Hyaluronic acid metabolism and chemotherapy resistance: recent advances and therapeutic potential

Abstract

Hyaluronic acid (HA) is a major component of the extracellular matrix, providing essential mechanical scaffolding for cells and, at the same time, mediating essential biochemical signals required for tissue homeostasis. Many solid tumors are characterized by dysregulated HA metabolism, resulting in increased HA levels in cancer tissue. HA interacts with several cell surface receptors, such as CD44 and RHAMM, thus co‐regulating important signaling pathways in cancer development and progression. In this review, we describe the enzymes controlling HA metabolism and its intracellular effectors emphasizing their impact in cancer chemotherapy resistance. We will also explore the current and future prospects of HA‐based therapy, highlighting the opportunities and challenges in the field.

Efficient PEGylated Dendrimer Nanoplatform for Codelivery of Hyaluronidase and Methotrexate: A New Frontier in Chemotherapeutic Efficacy and Tumor Penetration

“…Although the hyaluronic acid, as an anionic constituent of the ECM, plays a vital role in the proliferation, migration, inflammation, and morphogenesis of normal cells, its overexpression in malignant tumors creates formidable physical impediment, which is defined as a reliable prognostic marker for cancer development. , Indeed, thanks to its high swelling capacity and viscous nature, a high level of HA encumbers the infiltration of pharmacological agents across the TME. In addition, the interaction of accumulated HA with its diverse receptors, like cluster designation 44 (CD44), toll-like receptors 2,4 (TLR2,4), hyaluronan-mediated motility (RHAMM), and lymphatic vessel endothelial receptors (LYVE-1), modulates signaling pathways pertaining to tumorigenesis. , Hence, it is hypothesized that administration of an HA degradation enzyme (hyaluronidase), as a chemoadjuvant, not only conquers the poor result of chemotherapy but also can interfere with tumor growth and metastasis.…”