Hyaluronidase is a hyaluronic acid-degrading endoglycosidase that is present in many toxins and the levels of which are elevated in cancer.
Hyaluronidases (HAases)1 are a family of enzymes that are crucial for the spread of bacterial infections, toxins present in various venoms, and possibly, cancer progression (1-6). In humans, six HAase genes have been identified. These genes occur in clusters of three at two chromosomal locations (Ref. 7 and human genome blast search). HYAL1, HYAL2, and HYAL3 occur on chromosome 3p21.3, and PH20, HYAL4, and HYALP1 occur on chromosome 7q31.3. With the possible exception of HYAL4 and HYALP1, all other HAases degrade hyaluronic acid (HA) (7).HA is a nonsulfated glycosaminoglycan made up of repeating disaccharide units, D-glucuronic acid, and N-acetyl-D-glucosamine. HA is present in body fluids, tissues, and the extracellular matrix (8 -10). It keeps tissues hydrated and maintains osmotic balance and cartilage integrity (8, 10). HA also actively regulates cell adhesion, migration, and proliferation by interacting with specific cell surface receptors such as CD44 and RHAMM (11). The concentrations of HA are elevated in several inflammatory diseases and various carcinomas (e.g. bladder, prostate, breast, lung, colon, and so forth; Refs. 9 and 12-19). For example, we have shown that urinary HA concentration is a highly sensitive and specific marker for detecting bladder cancer, regardless of its grade (18,19). In tumor tissues, HA may promote tumor growth and metastasis probably by actively supporting tumor cell migration and offering protection against immune surveillance (20 -22). Small fragments of HA, generated by HAases, stimulate angiogenesis (23-25). We recently showed that HA fragments of ϳ10 -15 disaccharide units stimulate endothelial cell proliferation by acting through cell surface HA receptor, RHAMM, and activating the mitogenactivated protein kinase pathway (26). We have also shown that elevated levels of HYAL1-type HAase coincide with the presence of angiogenic HA fragments in prostate tumor tissues and in the urine of bladder cancer patients (17,27).Among the six HAases, HYAL1, HYAL2, and PH20 are well characterized. HYAL1 type HAase was originally purified from human plasma and urine (28, 29). However, we have shown that HYAL1 is the major tumor-derived HAase expressed in bladder and prostate cancer tissues (17,30). It has a optimum pH range of 4.0 -4.3, and the enzyme is 50 -80% active at pH 4.5 (17). have shown that a lack of functional HYAL1 results in a disorder called mucopolysaccharidosis IX. In this study the authors identified that aa Glu 268 is crucial for HYAL1 activity. HYAL2 was originally designated as the lysosomal HAase, and it cleaves high molecular mass HA into ϳ20-kDa HA fragments (32). It has a pH optimum of ϳ4.0 and is possibly less active than other HAases. HYAL-2 may also be exposed to the cell surface through a GPI anchor (32). The third HAase gene in the 3p21.3 locus is HYAL3. Although
