Proteoglycans in Cancer: Friends or Enemies? A Special Focus on Hepatocellular Carcinoma

Simple Summary Proteoglycans affect multiple molecular and cellular processes during the progression of solid tumors with a highly desmoplastic stroma, such as HCC. Due to their role in enhancing or limiting the traits of cancer cells underlying their aggressiveness, such as proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and stemness, these macromolecules could be exploited as molecular targets or therapeutic agents. Proteoglycans, such as biglycan, versican, syndecan-1, glypican-3, and agrin, promote HCC cell proliferation, EMT, and angiogenesis, while endostatin and proteoglycan 4 were shown to impair cancer neovascularization or to enhance the sensitivity of HCC cells to drugs, such as sorafenib and regorafenib. Based on this evidence, interventional strategies involving the use of humanized monoclonal antibodies, T cells engineered with chimeric antigen receptors, or recombinant proteins mimicking potentially curative proteoglycans, are being employed or may be adopted in the near future for the treatment of HCC. Proteoglycans are a class of highly glycosylated proteins expressed in virtually all tissues, which are localized within membranes, but more often in the pericellular space and extracellular matrix (ECM), and are involved in tissue homeostasis and remodeling of the stromal microenvironment during physiological and pathological processes, such as tissue regeneration, angiogenesis, and cancer. In general, proteoglycans can perform signaling activities and influence a range of physical, chemical, and biological tissue properties, including the diffusivity of small electrolytes and nutrients and the bioavailability of growth factors. While the dysregulated expression of some proteoglycans is observed in many cancers, whether they act as supporters or limiters of neoplastic progression is still a matter of controversy, as the tumor promoting or suppressive function of some proteoglycans is context dependent. The participation of multiple proteoglycans in organ regeneration (as demonstrated for the liver in hepatectomy mouse models) and in cancer suggests that these molecules actively influence cell growth and motility, thus contributing to key events that characterize neoplastic progression. In this review, we outline the main roles of proteoglycans in the physiology and pathology of cancers, with a special mention to hepatocellular carcinoma (HCC), highlighting the translational potential of proteoglycans as targets or therapeutic agents for the treatment of this disease.