CD44 antigen and Hyaluronan-mediated motility receptor (RHAMM) (CD44/RHAMM/ECM)

The CD44 antigen and Hyaluronan-mediated motility receptor (RHAMM) signaling axis, in conjunction with extracellular matrix (ECM) components such as hyaluronan, represents a complex regulatory system involved in tissue homeostasis and disease progression (Misra et al., 2015). CD44 is a transmembrane glycoprotein that acts as the primary cell-surface receptor for hyaluronan, mediating cell-cell and cell-matrix interactions (UniProt P04233). RHAMM, also known as HMMR, is a versatile protein that functions both as an extracellular hyaluronan receptor and an intracellular regulator of microtubule dynamics during mitosis (Maxwell et al., 2008). This axis is frequently hijacked in various cancers, where it promotes epithelial-to-mesenchymal transition (EMT), tumor invasion, and the maintenance of cancer stem cell populations (Chen et al., 2018). Beyond oncology, the CD44/RHAMM/ECM interaction plays a significant role in inflammatory diseases and wound healing by modulating leukocyte recruitment and fibroblast activation (Tolg et al., 2012). Therapeutic interventions targeting this axis include monoclonal antibodies like RG7356, hyaluronan-degrading enzymes such as Pegvorhyaluronidase alfa, and RHAMM-targeted peptide vaccines (NCT01641250, NCT02715804). However, the widespread expression of CD44 in normal tissues and the dual roles of RHAMM present challenges regarding systemic toxicity and off-target effects.

Other names

CD44-RHAMM axisHMMRPgp-1Hermes antigenHyaluronan receptorCD168H-CAMExtracellular matrix-receptor interaction

Competitive inhibition of hyaluronan binding to CD44 or RHAMM, enzymatic depletion of extracellular hyaluronan, and antibody-dependent cellular cytotoxicity (ADCC) against receptor-expressing cells.