Targeting selectins and selectin ligands in inflammation and cancer

Abstract

Inflammation and cancer metastasis are associated with extravasation of leukocytes or tumor cells from blood into tissue. Such movement is believed to follow a coordinated and sequential molecular cascade initiated, in part, by the three members of the selectin family of carbohydrate-binding proteins: E-selectin (CD62E), L-selectin (CD62L) and P-selectin (CD62P). E-selectin is particularly noteworthy in disease by virtue of its expression on activated endothelium and on bone-skin microvascular linings and for its role in cell rolling, cell signaling and chemotaxis. E-selectin, along with L- or P-selectin, mediates cell tethering and rolling interactions through the recognition of sialo-fucosylated Lewis carbohydrates expressed on structurally diverse protein-lipid ligands on circulating leukocytes or tumor cells. Major advances in understanding the role of E-selectin in inflammation and cancer have been advanced by experiments assaying E-selectin-mediated rolling of leukocytes and tumor cells under hydrodynamic shear flow, by clinical models of E-selectin-dependent inflammation, by mice deficient in E-selectin and by mice deficient in glycosyltransferases that regulate the binding activity of E-selectin ligands. Here, the authors elaborate on how E-selectin and its ligands may facilitate leukocyte or tumor cell recruitment in inflammatory and metastatic settings. Antagonists that target cellular interactions with E-selectin and other members of the selectin family, including neutralizing monoclonal antibodies, competitive ligand inhibitors or metabolic carbohydrate mimetics, exemplify a growing arsenal of potentially effective therapeutics in controlling inflammation and the metastatic behavior of cancer.

Figure 1. Therapeutic modalities targeting E-selectin and ligands of E-selectin in inflammation and cancer

PSGL-1 expressed on circulating leukocytes or tumor cells may promote cellular extravasation or metastasis by recognizing E-selectin expressed on blood vessel walls. The interaction could be blocked by competitive inhibitors, including antibodies that recognize E-selectin on the vascular wall, antibodies recognizing PSGL-1 on the leukocyte or tumor cell surface, or with soluble PSGL-1-Ig. The interaction may also be antagonized by metabolic inhibitors of glycosylation such as 4-F-GlcNAc. 4-F-GlcNAc can penetrate membranes of the cell and Golgi compartment, where it competes with GlcNAc for incorporation into the lactosamine backbones of PSGL-1. Incorporation of 4-F-GlcNAc truncates branching and elongation of glycans on PSGL-1, thereby, preventing synthesis of sLe^X or sLe^a by fucosyltransferases. Copyright 2007 Cynthia Turner/cynthiaturner.com 4-F-GlcNAc: Peracetylated-4-fluorinated-d-glucosamine; PSGL-1: P-selectin glycoprotein ligand-1.