Proteoglycans in cancer biology, tumour microenvironment and angiogenesis

Abstract

• Introduction • Perlecan: a pro-angiogenic proteoglycan • Endorepellin, a C-terminal fragment of perlecan with anti-angiogenic activity • Syndecans in cancer biology • Glypicans and the control of cancer growth • Role of heparanase and proteoglycan remodelling in cancer • Decorin and growth control • Genetic evidence for a role for decorin in carcinogenesis • Mechanism of decorin action: suppression of β-catenin and Myc levels • Lumican in cancer biology • Conclusions and perspectives Proteoglycans, key molecular effectors of cell surface and pericellular microenvironments, perform multiple functions in cancer and angiogenesis by virtue of their polyhedric nature and their ability to interact with both ligands and receptors that regulate neoplastic growth and neovascularization. Some proteoglycans such as perlecan, have pro- and anti-angiogenic activities, whereas other proteoglycans, such as syndecans and glypicans, can also directly affect cancer growth by modulating key signalling pathways. The bioactivity of these proteoglycans is further modulated by several classes of enzymes within the tumour microenvironment: (i) sheddases that cleave transmembrane or cell-associated syndecans and glypicans, (ii) various proteinases that cleave the protein core of pericellular proteoglycans and (iii) heparanases and endosulfatases which modify the structure and bioactivity of various heparan sulphate proteoglycans and their bound growth factors. In contrast, some of the small leucine-rich proteoglycans, such as decorin and lumican, act as tumour repressors by physically antagonizing receptor tyrosine kinases including the epidermal growth factor and the Met receptors or integrin receptors thereby evoking anti-survival and pro-apoptotic pathways. In this review we will critically assess the expanding repertoire of molecular interactions attributed to various proteoglycans and will discuss novel proteoglycan functions modulating cancer progression, invasion and metastasis and how these factors regulate the tumour microenvironment.