Abstract
Cancer cell tethering and rolling on the vascular wall is facilitated by various selectin: glycoprotein interactions which lead to eventual extravasation and metastases. The aberrantly underglycosylated mucin MUC1 has been shown to both abundantly express selectin binding moieties (sialyl Lewis x and a) and to consistently expose its core epitope. Flow cytometry was used to determine MUC1 expression on ZR-75-1 and MCF7 cells, while immunofluorescence microscopy was used to confirm the aberrant form of MUC1 and MUC1:ICAM-1 interactions. Each cell line was then perfused through combined E-selectin and ICAM-1 coated microtubes, as a model of the microvascular endothelium. ZR-75-1 and MCF7 were found to express abundant and low levels of underglycosylated MUC1, respectively. The rolling/adhesion profiles showed that ZR-75-1 cells, when compared to MCF7 cells, interact with E-selectin more efficiently resulting in sufficiently slow rolling velocities to form MUC1:ICAM-1 interactions thereby facilitating firm adhesion. The purpose and novelty of this work is the demonstration of the synergistic adhesion capabilities of MUC1 in the metastatic adhesion cascade, where the observed differential adhesion is consistent with the relative metastatic potential of the ZR-75-1 (highly metastatic) and MCF7 (weakly metastatic) cell lines.
Highlights
The mucin family of glycoproteins is traditionally associated with the protection of the epithelial layer and provides lubrication of luminal epithelial surfaces
For circulating tumor cells (CTCs) adhesion, cells may first establish transient interactions with the activated endothelium which facilitates cell tethering and rolling events (Tremblay et al, 2008; St Hill, 2011; Wirtz et al, 2011). These types of interactions are produced via selectins, a family of adhesion molecules expressed by the endothelium, and carbohydrate moieties, such as sialyl Lewis x or sialyl Lewis a, present on the selectin ligands expressed by CTCs (Borsig et al, 2002; Varki and Varki, 2007)
Similar to leukocyte recruitment to the endothelium, CTC tethering and rolling on the blood vessel wall under hydrodynamic shear stress are mediated by the selectin family of adhesion molecules (Geng et al, 2012)
Summary
The mucin family of glycoproteins is traditionally associated with the protection of the epithelial layer and provides lubrication of luminal epithelial surfaces. For CTC adhesion, cells may first establish transient interactions with the activated endothelium which facilitates cell tethering and rolling events (Tremblay et al, 2008; St Hill, 2011; Wirtz et al, 2011). These types of interactions are produced via selectins, a family of adhesion molecules expressed by the endothelium, and carbohydrate moieties, such as sialyl Lewis x (sLex) or sialyl Lewis a (sLea), present on the selectin ligands expressed by CTCs (Borsig et al, 2002; Varki and Varki, 2007). This series of events is commonly referred to as the metastatic adhesion cascade (Orr et al, 2000)
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