ReviewHyaluronan: Towards novel anti-cancer therapeutics
Section snippets
Historical perspective
The dawn of the “hyaluronan era” began in 1841, when German anatomist Friedrich G.J. Henle, credited, among others, with the discovery of the loop of Henle in the kidney, described the amorphous material between cells and called it “ground substance” [46]. Nowadays, “ground substance” is known to be predominantly composed of hyaluronan. As a matter of fact, “ground substance” is a mistranslation of German “Grundsubstanz”, which would be more accurately translated as “fundamental”, “primordial”
General profile of hyaluronan
Hyaluronic acid is a linear high-molecular-weight biopolymer composed of alternating units of Dglucuronic acid (GlcA) and N-acetyl-D-glucosamine (Glc-NAc), connected to each other with β-1,3- and β-1,4-glycosidic bonds (Fig. 1). The polymer is nearly perfect in its chemical repeats except for occasional deacetylated glucosamine residues [119]. The carboxyl group of D-glucuronic acid is dissociated at physiological pH values, resulting in the formulation of a negatively charged polymer that
Biomedical applications of hyaluronan
Hyaluronan has found a number of applications in medicine. The first product containing hyaluronan (Hyalgan) was registered in the 1960s by the Italian company Fidia and since then it has been used topically for the treatment of burns and skin ulcers. Some of the medical uses of hyaluronan are reviewed below [54, 58].
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Ophthalmology. Because of the viscoelastic properties of hyaluronan, it is used in a number of key ophthalmologic surgeries. It protects delicate eye tissues, provides space and
Biosynthesis...
Contrary to all glycosaminoglycans, which are produced in the Golgi apparatus, hyaluronan is synthesized at the inner side of plasma membranes to form huge aggregates of molecular mass up to 1 MDa. Afterwards, it is extruded through pore-like structures to the cell surface [107]. Hyaluronan is produced by cell membrane-bound proteins – glycosyltransferases – called hyaluronan synthases (HASs). The enzymes mediate the chemical reaction of transglycosylation of D-glucuronic acid and
Hyaluronan fragments
Hyaluronan as a polymer molecule exhibits a variety of chain lengths. High molecular weight hyaluronan (HMWH) attaining about 0.1 – 10 MDa (hundreds to thousands mers), low molecular weight hyaluronan (LMWH) of about tens kDa (about 50 mers) and oligosaccharides (oHA) of up to a few kDa (up to a dozen of mers) have distinctly different biological functions. HMWH is mainly involved in a variety of functions based on rheological properties as tissue hydration, shock absorption, decreasing
Hyaluronan-binding proteins
It was in 1979, when hyaluronan was, for the first time, demonstrated to bind specifically and with high affinity to a variety of cells [133]. Now it is evident that the actual pharmacological effects of hyaluronan molecules of various sizes described above are mediated through interactions with certain proteins called hyaladherins. The group of hyaluronan-binding proteins comprise cell surface receptors (CD44, RHAMM, Toll-like receptors, LYVE-1 and HARE) and extracellular matrix or blood
Towards hyaluronan-based therapeutics
The research on hyaluronan involvement in cancer pathogenesis laid the foundations for development of novel anti-cancer therapeutic strategies. HA-induced cancer cell growth and metastatic potential may be attenuated by targeting HA biochemical pathways. Three different therapeutic approaches may be indicated: (1) targeting hyaluronan metabolism, (2) targeting hyaladherins, and (3) HA-based drug delivery systems.
Concluding remarks
Hyaluronan is no longer perceived as only an inert component of connective tissue, functioning as one of the building materials of the body. It is a “dynamic” molecule with a rapid metabolism resulting in the presence of molecules of various sizes: finely fragmented oligosaccharides, intermediate LMWH to huge aggregates of HMWH. Hyaluronan is involved in intracellular signaling mediated by CD44 and RHAMM receptors that leads to cancer cell growth, adhesion, migration, invasion and metastasis.
Acknowledgment
The paper has been supported by the Medical University of Lodz with the grant for young scientists No. 502-03/1-023-01/502-14-159.
References (146)
- et al.
The impact of extracellular matrix on the chemoresistance of solid tumors – experimental and clinical results of hyaluronidase as additive to cytostatic chemotherapy
Cancer Lett
(1998) - et al.
Hyaluronan synthase 2 (HAS2) promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1 (TIMP-1)
J Biol Chem
(2011) - et al.
Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing
Am J Pathol
(2009) - et al.
CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion
J Biol Chem
(2004) - et al.
Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion
J Biol Chem
(2010) - et al.
Expression of recombinant hyaluronan synthase (HAS) isoforms in CHO cells reduces cell migration and cell surface CD44
Exp Cell Res
(1999) - et al.
Differential effect of molecular size HA in mouse chondrocytes stimulated with PMA
Biochim Biophys Acta
(2009) - et al.
PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo
Biomaterials
(2011) - et al.
Hyaluronic acid-based nanocarriers for intracellular targeting: interfacial interactions with proteins in cancer
Colloids Surf B Biointerfaces
(2012) - et al.
The six hyaluronidase-like genes in the human and mouse genomes
Matrix Biol
(2001)