CD44 glycoprotein in cancer: a molecular conundrum hampering clinical applications

Abstract

CD44 is a heavily glycosylated membrane receptor playing a key role in cell adhesion, signal transduction and cytoskeleton remodelling. It is also one of the most studied glycoproteins in cancer, frequently explored for stem cell identification, and associated with chemoresistance and metastasis. However, CD44 is a general designation for a large family of splicing variants exhibiting different degrees of glycosylation and, potentially, functionally distinct roles. Moreover, structural diversity associated with ambiguous nomenclature has delayed clinical developments. Herein, we attempt to comprehensively address these aspects and systematize CD44 nomenclature, setting milestones for biomarker discovery. In addition, we support that CD44 may be an important source of cancer neoantigens, most likely resulting from altered splicing and/or glycosylation. The discovery of potentially targetable CD44 (glyco)isoforms will require the combination of glycomics with proteogenomics approaches, exploring customized protein sequence databases generated using genomics and transcriptomics. Nevertheless, the necessary high-throughput analytical and bioinformatics tools are now available to address CD44 role in health and disease.

Target Score—A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

“…Building on previous insights from glycoproteomics analysis, we were then led to investigate the presence of GLUT1-STn in individual tumors. GLUT1 proteoforms, as frequently observed for other proteins in cancer [53] and have been predicted by Uniprot. Faced with these preliminary observations, we are engaging in more comprehensive glycoproteogenomics studies to fully characterize the nature of GLUT1 glycoforms in ESSC.…”

“…These modifications, together with difficulties in predicting the MW shift induced by glycosylation make it difficult to interpret WB singly on the MW predicted from protein amino acid sequence. Finally, we cannot exclude the expression of shorter GLUT1 proteoforms, as frequently observed for other proteins in cancer [53] and have been predicted by Uniprot. Faced with these preliminary observations, we are engaging in more comprehensive glycoproteogenomics studies to fully characterize the nature of GLUT1 glycoforms in ESSC.…”

O‐glycan truncation enhances cancer‐related functions of CD44 in gastric cancer

“…The molecular weight of CD44 largely varies among human cells, and ranges from 80 kDa to more than 250 kDa . This heterogeneity has been mainly attributed to three mechanisms, namely (a) alternative splicing at the RNA level , (b) extensive glycosylation of the protein backbone and (c) the possible proteolytic cleavage through metalloproteases at the cell surface .…”

Targeting the “Sweet Side” of Tumor with Glycan-Binding Molecules Conjugated-Nanoparticles: Implications in Cancer Therapy and Diagnosis

“…For instance, several polysaccharides such as chitosan, chondroitin sulfate, alginate, hyaluronic acid (HA) have been used to improve the active targeting of nanoparticle drug delivery systems [ 30 , 97 , 98 , 99 ]. Concerning HA, many studies have shown that HA-based nanoparticles can serve to efficiently target the CD44 glycoprotein, whose isoforms and their altered glycosylation are correlated with metastatic properties of human cancer [ 100 , 101 , 102 ]. Lastly, interesting models have been proposed and applied to various glycosylation targets, especially in combination with nanoparticle carrier systems.…”