Turning-Off Signaling by Siglecs, Selectins, and Galectins: Chemical Inhibition of Glycan-Dependent Interactions in Cancer

Abstract

Aberrant glycosylation, a common feature associated with malignancy, has been implicated in important events during cancer progression. Our understanding of the role of glycans in cancer has grown exponentially in the last few years, concurrent with important advances in glycomics and glycoproteomic technologies, paving the way for the validation of a number of glycan structures as potential glycobiomarkers. However, the molecular bases underlying cancer-associated glycan modifications are still far from understood. Glycans exhibit a natural heterogeneity, crucial for their diverse functional roles as specific carriers of biologically relevant information. This information is decoded by families of proteins named lectins, including sialic acid-binding immunoglobulin (Ig)-like lectins (siglecs), C-type lectin receptors (CLRs), and galectins. Siglecs are primarily expressed on the surface of immune cells and differentially control innate and adaptive immune responses. Among CLRs, selectins are a family of cell adhesion molecules that mediate interactions between cancer cells and platelets, leukocytes, and endothelial cells, thus facilitating tumor cell invasion and metastasis. Galectins, a family of soluble proteins that bind β-galactoside-containing glycans, have been implicated in diverse events associated with cancer biology such as apoptosis, homotypic cell aggregation, angiogenesis, cell migration, and tumor-immune escape. Consequently, individual members of these lectin families have become promising targets for the design of novel anticancer therapies. During the past decade, a number of inhibitors of lectin–glycan interactions have been developed including small-molecule inhibitors, multivalent saccharide ligands, and more recently peptides and peptidomimetics have offered alternatives for tackling tumor progression. In this article, we review the current status of the discovery and development of chemical lectin inhibitors and discuss novel strategies to limit cancer progression by targeting lectin–glycan interactions.

Galectin-1: A Jack-of-All-Trades in the Resolution of Acute and Chronic Inflammation

“…These broad immunoregulatory activities open novel therapeutic opportunities for reprogramming innate and adaptive immunity in a wide range of inflammatory conditions. Although Gal-1-targeted therapies, using neutralizing anti-Gal-1 mAb, glycoamines, or synthetic peptides, have been designed and validated in preclinical models to reinforce antitumor and antimicrobial immunity, Gal-1-agonistic drugs for limiting unresolved inflammation in diverse inflammation conditions are anticipated to be released (6,19,43,131,142). However, before Gal-1-based therapeutic agents will be embraced, several questions remain to be addressed: Do other members of the galectin family play compensatory roles in response to Gal-1 blockade?…”

Targeting Aberrant Sialylation to Treat Cancer

“…The interaction of cancer cell bound sialic acid with Siglecs can thus modulate immune cell phenotype and allow tumours to escape the immune system [64] ( Figure 2). Cancer-associated glycans, such as STn and sialyl T, are well characterised examples of this, being linked to the impaired maturation and activation of macrophages and dendritic cells, and are also implicated in the deactivation of natural killer (NK) cells and the formation of regulatory T cells [63,78,[80][81][82]. Hence, determining the specific glycan signature of cancer cells (known as the 'glyco-code') will be crucial to understand how glyans promote immune evasion [71,83].…”

Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression

“…In the postgenomic era, a major paradigm shift emerged involving the identification of relevant glycosylation changes occurring during tumor progression (Pinho and Reis, 2015). These involve modifications in terminal sialylation, fucosylation, O-glycan truncation, and N-and O-linked glycan branching (Cagnoni et al, 2016). These changes have provided unique signatures that are being capitalized for the discovery of clinical biomarkers and the design of new therapeutic strategies.…”