Glycosaminoglycans in cancer therapy

Abstract

Glycosaminoglycans (GAGs) are an important component of the tumor microenvironment (TME). GAGs can interact with a variety of binding partners and thereby influence cancer progression on multiple levels. GAGs can modulate growth factor and chemokine signaling, invasion and metastasis formation. Moreover, GAGs are able to change the physical property of the extracellular matrix (ECM). Abnormalities in GAG abundance and structure (e.g., sulfation patterns and molecular weight) are found across various cancer types and show biomarker potential. Targeting GAGs, as well as the usage of GAGs and their mimetics, are promising approaches to interfere with cancer progression. In addition, GAGs can be used as drug and cytokine carriers to induce an anti-tumor response. In this review, we summarize the role of GAGs in cancer and the potential use of GAGs and GAG derivatives to target cancer.

Revisiting the Syndecans: Master Signaling Regulators with Prognostic and Targetable Therapeutic Values in Breast Carcinoma

“…This may open new avenues for the possibilities of designing antibodies against GAG chains of SDCs on tumor cells. Nevertheless, the GAG chain length and sulfation degree/pattern are context-dependent in various cancers [ 165 ]. Thus, GAG chains of SDCs should be characterized in breast cancer to identify and effectively target their different ligand-binding sites.…”

“…However, due to the adverse effects caused by heparin, such as bleeding and thrombocytopenia [ 168 ], intense research studies have been performed to develop heparin analogs or HS mimetics with no anticoagulant activities and fewer side effects. In this regard, and based on the impressive data of their anticancer effects in preclinical models, the HS mimetics muparfostat (PI-88), pixatimod (PG545), and necuparanib (M402) entered clinical trial phases I, II, and III alone or in combined therapy to evaluate their safety and beneficial effects on the survival of a patient with different advanced solid cancers and multiple myeloma (reviewed in [ 165 , 169 ]). The mechanism of action of these HS-mimetics is primarily mediated via inhibition of heparanase-mediated angiogenesis and metastasis, competitive binding with growth factors, and/or activation of tumor-suppressing immune cells (e.g., natural killer and dendritic cells) [ 165 , 169 ].…”

“…In this regard, and based on the impressive data of their anticancer effects in preclinical models, the HS mimetics muparfostat (PI-88), pixatimod (PG545), and necuparanib (M402) entered clinical trial phases I, II, and III alone or in combined therapy to evaluate their safety and beneficial effects on the survival of a patient with different advanced solid cancers and multiple myeloma (reviewed in [ 165 , 169 ]). The mechanism of action of these HS-mimetics is primarily mediated via inhibition of heparanase-mediated angiogenesis and metastasis, competitive binding with growth factors, and/or activation of tumor-suppressing immune cells (e.g., natural killer and dendritic cells) [ 165 , 169 ]. An interesting study showed that in an ex vivo explant model of normal human female mammary tissue, heparanase upregulates the expression and cleavage of SDC1 rather than SDC4, resulting in high mammographic density (a strong and independent risk factor for breast cancer) with a fibrous stroma rich in SDC1.…”

Proteoglycans in breast cancer, identification and characterization by LC‐MS/MS assisted proteomics approach: A review

“…LC‐MS/MS is a robust tool for identification and characterization of GAGs as well, making it an ideal approach for complete and accurate characterization of PGs as a whole. Abnormalities of GAGs structure and characteristics, including sulfation patterns and molecular weight, are useful to develop a GAGs based biomarkers in cancer [95]. Chondroitin sulfate is actively involved in breast cancer invasion and progression.…”

Exostosin 1 Knockdown Induces Chemoresistance in MV3 Melanoma Cells by Upregulating JNK and MEK/ERK Signaling

“…Heparan sulfates (HS), repeating dimer units of glucuronic acids and glucosamines, are of crucial importance in communication as functional components of PGs, even since they are also constituents of the ECM [ 6 ]. As is known, tumor cells display an aberrant expression pattern of HSPG [ 7 ] and thus affect multiple processes such as cell growth, invasiveness, or metastasis by binding growth factors, cytokines, coagulation factors, etc., to the HS moieties. For example, the HSPG syndecan 1 has been addressed in several reports and outlined in its pro-tumorigenic functions [ 8 , 9 ].…”