Endocan in Cancers: A Lesson from a Circulating Dermatan Sulfate Proteoglycan

As most proteoglycans exert their biological activities in the pericellular region, circulating Endocan has appeared since its discovery as an atypical dermatan sulfate proteoglycan, with distinctive structural and functional properties. Endocan is naturally expressed by endothelial cells, highly regulated in presence of proinflammatory and proangiogenic molecules, binds to matrix proteins, growth factors, integrin, and cells, and may be then considered as an accurate marker of endothelial activation. Consequently, Endocan expression has been associated with a growing number of pathological conditions where endothelium gets challenged and notably in highly vascularized cancers. In this context, Endocan has indeed been rapidly emerging as a promising tissue- and blood-based marker of the vascular growth and neoangiogenesis during cancer progression. Furthermore, very recent studies have reported an expression of Endocan by the tumor cells themselves. This highlights Endocan as a multifaceted molecule with a great interest for researchers and clinicians to better understand tumor development, from the bench to the clinics. With promising perspectives of clinical applications, Endocan thus appears as an exciting model for on going and future developments of proteoglycan-based approaches in cancer diagnostics and/or therapy. 1. Introduction During the past 20 years, proteoglycans (PGs) have emerged as critical modulators of most major cellular processes, including cell proliferation, adhesion, and migration, and have been involved in many pathological conditions, such as inflammation, cancer, or infection [1–5]. These complex glycoproteins, which consist of a core protein bearing polysaccharide chains of glycosaminoglycans (GAGs), are abundantly found at the surface of cells and in extracellular matrices (ECMs). From there, they benefit from an ideal positioning to interact, either through their protein core or their GAG chains, with soluble signaling effectors (growth factors, cytokines, chemokines…) [6, 7], structural components of the ECM (fibronectin, collagens…) and membrane-associated proteins (receptors, integrins…) [8–11], or intracellular molecules (PKC, Syntenin, CASK/Lin-2…) [12, 13]. However, PG activities are not restricted to the control of local contacts and molecular interactions at the cell surface vicinity. Shedding of cell-surface PGs (particularly HSPG Syndecans and Glypicans), enabling release of soluble GAG-associated ectodomains, is known to play a key role in many physiopathological conditions, such as wound healing, inflammation,