Hydranulase are a family of five human enzymes that have been differentially implicated in the

progression of many solid tumor types, both clinically and in functional studies. Advances in the past 5
years have clarified many apparent contradictions: by demonstrating that specific hyaluronidases have
alternative substrates to hyaluronan (HA) or do not exhibit any enzymatic activity, that high-molecular
weight HA polymers elicit signaling effects that are opposite those of the hyaluronidase-digested HA
oligomers, and (3) that it is actually the combined overexpression of HA synthesizing enzymes with
hyaluronidases that confers tumorigenic potential. This review examines the literature supporting these
conclusions and discusses novel mechanisms by which hyaluronidases impact invasive tumor cell
processes. In addition, a detailed structural and functional comparison of the hyaluronidases is
presented with insights into substrate selectivity and potential for therapeutic targeting. Finally,
technological advances in targeting hyaluronidase for tumor imaging and cancer therapy are
summarized.

Hyaluronidases as Anti-Cancer Chemotherapeutic Agents

Hyaluronidases have long been added to anti-cancer regimens, particularly in Europe. Tumors previously
resistant to chemotherapy become sensitive when hyaluronidase is added The enzyme may decrease
intratumoral pressure, permitting drugs to penetrate the malignancy. However, studies are available
suggesting that hyaluronidase has intrinsic anti-tumor activity.

Anti-Cancer Properties of Hyaluronidase

Evidence for the anti-cancer effects of hyaluronidase come from experimental model systems. The
enzyme enhances the anti-cancer effects of adriamycin in vitro Human cancers grown in SCID mice
regress dramatically following administration of purified testicular hyaluronidas Over expression of
HYAL-1 suppresses tumorigenicity in a model for colon carcinoma . Hyaluronidase administration delays
the appearance of carcinogen-induced tumors Hyaluronidase treatment also prevents lymph node
invasion in a murine model for T-cell lymphoma The mouse has several alleles for HYAL-1, while there is
only one in the human. The murine alleles have different levels of circulating hyaluronidase activity. The
growth rates of murine malignancies correlate inversely with enzyme levels Hyaluronidase also blocks
TNF-mediated cancer cell death, reverses multidrug resistance and alters cell cycle kinetics of chemo-
resistant carcinomas