CD44 and other hyaluronan receptors (CD44/HA receptors)

CD44 and other hyaluronan (HA) receptors, including RHAMM (CD168), LYVE-1, and HARE (Stabilin-2), are a group of cell-surface glycoproteins that mediate the biological effects of hyaluronan, a major component of the extracellular matrix [1.1.1, 1.6.1]. CD44 is the primary receptor and is involved in cell adhesion, migration, and signaling, often acting as a marker for cancer stem cells and playing a key role in tumor metastasis and chemoresistance [1.3.1, 1.3.4]. RHAMM primarily regulates cell motility and is frequently overexpressed in various cancers, while LYVE-1 and HARE are involved in lymphatic trafficking and systemic HA clearance, respectively [1.2.2, 1.5.4, 1.1.3]. These receptors are considered significant therapeutic targets due to their involvement in cancer progression, chronic inflammation, and wound healing [1.4.3, 1.6.3]. Current drug development strategies include monoclonal antibodies like RG7356, peptide inhibitors, and hyaluronan-drug conjugates that exploit receptor-mediated endocytosis for targeted delivery [1.4.5, 1.6.2]. However, the widespread expression of these receptors in normal tissues, such as the skin and hematopoietic system, has led to significant safety concerns, including severe dermatological toxicities in clinical trials [1.4.5]. The complexity of alternative splicing, which generates numerous isoforms like CD44v6, further complicates the development of selective therapies [1.3.1, 1.4.2]. Despite these challenges, targeting the hyaluronan-receptor axis remains a promising approach for treating aggressive malignancies and inflammatory disorders [1.4.4, 1.6.1].

Other names

Hyaluronan receptorsHA receptorsP-glycoprotein 1CD168LYVE-1Stabilin-2RHAMMHMMRSTAB2Lymphocyte homing receptor

The primary mechanisms of action include the use of neutralizing monoclonal antibodies to block hyaluronan-receptor interactions, peptide-based inhibitors to sequester hyaluronan or disrupt signaling complexes, and hyaluronan-drug conjugates that utilize receptor-mediated endocytosis for the targeted delivery of cytotoxic agents to receptor-overexpressing cells.