The glycosaminoglycan hyaluronan (HA) is a major component of extracellular matrices with many diverse functions that depend on its chain size and its interactions with various effective proteins and cell receptors. Such interactions trigger several intracellular signaling pathways that regulate growth, differentiation and migration. HA is implicated in physiological and pathological processes, including embryogenesis, morphogenesis, wound healing, tissue repair, inflammation and the progression of several diseases, among them cancer and diabetes. Recent data suggest a regulatory role of HA in cancer cell migration, invasion and metastasis, and implicate its interaction with variants of the cell surface HA receptor CD44 in the molecular targeting of solid tumors. HA research areas are expanding so rapidly that it is not possible to cover all HA functions. The three thematic minireviews, however, provide the reader with focused assessments of the current HA research areas.
The first minireview by Wang et al. focuses on the discovery of monocyte-adhesive HA matrices and how they have morphed into various pathologies, including inflammatory bowel disease, wound healing, asthma and diabetes. Notably, the unique mechanism by which HA is normally synthesized, namely the utilization of cytosolic substrates with extrusion of the growing HA polymer into the extracellular matrix, has a major role in its large variety of normal and pathological functions. This is an emerging area of research that will impact on most, if not all, inflammatory processes.
The second minireview by Tammi et al. focuses on the novel regulatory points in HA synthesis that have recently been discovered. Furthermore, it highlights the role of several factors influencing the expression of the HA synthases (HASs), as well as the transcriptional events in the HAS gene promoter, traffic of HAS from the Golgi apparatus to the plasma membrane, post-translational modifications of the HAS protein and the pivotal role of the UDP-sugars as HAS substrates and feedback controllers of HAS expression. As the accumulation of HA in malignant tumors promotes their growth and spread, the identification of control points of HA synthesis may offer opportunities for drug development.
The third minireview by Misra et al. focuses on new aspects concerning the interaction of HA with CD44 variants (CD44v) and how this interaction triggers several intracellular signaling pathways regulating proliferation, migration and differentiation. Reactive stroma in cancer is often characterized by an increase in cancer-associated fibroblasts/myofibroblasts, which produce an array of growth factors and chemokines that amplify the synthesis of HA. The interaction of HA with CD44v facilitates cancer progression and invasion/metastasis with respect to stromal HA crosstalk with epithelium CD44v. This minireview highlights recent findings in tumor–stromal interactions and their possible roles in HA–CD44v-induced tumor growth and invasion, together with fresh insights into the enigmatic nature of CD44 splice variants, and how the suppression of HA–CD44v interaction may be a novel therapeutic target.
We hope that this thematic minireview series will bring these emerging concepts to the readers, will highlight the importance of HA in the signaling and regulation of cellular events, and will stimulate new studies in this very interesting research area that will provide a deeper understanding of disease progression and treatment.
[ Dr Hascall is a staff member of the Department of Biomedical Engineering and Orthopedic Surgery at the Cleveland Clinic, Cleveland, Ohio, and a Professor of Biological Chemistry at Case Western Reserve University. He is currently an Associate Editor for the Journal of Biological Chemistry. His current research interests include connective tissue biology and the role of HA matrices in inflammations. Dr Hascall is a co-founder of the International Society for Hyaluronan Sciences (ISHAS) and has authored over 250 papers and book chapters on the structure and function of proteoglycans and HA, and their involvement in tissue organization and function. He has received honorary degrees at the University of Lund, Sweden, and the University of Kuopio, Finland, and was honored by the University of Patras, Greece, in 2009. ]
[ Dr Karamanos is a Professor of Biochemistry at the University of Patras, Greece. He has been the driving force in coordinating the Meetings of Matrix Biology, the FEBS Advanced Lecture Courses on Matrix Pathobiology, Signaling and Molecular Targets in Greece. His current research interests include the importance of proteoglycans, glycosaminoglycans and metalloproteinases in cell signaling and in the molecular targeting of cancer. Dr Karamanos has published more than 200 papers and book chapters and is the Vice-President of the Hellenic Society of Biochemistry and Molecular Biology, the contact person for the Federation of Connective Tissue Societies, and the current Head of the Department of Chemistry, University of Patras. ]