Proteoglycans in health and disease: emerging concepts and future directions

Abstract

Proteoglycans are emerging as key molecules in a variety of cellular processes because of their unique capacities to regulate growth factor-mediated signaling pathways, thereby affecting many physiological and pathological processes, including, among others, cancer, angiogenesis, fibrosis, immunity and infectious diseases. The field has expanded so far and so fast that it is impossible to cover all proteoglycan biology. However, the four thematic minireviews provide the reader with a focused assessment of critical and emerging areas in ‘proteoglycanology’. The first minireview by Iozzo and Schaefer focuses on the role of the small leucine-rich proteoglycans (SLRPs) in cell signaling. Members of the SLRP gene family, now expanded to encompass five distinct classes, affect several receptor tyrosine kinases, including epidermal growth factor receptor, insulin-like growth factor receptor type 1 and hepatocyte growth factor receptor (Met). Often the interaction is antagonistic leading to receptor tyrosine kinase internalization and degradation, and ultimately to inhibition of cell growth. SLRPs have recently been linked to the regulation of factors in innate immunity and inflammation such as Toll-like receptors and purinergic P2X receptors. This is an expanding area of new research and suggests that SLRPs might have acquired a variety of functions through evolution. The second minireview by Manon-Jensen et al. focuses on the function of the cell-surface syndecans and their active enzymatic shedding. It is well established that proteolytic processing of cell-surface proteoglycans plays a key role in cell adhesion, migration, survival, differentiation and proliferation. Cleavage of the syndecan protein cores is constitutive, although this process is accelerated in wound healing and invasive cancer. Notably, shedding of the syndecans alters the cell-surface receptor dynamics and provides soluble ectodomains that can function as paracrine or autocrine effectors, or competitive inhibitors. The third minireview by Barash et al. focuses on new heparanase roles in cancer progression and metastasis. The activity of heparanase, an endo-β-d-glucuronidase which cleaves heparan sulfate chains at a limited number of sites, correlates with enhanced metastatic potential. Heparanase is also involved in angiogenesis, inflammation and autoimmunity, involving migration of vascular endothelial cells and activated cells of the immune system. Heparanase might also work in an enzymatic activity-independent manner, enhancing adhesion and migration of endothelial cells and promoting phosphorylation of signaling molecules such as Akt and Src. Human heparanase splice variants devoid of enzymatic activity and endowed with pro-tumorigenic characteristics may provide a mechanistic explanation for this function. The fourth minireview by Theocharis et al. focuses on the potential pharmacological targeting of proteoglycans in malignancy. The basic assumption is that proteoglycan metabolism is markedly altered during malignant transformation and progression, and that the synthesis of stromal proteoglycans is regulated by factors secreted by cancer cells. Thus, the modified tumor stroma might facilitate cancer cell growth and spreading, and the expression of proteoglycans in stromal cells may serve as prognostic markers for tumor progression and patient survival. We hope that this thematic minireview series will stimulate new studies in this interesting area of research and will attract new investigators to the field of proteoglycanology.