A Trickster in Disguise: Hyaluronan’s Ambivalent Roles in the Matrix

Abstract

Hyaluronan (HA) is a simple but diverse glycosaminoglycan. It plays a major role in aging, cellular senescence, cancer, and tissue homeostasis. In which way HA affects the surrounding tissues greatly depends on the molecular weight of HA. Whereas high molecular weight HA is associated with homeostasis and protective effects, HA fragments tend to be linked to the pathologic state. Furthermore, the interaction of HA with its binding partners, the hyaladherins, such as CD44, is essential for sustaining tissue integrity and is likewise related to cancer. The naked mole rat, a rodent species, possesses a special form of very high molecular weight (vHMW) HA, which is associated with the extraordinary cancer resistance and longevity of those animals. This review addresses HA and its diverse facets: from HA synthesis to degradation, from oligomeric HA to vHMW-HA and from its beneficial properties to the involvement in pathologies. We further discuss the functions of HA in the naked mole rat and compare them to human conditions. Though intensively researched, this simple polymer bears some secrets that may hold the key for a better understanding of cellular processes and the development of diseases, such as cancer.

Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy

“…Synthesis of HA is orchestrated by HA synthases (HAS1-3). These enzymes require uridine diphosphate-GlcNAc (UDP-GlcNAc) as one of the primary substrates for synthesis of HA (23,24). In a cell, UDP-GlcNAc is synthesized via the hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis that utilizes glutamine and glucose to make this nucleic acid sugar (25,26).…”

Hyaluronan: molecular size‐dependent signaling and biological functions in inflammation and cancer

“…HMW HA is also responsible for tissue hydration due to its ability to bind high amounts of water. Because of this property, HA is able to lubricate and space‐fill tissues . HAS2 produces HMW HA and its deficiency results in embryonic lethality and failure of the endocardial cushion formation, along with defects in yolk sac and vasculogenesis .…”

“…HYALs are hydrolases that cleave the β‐(1,4) linkage and they are active in a large pH range. There are six HYALs so far recognized in humans: HYALs 1‐4, HYALP, and PH‐20 . The degrading activity of HYALs is not strictly related to HA, but can be also extended to other GAGs; HYAL4, for example, is able to cleave chondroitin sulfate , with no evidence of HA catabolic activity.…”

Equilibrium Modeling of the Mechanics and Structure of the Cancer Glycocalyx

“…Abundant production of linear polysaccharides called glycosaminoglycans (GAGs) is predictive of the aggressiveness of several cancers. In particular, hyaluronic acid (HA), a polysaccharide composed of repeating disaccharide units, strongly correlates with diverse cancer types (7)(8)(9). HA molecules typically resemble flexible chains, although decoration with proteoglycans, such as aggrecans and versicans, can rigidify and extend the chains (10).…”