Hyaluronic Acid Dynamics in Cancer and Inflammation

Hyaluronic acid (HA), a hydrophilic glycosaminoglycan abundant in the extracellular matrix, regulates tissue homeostasis through its unique viscoelastic properties and rapid turnover. Synthesised at the cell surface by hyaluronan synthases and degraded by hyaluronidases and oxidative processes, HA exists in a spectrum of molecular weights that dictate contrasting biological activities. High-molecular-weight HA typically maintains tissue integrity and suppresses inflammation, whereas fragmented low-molecular-weight HA acts as a damage-associated molecular pattern, activating innate immune responses and promoting angiogenesis. In malignancy, elevated HA deposition within the tumour microenvironment enhances matrix stiffness, fosters cell migration and invasion, and modulates receptor-mediated signalling through CD44 and RHAMM. Concurrently, HA fragments exacerbate inflammatory cascades that can facilitate tumour progression or, in certain contexts, trigger resolution pathways. Understanding the balance of HA synthesis, degradation and receptor interactions is critical to elucidating its dualistic roles in inflammation and cancer and to developing strategies that either reinforce tissue barriers or attenuate pathological signalling.

Research from Nature Portfolio

Recent work has examined the evolution and regulation of high-molecular-weight HA across species with exceptional cancer resistance. Genetic analyses of subterranean mammals reveal adaptive mutations in HA-synthesising and ‑degrading enzymes that yield abundant ultrahigh-molecular-weight polymers. These findings shed light on how molecular weight modulation confers enhanced tissue elasticity, resistance to oxidative stress and suppression of aberrant cell proliferation, offering a blueprint for therapeutic bioengineering of HA in oncology and regenerative medicine. This comparative approach underscores the significance of precise enzymatic control in dictating HA’s protective versus pathogenic roles.

Hyaluronic Acid Dynamics in Cancer and Inflammation publication trend

The graph below shows the total number of articles in hyaluronic acid dynamics in cancer and inflammation across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular matrix (ECM): A network of proteins and polysaccharides that provides structural and biochemical support to surrounding cells.

Hyaluronan synthases (HAS1–3): Enzymes located on the cell surface responsible for polymerising HA chains of varying lengths.

Hyaluronidases: A family of enzymes that degrade HA into fragments, influencing inflammatory and cellular signalling.

CD44 and RHAMM: Cell surface receptors for HA that mediate downstream signalling pathways involved in cell adhesion, migration and proliferation.

Molecular weight (of HA): Refers to the size of HA polymers, which determines their biological function; high molecular weight generally stabilises tissues, low molecular weight often promotes inflammation.

References

1. Evolution of high-molecular-mass hyaluronic acid is associated with subterranean lifestyle. Nature Communications (2023).
2. Hyaluronic Acid in the Third Millennium. Polymers (2018).
3. Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer. Frontiers in Immunology (2015).
4. 4-Methylumbelliferone Treatment and Hyaluronan Inhibition as a Therapeutic Strategy in Inflammation, Autoimmunity, and Cancer. Frontiers in Immunology (2015).
5. Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. International Journal of Cell Biology (2015).