Hyaluronan-CD44 axis orchestrates cancer stem cell functions

The prominent role of CD44 in tumor cell signaling together with its establishment as a cancer stem cell (CSC) marker for various tumor entities imply a key role for CD44 in CSC functional properties. Hyaluronan, the main ligand of CD44, is a major constituent of CSC niche and, therefore, the hyaluronan-CD44 signaling axis is of functional importance in this special microenvironment. This review aims to provide recent advances in the importance of hyaluronan-CD44 interactions in the acquisition and maintenance of a CSC phenotype. Hyaluronan-CD44 axis has a substantial impact on sternness properties of CSCs and drug resistance through induction of EMT program, oxidative stress resistance, secretion of extracellular vesicles/exosomes and epigenetic control. Potential therapeutic approaches targeting CSCs based on the hyaluronan-CD44 axis are also presented.