Hyaluronan regulation of endothelial barrier function in cancer

Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated by endothelial cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including tumor angiogenesis and metastasis. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through specific mechanisms including HA-binding protein signaling in caveolin-enriched microdomains, a subset of lipid rafts. Certain disease states, including cancer, increase enzymatic hyaluronidase activity and reactive oxygen species generation, which break down high molecular weight HA (HMW-HA) to low molecular weight fragments (LMW-HA). LMW-HA can activate specific HA-binding proteins during tumor progression to promote disruption of endothelial cell-cell contacts. In contrast, exogenous administration of HMW-HA promotes enhancement of vascular integrity. This review focuses on the roles of HA in regulating angiogenic and metastatic processes based on its size and the HA-binding proteins present. Further, potential therapeutic applications of HMW-HA in treating cancer are discussed.