Towards Effective Targeting of Tumour-associated CD44v Isoforms: why post-translational modifications matter

The CD44 glycoprotein is the major cell surface receptor for hyaluronic acid (HA) and its standard isoform (CD44s) is ubiquitously expressed in mammals. Since variant isoforms (CD44v) have been depicted as cancer stem cell (CSC) markers with instrumental signaling roles in the (pre)metastatic niche, they have recently attracted general interest for the development of targeted therapies. An in-depth insight into the different behaviour of standard and variant isoforms in terms of ligand interaction and downstream signaling is needed for the design of optimum HA-based drug delivery strategies because the affinity of HA (soluble or on a substrate) to CD44 depends on its chain length and on its spatial arrangement, therefore the way HA is presented on a carrier. In this work we offer an updated overview of the current knowledge of CD44v in cancer; importantly, we focus on post-translational modifications of variant exon sequences and how they can have an impact on several cellular processes. As the design of targeted drug delivery systems to tumour-specific receptors requires a deep knowledge of molecular biology, the aim is to provide a full breadth of the heterogeneous CD44 protein family and study the distinct interaction of tumour-associated CD44v isoforms towards HA and HA-based nanocarriers.