: Nafis
authors.initials: N
authors.lastname: Hasan
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kamal
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Vineet
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Bilegtsaikhan
authors.initials: B
authors.lastname: Tsolmon
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, 07601, USA.
authors.forename: K Stephen
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX, 77030, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Gorenstein
authors.affiliation: Department of Internal Medcine, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 800 NE, 10th, Oklahoma City, OK, 73104, USA.
authors.forename: Wajeeha
authors.initials: W
authors.lastname: Razaq
authors.affiliation: Department of Pathology, Medical College of Wisconsin Cancer Center, 8701 Watertown Plank Rd, Milwaukee, WI, 53226, USA.
authors.forename: Hallgeir
authors.initials: H
authors.lastname: Rui
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK, 73104, USA. takemi-tanaka@ouhsc.edu.|Stephenson Cancer Center at the University of Oklahoma Health Sciences Center, 975 NE 10th, Oklahoma City, OK, 73104, USA. takemi-tanaka@ouhsc.edu.
authors.forename: Takemi
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D019040:E-Selectin / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C497483:CD44 protein, human; D019040:E-Selectin; D018960:Hyaluronan Receptors
keywords: CD44; E-selectin; Hematogenous metastasis; Shear-resistant adhesion; sE-selectin