Abstract
On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) consisting of proteoglycans and glycosaminoglycans (GAGs). Disruption of endothelial cell (EC) GCX by a vascular endothelial growth factor (VEGF, VEGF-A165), a tumor secretion, was found to be an early event in tumor cell (TC) metastasis across vascular barriers. However, how the TC secretion VEGF affects its own GCX is unknown. To investigate the VEGF effect on TC GCX and to elucidate the ultrastructural organization of EC and TC GCX and their alteration by VEGF, we employed super-resolution stochastic optical reconstruction microscopy to observe the spatio-chemical organizations of the heparan sulfate (HS) and hyaluronic acid (HA), two representative GAGs of GCX, on human cerebral microvascular endothelial cells (hCMEC) and malignant breast cancer cells MDA-MB-231 (MB231). We found that HS and HA have distinct organizations on hCMEC and MB231. Only HS of hCMEC is perpendicular to the cell surface, while HA of hCMEC as well as HS and HA of MB231 all lie in the same plane as the cell surface where they appear to weave into a 2D network covering the cell. We also found that VEGF significantly reduces the length and coverage of HS on hCMEC but does not change the thickness and coverage of HA on hCMEC. On the contrary, VEGF significantly enhances the coverage of HS and HA on MB231 although it does not alter the thickness. The differential effects of VEGF on the GCX of TC and that of EC may favor TC adhesion and transmigration across EC barriers for their metastasis.
Highlights
On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) layer of a mucopolysaccharide structure consisting of glycoproteins, acidic oligosaccharides, terminal sialic acids (SA), proteoglycans, and glycosaminoglycans (GAGs), including heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA)
HS of human cerebral microvascular endothelial cells (hCMEC) is perpendicular to the cell surface, while HA of hCMEC as well as HS and HA of MB231 all lie in the same plane as the cell surface where they appear to weave into a 2D network covering the cell
The diameter of HA at MB231, 404 6 78 nm (n 1⁄4 113), is comparable to that of HA at hCMEC, which is 416 6 80 nm (n 1⁄4 107) (p 1⁄4 0.26). These results suggest that HA elements of hCMEC and MB231 are from the same core protein, but HS elements might be from different core proteins
Summary
On the surface of every mammalian cell, there is a matrix-like glycocalyx (GCX) layer of a mucopolysaccharide structure consisting of glycoproteins, acidic oligosaccharides, terminal sialic acids (SA), proteoglycans, and glycosaminoglycans (GAGs), including heparan sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA). The GCX at the endothelial cells (ECs) lining the inner side of our blood vessels is a mechano-sensor to the blood flow, a regulator controlling the material exchange between circulating blood and the surrounding tissue and a barrier restricting the interaction between the circulating cells and the ECs forming the vascular wall.. Recent studies found that a bulkier GCX on TCs is associated with increased migration and metastatic potential of cancers.. The TC GCX responds to the interstitial flow-induced shear forces by secreting matrix metalloproteinases to degrade the surrounding ECM. This makes it easier for TCs to migrate through the tissue and invade the nearby vasculature.. The bulky GCX on the circulating TCs, such as HA, creates a barrier to therapeutic agents and a shield to the blood flow induced friction forces. This makes it easier for TCs to migrate through the tissue and invade the nearby vasculature. The bulky GCX on the circulating TCs, such as HA, creates a barrier to therapeutic agents and a shield to the blood flow induced friction forces.
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