Glycosylation in the Tumor Microenvironment: Implications for Tumor Angiogenesis and Metastasis

Abstract

Just as oncogene activation and tumor suppressor loss are hallmarks of tumor development, emerging evidence indicates that tumor microenvironment-mediated changes in glycosylation play a crucial functional role in tumor progression and metastasis. Hypoxia and inflammatory events regulate protein glycosylation in tumor cells and associated stromal cells in the tumor microenvironment, which facilitates tumor progression and also modulates a patient's response to anti-cancer therapeutics. In this review, we highlight the impact of altered glycosylation on angiogenic signaling and endothelial cell adhesion, and the critical consequences of these changes in tumor behavior.

Keywords: N-glycosylation; O-glycosylation; angiogenesis; endothelial; glycosaminoglycans; glycosylation; hypoxia; inflammation; metastasis; tumor microenvironment.

Figure 1

Major classes of glycans and glycosaminoglycans involved in endothelial cell signaling and adhesion. Representative glycan-binding lectins (Gal-1, Gal-3, E-selectin, P-selectin, and L-selectin), growth factors (such as vascular endothelial growth factor, VEGF), and glycoconjugates including N- and O-linked glycans, and glycosaminoglycans, are shown. Abbreviations: HS, heparan sulfate; CS, chondroitin sulfate; HA, hyaluronan; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; Man, mannose; Gal, galactose; Fuc, fucose; Sialic acid, N-acetylneuraminic acid; GlcA, glucuronic acid; IdoA, iduronic acid; S, sulfate.

Figure 2

Tumor microenvironment-mediated changes in endothelial cell glycosylation. Endothelial glycoproteins are shown, including integrins, receptor tyrosine kinases (RTKs), VE-cadherin, and Ig-like cell adhesion molecules (IgCAMs). Glycans synthesized in the endoplasmic reticulum (ER) and Golgi have the potential to alter signaling and adhesion.

Figure 3

Glycan-mediated intravasation, rolling, and extravasation. Glycan modifications on endothelial cells (red) alter endothelial adhesion and may contribute to endothelial permeability and tumor cells (blue) intravasation. Circulating lectins such as Gal-3 and endothelial lectins including E-selectin initiate rolling, adhesion, and extravasation of tumor cells to the endothelium, frequently at distant sites. Integrins also assist in this process.