CD44 glycoprotein in cancer: A molecular conundrum hampering clinical applications

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.The authors wish to acknowledge the Portuguese Foundation for Science and Technology (FCT) for the human resources Grants: Ph.D. Grants SFRH/ BD/105355/2014 (RA), SFRH/BD/111242/2015 (AP), SFRH/BD/127327/2016 (CG); Postdoctoral Grants SFRH/BPD/101827/2014 (LL) and SFRH/ BPD/111048/2015 (JAF). FCT is co‑financed by European Social Fund (ESF) under Human Potential Operation Programme (POPH) from National Strategic Reference Framework (NSRF). The authors also acknowledge FCT the funding for CI‑IPOP research unit (PEst‑OE/SAU/UI0776/201), the Portuguese Oncology Institute of Porto Research Centre (CI‑IPOP‑29‑2014; CI‑IPOP‑58‑2015) and Ph.D. Programs in Biomedicine and Pathology and Molecular Pathology of ICBAS‑University of Porto