The state of CD44 activation in cancer progression and therapeutic targeting

CD44, a non-kinase transmembrane glycoprotein, is ubiquitously expressed on various types of cells, especially cancer stem cells (CSCs), and has been implicated in cancer onset and aggressiveness. The major ligand for the CD44, hyaluronan (HA), binds to and interacts with CD44, which in turn triggers downstream signaling cascades, thereby promoting cellular behaviors such as proliferation, motility, invasiveness and chemoresistance. The CD44-HA interaction is cell-specific and strongly affected by the state of CD44 activation. Therefore, the binding of HA to CD44 is essential for the activation of CD44 during which the detailed regulatory mechanism needs to be clarified. Different CD44 activation states distribute in human carcinoma and normal tissue; however, whether CD44 activation is a critical requirement for tumor initiation, progression and notorious CSC properties remains to be clarified. A deeper understanding of the regulation of CD44 activation may facilitate the development of novel targeted drugs in the future. Here, we review the current findings concerning the states of CD44 activation on the cell surface, the underlying regulatory mechanisms of CD44 activation, the known role for CD44 activation in tumor progression and CSC hallmarks, as well as the potential of HA-coated nanoparticle for targeting activated CD44 for cancer therapy.