Cell-surface heparan sulfate proteoglycans as multifunctional integrators of signaling in cancer

Proteoglycans (PGs) represent a large proportion of the components that constitute the extracellular matrix (ECM). They are a diverse group of glycoproteins characterized by a covalent link to a specific glycosaminoglycan type. As part of the ECM, heparan sulfate (HS)PGs participate in both physiological and pathological processes including cell recruitment during inflammation and the promotion of cell proliferation, adhesion and motility during development, angiogenesis, wound repair and tumor progression. A key function of HSPGs is their ability to modulate the expression and function of cytokines, chemokines, growth factors, morphogens, and adhesion molecules. This is due to their capacity to act as ligands or co-receptors for various signal-transducing receptors, affecting pathways such as FGF, VEGF, chemokines, integrins, Wnt, notch, IL-6/JAK-STAT3, and NF-κB. The activation of those pathways has been implicated in the induction, progression, and malignancy of a tumor. For many years, the study of signaling has allowed for designing specific drugs targeting these pathways for cancer treatment, with very positive results. Likewise, HSPGs have become the subject of cancer research and are increasingly recognized as important therapeutic targets. Although they have been studied in a variety of preclinical and experimental models, their mechanism of action in malignancy still needs to be more clearly defined. In this review, we discuss the role of cell-surface HSPGs as pleiotropic modulators of signaling in cancer and identify them as promising markers and targets for cancer treatment.