Physical biology in cancer. 3. The role of cell glycocalyx in vascular transport of circulating tumor cells

Abstract

Circulating tumor cells (CTCs) in blood are known to adhere to the luminal surface of the microvasculature via receptor-mediated adhesion, which contributes to the spread of cancer metastasis to anatomically distant organs. Such interactions between ligands on CTCs and endothelial cell-bound surface receptors are sensitive to receptor-ligand distances at the nanoscale. The sugar-rich coating expressed on the surface of CTCs and endothelial cells, known as the glycocalyx, serves as a physical structure that can control the spacing and, thus, the availability of such receptor-ligand interactions. The cancer cell glycocalyx can also regulate the ability of therapeutic ligands to bind to CTCs in the bloodstream. Here, we review the role of cell glycocalyx on the adhesion and therapeutic treatment of CTCs in the bloodstream.

Keywords: adhesion; drug delivery; metastasis; microvasculature.

Fig. 1.

Schematics of the endothelial (A) and tumor (B) cell glycocalyx (not drawn to scale). A: endothelial cell glycocalyx can extend 150–500 nm from the endothelial cell surface, with a typical spacing of 20 nm between glycocalyx components. [Adapted from Weinbaum et al. (130).] B: tumor cell glycocalyx consists of similar components but is characterized by greater content of hyaluronan, which is tethered to the tumor cell membrane by CD44.

Fig. 2.

Glycocalyx effects on circulating tumor cell (CTC) adhesion in the microvasculature. A: under normal physiological conditions, the endothelial cell glycocalyx thickness is greater than the length of most adhesion receptors and acts as a barrier to cell adhesion. B: alterations in shear stress, inflammatory conditions, and matrix metalloproteinase (MMP) exposure can cause shedding and/or remodeling of the glycocalyx, increasing the number of available receptors to bind to adhesion ligands on CTCs.

Fig. 3.

E-selectin-mediated delivery of therapeutics to CTCs in the bloodstream. Under physiological flow conditions, E-selectin-conjugated nanoparticles can rapidly bind to E-selectin ligands on the CTC surface. This adhesive interaction can be utilized to deliver a variety of therapeutic ligands or small molecules to CTCs, which can then induce CTC apoptosis.

Fig. 4.

Glycocalyx as a barrier to therapeutic delivery. Overexpression of glycocalyx components, such as hyaluronan, can create a molecular barrier to “shield” therapeutic-binding receptors from interaction with therapeutic ligands.