Keratan Sulphate in the Tumour Environment

Abstract

Keratan sulphate (KS) is a bioactive glycosaminoglycan (GAG) of some complexity composed of the repeat disaccharide D-galactose 1→4 glycosidically linked to N-acetyl glucosamine. During the biosynthesis of KS a family of glycosyl transferase and sulphotransferase enzymes act sequentially and in a co-ordinated fashion to add D-galactose (D-Gal) then N-acetyl glucosamine (GlcNAc) to an GlcNAc acceptor residue at the reducing terminus of a nascent KS chain to effect chain elongation. D-Gal and GlcNAc can both undergo sulphation at C6 but this occurs more frequently on GlcNAc than D-Gal. Sulphation along the developing KS chain is not uniform and contains regions of variable length where no sulphation occurs, regions which are monosulphated mainly on GlcNAc and further regions of high sulphation where both of the repeat disaccharides are sulphated. Each of these respective regions in the KS chain can be of variable length leading to KS complexity in terms of chain length and charge localization along the KS chain. Like other GAGs it is these variably sulphated regions in KS which define its interactive properties with ligands such as growth factors, morphogens and cytokines and which determine the functional properties of tissues containing KS. Further adding to KS complexity is the identification of three different linkage structures in KS to Asparagine (N-linked) or to Threonine or Serine residues (O-linked) in proteoglycan core proteins which has allowed the categorization of KS into 3 types, namely KS-I (corneal KS, Nlinked), KS-II (skeletal KS, O-linked) or KS-III (brain KS, O-linked). KS-I to III are also subject to variable addition of L-fucose and sialic acid groups. Furthermore, the GlcNAc residues of some members of the mucin-like glycoprotein family can also act as acceptor molecules for the addition of D-Gal and GlcNAc residues which can also be sulphated leading to small low sulphation glycoforms of KS. These differ from the more heavily sulphated KS chains found on proteoglycans. Like other GAGs, KS has evolved molecular recognition and information transfer properties over hundreds of millions of years of vertebrate and invertebrate evolution which equips them with cell mediatory properties in normal cellular processes and in aberrant pathological situations such as in tumourogenesis. Two KS-proteoglycans in particular, podocalyxcin and lumican are cell membrane, intracellular or stromal tissue associated components with roles in the promotion or regulation of tumour development, mucin-like KS-glycoproteins may also contribute to tumourogenesis. A greater understanding of the biology of KS may allow better methodology to be developed to more effectively combat tumourogenic processes.

Overexpression of Dehydrogenase/Reductase 9 Predicts Poor Response to Concurrent Chemoradiotherapy and Poor Prognosis in Rectal Cancer Patients

“…Especially, KS type II attaches to a threonine or serine (Thr/Ser) residue on the core protein via an O -linked mucin-type structure (core 2, GalNAc-Thr/Ser). During the biosynthesis of KS, several glycosyltransferases and sulfotransferases act to add Gal or GlcNAc to an acceptor residue for chain elongation and undergo sulfation at carbon position 6 (C6) on Gal-GlcNAc either individually or collectively, respectively ( 30 ). The chain length and sulfation degree (charge heterogeneity) of KS increase with the age of the connective tissues where it is enriched in and their pathological status, including tumor development.…”

A novel comprehensive immune-related gene signature as a promising survival predictor for the patients with head and neck squamous cell carcinoma

“…For example, the pathway of focal adhesion in HNSCC participates in the development of distant metastasis to lymph nodes [ 51 ]. The keratan sulphate in the tumor environment plays a vital role in the promotion or regulation of tumor development [ 52 ]. The chondroitin sulfate glycosaminoglycan biosynthesis pathway can promote and regulate tumor progression and metastasis by influencing important biological processes such as cell growth, adhesion, signal transduction, and lipid metabolism [ 53 ].…”

Importance of Heparan Sulfate Proteoglycans in Pancreatic Islets and β-Cells

“…Concurrently, in mouse islets, the disaccharide content of CS and DS, the other GAGs of HS, were below the detection limits of the high-performance liquid chromatography (HPLC) [ 8 , 21 ] and immunostaining methods [ 14 , 30 ]. Although there are no reports of the detection of KS chains in pancreatic islets, the presence of lumican, a KS core protein, has been reported in human pancreatic α-cells and human pancreatic ductal adenocarcinoma cells [ 31 , 32 , 33 , 34 , 35 , 36 ]. Hyaluronan accumulates in islets as T1DM progresses and presents indirect β-cell destruction by inducing inflammation [ 37 , 38 , 39 , 40 ].…”