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. gene, yeast agglutinin) and HP (activation of the receptor [16]. and the group identified two hypoxia-responsive elements upstream to the transcriptional start site of the Gal-1 gene that are essential for HIF-1-mediated galectin-1 expression [16]. Tumor Clevidipine microenvironment-dependent changes in endothelial cell glycosylation are summarized in Figure 2. Open in a separate window 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. 6. Glycosaminoglycans in Tumor Angiogenesis and Metastasis Within the ECM, GAGS play a role in regulating migration of endothelial cells, providing a scaffold that guides endothelial cell tube formation, and stabilizes neovasculature. An excellent review by Oliveira-Ferrer, et al. describes the varied roles of GAGs in metastasis [117]. Here, we will primarily discuss the role of GAGs as they relate to endothelial cell function (or dysfunction) in cancer. 6.1. Heparan Sulfate Proteoglycans (HSPGs) HSPGs are a well-studied group of proteins that bear long heparan sulfate chains consisting of 50C200 glucuronic acid disaccharide repeats with variable patterns of sulfation, and reside both on the endothelial cell surface and within the extracellular matrix. HSPG modifications including sulfation create binding sites for various ligands, including adhesive proteins, chemokines, growth factors and growth factor-binding proteins, proteases and protease inhibitors, and morphogens [118,119,120,121,122]. Critically, these relationships are sensitive to Clevidipine the position and linkage of sulfate modifications. Transmembrane HSPGs including syndecans, glycpicans, and perlecan reside within the cell surface and are involved in extracellular matrix assembly and maintenance. Both VEGFR2 and VEGF (including VEGF165 but not VEGF121) interact with heparan sulfate, and ligand-stimulation has been reported to increase heparan sulfate-VEGFR2 complex formation and vascular permeability [111]. VEGF HS-binding domains encoded by exons 6 and 7 are responsible for the connection of VEGF Clevidipine ligands with HS, and result in the sequestration of VEGF in the extracellular matrix that may consequently become released by proteases and heparanase during ECM degradation by proteases associated with angiogenesis [123,124,125]. The ability of VEGF165 to bind HS is definitely partially controlled by its connection with endothelial transglutaminase-2 [126]. Clevidipine Additional growth factors, including PDGF-B, consist of HS-interacting domains [127,128]. TGF- isoforms also bind HS, and HS plays a role in gradient formation of cytokines [129,130]. By regulating heparan sulfate modifications on endothelial cells, heparan sulfatases impact tumor angiogenesis in a number of contexts, including ovarian and breast malignancy. Downregulation of endosulfatases responsible for removal of 6-sulfate from HS in response to hypoxia, as well as downregulation in tumor cells, results in the presence of more highly sulfated forms of HS, therefore increasing growth element binding and downstream signaling [131]. 6.2. Chondroitin Sulfate (CS) Chondroitin sulfate (CS), composed of GBP2 repeating units of the disaccharide GalNAc-GlcA, is also variably-sulfated inside a tissue-specific manner by carbohydrate sulfotransferases. Expression of specific sulfated forms of CS on the surface of tumor cells facilitates their connection with platelets and endothelial cells by creating ligands that bind P-selectin, e.g., in breast cancer [132]. Moreover, the sulfation pattern of CS on versican appears to be critical for connection with L-selectin, P-selectin, and CD44, molecules involved in endothelial cell adhesion and/or tumor angiogenesis [133]. However, the full part of such modifications in tumor angiogenesis remains to be identified. 6.3. Hyaluronan (HA) Hyaluronan (HA) is definitely a negatively charged, nonsulfated GAG. Unlike additional GAGs, hyaluronan (HA) is not covalently linked to a core protein. Rather, it is deposited in the extracellular matrix, where it may interact with ECM proteins and additional GAGs. In healthy cells, the coordinated manifestation and activity of HA synthases and hyaluronidases maintain a homeostasis. In tumors, higher manifestation of low-molecular excess weight HA is definitely often present and is associated with inflammatory conditions [134], and contributes to tumor angiogenesis by impairing cellular adhesion [135,136]. HA also seems to play a role in tumor-associated macrophage trafficking to tumor stroma [137]. 7. Endothelial Glycosylation Regulates Tumor Cell Trans-Endothelial Migration The binding to glycosylated epitopes on tumors by selectins (E-selectin, P-selectin) and galectins indicated on endothelial cells, and of tumor-expressed lectins to endothelial glycans, mediates a process of rolling followed by stable heterotypic adhesion. This process mirrors the process through which platelets and leukocytes interact with the endothelium. The Clevidipine glycan-binding proteins on endothelial cells identify glycan substructures on platelets, leukocytes, and circulating tumor cells. Conversely, L-selectin indicated on leukocytes (specifically, T cells) also recognizes glycan constructions on endothelial cells, permitting leukocytes to.