Heparan sulfate chains in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) corresponds to the vast majority of liver cancer cases, with one of the highest mortality rates. Major advances have been made in this field both in the characterization of the molecular pathogenesis and in the development of systemic therapies. Despite these achievements, biomarkers and more efficient treatments are still needed to improve its management. Heparan sulfate (HS) chains are polysaccharides that are present at the cell surface or in the extracellular matrix that are able to bind various types of molecules, such as soluble factors, affecting their availability and thus their effects, or to contribute to interactions that position cells in their environments. Enzymes can modify HS chains after their synthesis, thus changing their properties. Numerous studies have shown HS-related proteins to be key actors that are associated with cellular effects, such as tumor growth, invasion, and metastasis, including in the context of liver carcinogenesis. The aim of this review is to provide a comprehensive overview of the biology of HS chains and their potential importance in HCC, from biological considerations to clinical development, and the identification of biomarkers, as well as therapeutic perspectives.

Keywords: biomarkers; heparan sulfate; hepatocellular carcinoma; praoteoglycans.

Figure 1.

Schematic representation of major HSPG structures and localization in the liver. Various types of HSPG are found in the liver and can be classified according to their localization: at the basement membrane (agrin, collagen XVIII, perlecan), in the secretory vesicles (serglycin), and at the cell surface (syndecans, glypicans, neuropilin 1, betaglycan, CD44v3). Cell-surface HSPGs can undergo cleavage (shedding) to be released into the ECM. The structure of a HSPG consists of HS chains that are attached to core proteins. HS chains are represented here in the form of alternating hexagons of different colors, corresponding to different types of sugar residues (straight lines). Core proteins correspond to the thick curves.

Figure 2.

Heparan sulfate chain features and enzymes associated with their biosynthesis. During the synthesis of HS chains, along with polymerization of the sugar units, modifications are performed by different enzymes (sulfotransferases and glucuronyal C5 epimerase) to create specific regions that can bind to ligands alternating NA and NS sequences. The curved arrows indicate the position of enzymatic action. 2-OST, 3-OST, and 6-OST catalyse the transfer of a sulfate group to the sugar residues at different positions. Glucuronyl C5-epimerase converts glucuronic acid into iduronic acid. The NA domain corresponds to a sequence of repeated N-acetylated disaccharide units; the NS domain corresponds to a sequence of repeated N-sulfated disaccharide units. Glu Ac = glucuronic acid, Idu Ac = iduronic acid, NAc Glc = N-Acetylglucosamine, OST = O-sulfotransferases.

Figure 3.

Heparan sulfate chain features and enzymes associated with their extracellular modifications. Extracellular modifications can be carried out by the action of sulfatases (SULF1 and SULF2) and heparanase (HPSE). The scissors indicate enzymatic action. The first scissors correspond to the action of SULFs with the removal of sulfate groups at carbon position 6 of glucosamines. The second scissors correspond to the action of HPSE, with the cleavage of HS chains in sequences of repeated N-sulfated disaccharide units.