Multifaceted roles of CD44 in cancer progression and targeted therapeutic strategies
TL;DR
The study reveals that glycosylation and phosphorylation of CD44 regulate its ligand-binding affinity and cell migration, and suggests that targeting CD44, particularly its variant forms, could disrupt cancer stem cell maintenance and metastasis, offering potential therapeutic avenues.
Abstract
CD44, a multifunctional transmembrane glycoprotein, is not only a bystander but also a crucial driver of cancer progression that promotes cancer stem cell maintenance, metastasis, and resistance to therapy. Therefore, CD44 is recognized as a promising therapeutic target in advanced malignancies. Here, we discuss its unique features, such as its structural diversity, which arise from alternative splicing and the post-translational modifications of cleavage and phosphorylation. In addition, we discuss the function of CD44 as a multivalent cell adhesion receptor for extracellular matrix components, including hyaluronic acid, fibronectin, osteopontin, and TSG6, thereby regulating lymphocyte activation, cell–cell interactions, cell adhesion, and migration within the extracellular matrix. Moreover, the emerging role of CD44 as a co-receptor of receptor tyrosine kinases such as epidermal growth factor receptor, c-MET, and vascular endothelial growth factor receptor 2 is highlighted to elucidate the contribution of CD44 to malignant signaling networks. We also discuss its potential as a therapeutic target in advanced cancers, particularly its applications in unconjugated antibodies, antibody–drug conjugates, peptide-based inhibitors, and chimeric antigen receptor-T cell therapies. We conclude by addressing the limitations observed in clinical studies and outlining promising opportunities for future development. CD44 is a transmembrane glycoprotein involved in various cellular functions, including cell adhesion, migration, and lymphocyte activation. It is recognized as a cancer stem cell marker and therapeutic target owing to its high expression in advanced cancer stages. This study explores structural diversity of CD44, focussing on its isoforms generated through alternative splicing and post-translational modifications. The authors highlight the role of CD44 in cancer progression, emphasizing its interactions with extracellular matrix components such as hyaluronic acid and osteopontin. The study reveals that glycosylation and phosphorylation of CD44 regulate its ligand-binding affinity and cell migration. Notably, interaction of CD44 with receptor tyrosine kinases, such as epidermal growth factor receptor and vascular endothelial growth factor, enhances oncogenic signaling pathways. The findings suggest that targeting CD44, particularly its variant forms, could disrupt cancer stem cell maintenance and metastasis, offering potential therapeutic avenues. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.