**1. Introduction**

After decades of knowledge about the cellular signalling pathways mediated by glycoconjugates and the impact of the glycan structural characteristics in defining specific cellular responses, researchers are taking advantage of the multiple features of glycosaminoglycans (GAGs) to develop new tools for improving the clinical management of cancer. GAGs are long linear chains of heterogeneous saccharides, comprising one of the major biomolecules class found in all mammalian cells [1]. GAGs have been extensively studied, and their interactions with growth factors, morphogens, chemokines, extracellular matrix (ECM) proteins and their bioactive fragments, receptors, lipoproteins and pathogens are well described [1–5]. This dynamic network orchestrates several essential functions, from critical steps in embryogenesis and early development to ECM (re)modelling and cell signalling regulation in various physiological and pathological contexts, such as metabolic and neurodegenerative diseases, infections and cancer [6,7]. This review focuses on one particular class of GAGs: Heparan sulfate (HS). HS are anionic polysaccharide chains that assemble as disaccharide building blocks of glucuronic acid (GlcA) linked to *N*-acetylglucosamine (GlcNAc) and undergo extensive modification through the action of at least

**Citation:** Faria-Ramos, I.; Poças, J.; Marques, C.; Santos-Antunes, J.; Macedo, G.; Reis, C.A.; Magalhães, A. Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management. *Biomolecules* **2021**, *11*, 136. https://doi.org/ 10.3390/biom11020136

Received: 11 December 2020 Accepted: 18 January 2021 Published: 21 January 2021

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four families of sulfotransferases and one epimerase. HS chains are covalently linked to a core protein to form heparan sulfate proteoglycans (HSPGs), which can be expressed at the cell membrane, released into the ECM [8] or secreted in extracellular vesicles (EVs) [9,10]. The HSPGs are the main mediators of cellular interaction with an enormous number of ligands. Over the last decade, new insights have emerged regarding the mechanisms and the biological significance of those interactions [7,11–13], and in this last couple of years, their biomedical potential has been at the forefront in glycobiology translational research [14–16]. HS interfere in many steps of tumour progression, such as cancer cell proliferation, immune response escaping, invasion of neighbour tissues and metastasis [7,9,17]. Moreover, the aberrant expression of different HSPGs and of the key enzymes involved in HS biosynthesis and post-synthesis modifications impact cancer cell behaviour [17,18]. The interplay between researchers and clinicians has been key to identify the major needs in the clinical practice, and therefore, propel a better understanding on the potential of HS with the ultimate goal of improving cancer patients' management. This ladder could not be scaled without the parallel development of powerful analytical equipment and approaches for glycan characterisation [19,20]. These biotechnological advances have contributed to unravel important features regarding the chemical diversity of HS structures, along with the intricate regulation of its biosynthetic pathways.

This review presents the main HS and HSPGs biological functions, from physiological to disease contexts, and summarises the most recent findings on HS as biomarkers and/or as therapeutic targets.
