Heparan sulfate signaling in cancer

Abstract

Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases, and heparanases. HS has important emerging roles in oncogenesis, and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network.

Keywords: heparan sulfate; heparanase; heparin; metastasis; sulfatase; sulfyltransferase.

Figure I. HS structure and modification

Heparin and HS consist of a xylose(Xyl)-galactose(Gal)-galactose-glucuronic acid (GlcA) linkage tetrasaccharide followed by repeating disaccharide units (inset) variably sulfated at the 3-O, 6-O, or N-sites on glucosamine (GlcNAc), and the 6-O site on glucuronic acid. Dashed circles indicate sulfation reactions. Starred numbers indicate the highly regulated order of reactions. Heparanases and sulfatases further modify HS structure (scissors).

Figure 1. Anticoagulant effects of heparin and HS

Endothelial heparan sulfate proteoglycans (HSPGs) and heparin bind antithrombin III via the sulfated glucosamine (GlcNAc) and glucuronic acid (GlcA) heparin pentasaccharide recognition sequence shown in the inset. Antithrombin in turn binds thrombin, factor IXa, and factor Xa to prevent coagulation. Antithrombin monomer reproduced with permission from K. Murphy (http://en.wikipedia.org/wiki/File:Antithrombin_monomer.jpeg).

Figure 2. HS ternary complex formation

Heparan sulfate proteoglycans (HSPGs) and heparin bind fibroblast growth factor (FGF)-2 via 2-O-sulfate on glucuronic acid and N-sulfate on glucosamine, as well as FGF receptors (FGFR1) via 6-O-sulfate on glucosamine to enhance downstream signaling via Janus kinase/signal transducers and activators of transcription (JAK/STAT), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), mitogen-activated protein kinases (MAPK), Ras homology (RhoA), or diacylglycerol/protein kinase C/calcium (DAG/PKC/Ca²⁺).

Figure 3. Soluble HSPGs released from the tumor stroma alter cancer cell signaling

Heparan sulfate proteoglycans (HSPGs) cleaved from the stromal cell surface and released in soluble form can bind ligands including FGF2 and receptors including FGFR1 to alter cancer cell signaling (inset). Soluble HSPGs (sHSPG) can decrease (A) or increase (B) extracellular signal-regulated kinase (ERK 1/2) phosphorylation, translocation to the nucleus and activation of transcription factors (TF). Examples from pancreatic cancer, breast cancer, and neuroblastoma are shown.

Figure 4. Heparan sulfate effects on cancer cell biology

Heparan sulfate has demonstrated roles in tumor cell proliferation, tumor angiogenesis, metastasis and terminal differentiation. The roles of specific heparan sulfate proteoglycans (HSPGs), including syndecans (SDC), glypicans (GPC), the type III transforming growth factor β receptor (TβRIII), neuropilin 1 (Nrp1), perlecan, collagen XVIII, and CD44, are depicted.