**1. Introduction**

The tumor microenvironment (TME) is composed of cancerous, non-cancerous, stromal, and immune cells that are surrounded by the components of the extracellular matrix (ECM) [1]. The ECM is a significant component of the TME with a vital role in cancer's pathogenesis [2,3]. It is well established that TME plays an essential role in tumorigenesis. Indeed, tumor growth and metastasis steps, e.g., primary lesion development, intravasation, extravasation, and metastasis to anatomically distant sites, are executed via the discrete interplay of the tumor cells with their microenvironment [4]. Glycosaminoglycans (GAGs), natural biomacromolecules, and essential ECM and cell membrane components are extensively altered in cancer tissues [5]. Indeed, these heteropolysaccharides vital in supporting homeostasis have also been established to participate in inflammatory, fibrotic, and pro-tumorigenic processes [6–9]. Both free GAGs and GAGs bound into the protein cores of proteoglycans- (PG) are crucial mediators of cellular and ECM microenvironments, with the ability to specifically bind and regulate the function of ligands and receptors crucial to cancer genesis [4,10,11].

**Citation:** Berdiaki, A.; Neagu, M.; Giatagana, E.-M.; Kuskov, A.; Tsatsakis, A.M.; Tzanakakis, G.N.; Nikitovic, D. Glycosaminoglycans: Carriers and Targets for Tailored Anti-Cancer Therapy. *Biomolecules* **2021**, *11*, 395. https://doi.org/ 10.3390/biom11030395

Academic Editor: Vladimir N. Uversky

Received: 27 January 2021 Accepted: 4 March 2021 Published: 8 March 2021

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Structurally, GAGs are linear, long-chained polysaccharides consisting of repeating disaccharide units linked by glycosidic bonds. These building blocks are composed of N-acetylated hexosamine and uronic acid. The type of the disaccharide repeating unit and its modifications, including discrete sulfation patterns, allows the classification of GAGs into specific categories, e.g., chondroitin sulfate (CS)/dermatan sulfate (DS), heparin (Hep)/heparan sulfate (HS), keratan sulfate (KS) and hyaluronan (HA) [12–15]. KS chains contain galactose instead of uronic acid in their disaccharide building blocks [15]. CS/DS, HS/Hep, and KS chains are covalently bound into the protein cores of proteoglycans [6]. On the other hand, the non-sulfated GAG HA is not bound into the proteoglycan core but is secreted to the ECM of almost all tissues [13].

Bound GAGs are initially synthesized on core proteins at the Golgi lumen. Their glucuronic acid—N-acetylglucosamine/N-acetylgalactosamine(GlcA-GlcNAc/GalNAc) or, in the case of KS, galactose-N-acetylglucosamine (Gal-GlcNAc) repeating units are subjected to significant structural modification, including sulfation and in the case of HS/CS epimerization at the Golgi apparatus. Moreover, the desulfationof HS chains is performed at the cell membrane compartment [16]. The fine modifications result in an astonishing number of divergent GAG structures.

The GAG fine modifications define, to no small degree, the specificity of their binding with proteins. Notably, GAGs have been shown to interact with more than 500 proteins [17]. The interactions of GAGs with membrane receptors, ECM proteins, chemokines, and cytokines, as well as enzymes and enzyme inhibitors, are crucial in both development and homeostasis [18,19]. Likewise, GAGs' interactions with the above, both soluble and insoluble ligands, play a vital role in various diseases, including cancer [20]. By modulating numerous signaling pathways, GAGs exert distinct effects on cancer cells' functions, cancer stroma interactions, and cancer-associated inflammation, thus regulating essential processes for tumor progression and metastasis [1,4,6,21].

During disease progression, the GAG fine structure changes in a manner associated with disease evolution. Thus, changes in the GAG sulfation pattern are immediately correlated to malignant transformation [22]. Their molecular weight, distribution, composition, and subtle modifications, including sulfation, exhibit distinct alterations during cancer development [23,24]. Thus, most tumor types exhibit increased CS content with an increase in the 6-O-sulfated and/or unsulfated disaccharide content and a decrease in the 4-O-sulfation level due to changes in relevant enzyme activities [23,24]. Likewise, an aberrant HS sulfation pattern has been correlated to tumorigenesis. It was shown that the *N*-sulfation of GlcNresidues in specific domains along the HS chain facilitate tumor angioegenesis [25]. The expression of HS 6*O*-sulphated disaccharide content was shown to be increased during chondrosarcoma [26] and colon carcinoma progression [27].

GAGs and GAG-based molecules, due to their unique properties, are suggested as promising effectors for anticancer therapy [28]. Considering their participation in tumorigenesis, their utilization in drug development has been the focus of both industry and academic research efforts [29]. These efforts have been developing in two main directions; (i) utilizing GAGs as targets of therapeutic strategies and (ii) employing GAGs exquisite specificity and excellent physicochemical properties for targeted delivery of cancer therapeutics.

This review will discuss recent developments and the broad potential of GAG utilization for cancer therapy.
