Heparan sulfate proteoglycans as targets for cancer therapy: a review

Abstract

Heparan sulfate proteoglycans (HSPGs) play important roles in cancer initiation and progression, by interacting with the signaling pathways that affect proliferation, adhesion, invasion and angiogenesis. These roles suggest the possibility of various strategies of regulation of these molecules. In this review, we demonstrated that the anticancer drugs can regulate the heparan sulfate proteoglycans activity in different ways: some act directly in core protein, and can bind to a specific type of HSPG. Others drugs interact with glycosaminoglycans chains, and others can act directly in enzymes that regulate HSPGs levels. We also demonstrated that the HSPGs drug targets can be divided into four groups: monoclonal antibodies, antitumor antibiotic, natural products, and mimetics peptide. Interestingly, many drugs demonstrated in this review are approved by FDA and is used in cancer therapy (Food and Drug Administration) like trastuzumab, panitumumab, bleomycin and bisphosphonate zoledronic acid (ASCO) or are in clinical trials like codrituzumab and genistein. This review should help researchers to understand the mechanism of action of anticancer drugs existing and also may inspire the discovery of new drugs that regulate the heparan sulfate proteoglycans activity.

VAR2HP recognizing heparin‐like epitopes in targeted therapy and diagnosis of tumors

“…31 Especially in some diseased cells, HS overexpresses along with proteoglycan overexpression or produces special structures. 31,32 HSrelated proteoglycans, such as GPC3 and CD44, 33 are often used as targets or biomarker molecules for some cancerous cells. However, due to the lack of probes or antibodies specifically against tumorrelated GAG epitopes, the study and application of GAGs used as target molecules are limited.…”

Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

“…Nevertheless, additional factors of this work, such as VEGF-A, ET-1 and the IGF-pathway, can be expected to make an additional contribution to the Sdc-1-dependent angiogenesis phenotype, albeit in a cell type-specific manner. Cell type- and context-dependent effects for Sdc-1 are not surprising, as it acts as an important co-receptor for a multitude of signaling pathways, including receptor tyrosine kinases, G-protein-coupled chemokine receptors, morphogen signaling, and possible notch signaling [ 7 , 8 , 11 ]. Independent of the nature of the signaling pathways, it is remarkable that Sdc-1 depletion in all three TNBC cell lines resulted in a general decrease in the secretion of multiple proangiogenic factors ( Figure 2 ).…”

“…Angiogenesis is a complex process that is highly regulated through a plethora of cues secreted by different tumor microenvironmental cells and multiple signaling pathways, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and tissue factor (TF) [ 3 , 6 ]. Notably, the activity of angiogenic factors depends on their interaction with proteoglycan coreceptors at the cell surface [ 7 , 8 ].…”

The metabolic enzyme EXT1 is sufficient to induce the epithelial-mesenchymal transition program in cancers

“…The extracellular matrix (ECM) is enriched in proteoglycan (PG) and glycosaminoglycan (GSG) that form a complex network between the cells 6 . Heparan sulfate proteoglycans (HSPGs) are the most abundant PG 7 , ubiquitously expressed on the cell surface of diverse cell types, including tumors 8,9 . HSPGs are composed of repeating units of glucosamine and glucuronic acid (GlcA) 8 , which are heavily modified with various sulfate groups 10 , resulting in highly dynamic and negatively charged structures 9 .…”

“…Heparan sulfate proteoglycans (HSPGs) are the most abundant PG 7 , ubiquitously expressed on the cell surface of diverse cell types, including tumors 8,9 . HSPGs are composed of repeating units of glucosamine and glucuronic acid (GlcA) 8 , which are heavily modified with various sulfate groups 10 , resulting in highly dynamic and negatively charged structures 9 . This modification provides binding sites for positively charged amino acids present in a broad spectrum of soluble growth factors, cytokines, membrane proteins, and components of the ECM 11,12 .…”