Hyaluronan Metabolism: a Major Paradox in Cancer Biology

Paradoxically, both hyaluronan (HA) and hyaluronidases, the enzymes that eliminate HA, can correlate with cancer progression. Levels of HA on the surface of tumor cells are indicators of poor outcome. Certain hyaluronidases, products of tumor suppressor genes eliminated in the course of tumor spread, are used clinically in anti-cancer chemotherapy regimens. Such information would indicate that cancer progression is inhibited by hyaluronidase. Yet progression of certain cancers correlates with levels of hyaluronidase activity. An attempt is made here to understand such apparent contradictions by examining details of HA metabolism. Anabolic and catabolic pathways are comprised of the HA synthases and hyaluronidases, respectively. There are several enzymes that synthesize HA, each under a different control mechanism, generating products of differing polymer size. The hyaluronidases degrade HA in step-wise fashion, the polymer decreasing in size in quantum steps, each size-specific polymer having a different biological activity. Superimposed on these are the potent hyaluronidase inhibitors, about which very little is known. These components of HA metabolism are reviewed here for possible roles in supporting or suppressing malignant transformation, growth, invasion and metastatic spread of tumors. Such a systematic approach may reveal mechanisms used in the course of cancer progression, resolve some of the apparent disparities, render new prognostic markers, and provide new targets for therapeutic intervention.