Hyaluronidases in cancer biology

Hyaluronan is a megadalton glycosaminoglycan polymer critical for maintaining the integrity of the extracellular matrix. It can exist in a protein-bound state with aggregating proteoglycans, where it expands the extracellular matrix and modulates cell-cell interactions. It also exists in lower molecular weight forms that participate in a myriad of biological functions. It is unique in that much of it is degraded within hours of its synthesis. High molecular weight hyaluronan, a reflection of intact healthy tissues, is normally produced by hyaluronan synthases at the plasma membrane. It is catabolized by the action of an extracellular plasma membrane-tethered hyaluronidase that is coordinated with intracellular lysosomal hyaluronidases and exoglycosidases. This occurs in local tissues and lymph, with the remainder being cleared by the sinusoidal liver endothelium upon entering the vascular compartment. Elevated extracellular levels of hyaluronan and its partially catabolized oligomers are found in certain malignancies, potentially due to decoupled synthesis and degradation. Furthermore, partially depolymerized hyaluronan in the extracellular environment may have properties not found in the multivalent high molecular weight polymer in malignancies. Functional perturbations of hyaluronan synthesis and degradation have revealed active roles of the synthases and hyaluronidases in epithelial mesenchymal conversion, stroma and vascular formation, interstitial fluid pressure and chemosensitivity. While at least three confirmed hyaluronidases exist in the human genome (HYAL1, HYALl2 and PH20), functional perturbation of these genes in mice have failed to identify a simple linear catabolic circuit. The family of enzymes responsible for the synthesis and degradation of hyaluronan are being characterized. The fragmented forms of hyaluronan, largely a sign of cellular distress, occur in abundance in many malignancies. These small hyaluronan oligomers are assumed to be largely a result of hyaluronidase activity. Precisely how particular-sized fragments are generated and maintained is not known. Presumably, hyaluronan-binding proteins, in addition to the proteoglycans, participate in this process. Hyaluronidase inhibitors are now recognized, as well as growth factors that enhance the synthetic enzymes. A complete understanding of the anabolic and catabolic systems for hyaluronan may provide new dimensions into our understanding of cancer progression, as well as new opportunities for therapeutic intervention.