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 sialofucosylated 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-selectindependent 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.

Embryonic trafficking of γδ T cells to skin is dependent on E/P selectin ligands and CCR4

“…Only PSGL-1 has been identified as a leukocyte P-lig (25). The binding motif for E selectin is an α2,3-sialylated, α1,3-fucosylated glycan, the prototype of which is sialyl Lewis x .…”

“…Both PSGL-1 and CD43 can function as CLA in human T cells (25). Skin-homing memory T cells use CLA to tether and roll on E selectin that is constitutively expressed on dermal microvasculature.…”

“…A critical set of enzymes that mediate the generation of these carbohydrate ligands are the α1,3 fucosyltransferases (FTs). Both FTIV and FTVII are expressed in skin-homing effector/memory T cells, and mice deficient in both these enzymes cannot generate E-lig and P-lig on T cells (25). Subsequent to their tethering and rolling on the endothelial surface, skin-homing T cells must be activated by through chemokine receptors, and CCR4 has emerged as a critical receptor in this process.…”

The importance of Helicobacter pylori in the development of gastric MALT lymphoma — induction of proliferation and immune suppression

“…Reducing Treg activity promotes the shift of the tumor microenvironment from being strongly suppressive to the physiologically active [45,46]. Among potential methods that can achieve this effect are: IL-10 receptor blockade [47], selectin blockade [48], inhibition of chemokines responsible for Treg cells recruitment (CCL17, CCL22, CCL20 or CXCL13), blocking chemokine receptors specifically expressed by Treg effector cells (e.g. CCR4), inhibition of CTLR-4 co-inhibitory molecules expressed constitutively on the surface of Treg cells, or exogenous IL-2 administration (capable of reducing suppressive activity of Treg cells) [46].…”

Evaluation of serum soluble E-selectin in breast cancer

“…Several tumor cells which were isolated from different cancers express high levels of Eselectin ligand which is sialyl Lewis X on their cell surface and have the capacity to adhere to endothelial surface that express Eselectin leading to tumor dissemination (Gout et al, 2008;Barthel et al, 2007).…”