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 tissues. HA interacts with several cell surface receptors, such as cluster of differentiation 44 and receptor for hyaluronan-mediated motility, 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 on cancer chemotherapy resistance. We will also explore the current and future prospects of HA-based therapy, highlighting the opportunities and challenges in the field.

Keywords: chemoresistance; cluster of differentiation 44; extracellular matrix; hyaluronic acid.

Fig. 1

Hyaluronic acid (HA) synthesis, catabolism, regulation, and functions. HA is synthesized at the plasma membrane by the transmembrane hyaluronan synthases (HAS): HAS1, HAS2, and HAS3, using the UDP‐GlcNAc and UDP‐GlcUA as precursors. Generally, high‐molecular weight HA (HMW‐HA) is predominant in normal tissues. During tumor initiation and progression, HMW‐HA is rapidly degraded by hyaluronidases (HYAL) into low‐molecular weight HA (LMW‐HA) and small fragments of different lengths, which may possess pro‐inflammatory and pro‐angiogenic functions, promoting tumor growth, metastasis, and therapy resistance. This figure was created with BioRender.com.

Fig. 2

Mechanisms of hyaluronic acid (HA)‐mediated chemoresistance in tumors. (1) CD44 regulates receptor tyrosine kinase (RTK) activation and modulates different antiapoptotic signaling pathways, which promote chemoresistance. (2) HA‐CD44 interaction regulates multidrug resistance in cancer cells. (3) HA‐CD44 axis regulates cancer stem cell (CSC) properties through induction of oxidative stress resistance. (4) HA acts as a biophysical barrier impairing vascular function and drug delivery in tumor cells. This figure was created with BioRender.com.

Fig. 3

Potential applications of targeting hyaluronic acid (HA) in cancer therapy. Three strategies have been employed to target HA in cancer: targeting HA synthesis (1), targeting HA degradation (2), and targeting HA receptors (3). This figure was created with BioRender.com.