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Publisher Summary Hyaluronan synthase (HAS) expression provides powerful tools for understanding the in vivo function of hyaluronan (HA), particularly in connection with cancer cell behavior. The central aim of the present review is to highlight the role of HA in cancer progression with respect to abnormal HA biosynthesis. A wealth of data is accumulated on HA function in the promotion of malignancies, which shows that enhanced cancer invasion and dissemination may be partly dependent on the mesenchymal conversion of cancer cells by HA overexpression. Furthermore, recent studies have enabled postulation of reliable mechanisms by which HA influences tumor growth and invasion by modulating the tumor microenvironment to recruit stromal cells and vasculature. Although the angiogenic function of HA oligosaccharides is well-established, the anti-angiogenicity of high molecular weight HA being modulated by HA-binding molecules needs further clarification and study. The roles of HA in cancer progression may differ according to the HAS isoforms expressed, meaning cancer cells at different stages may differentially utilize the three HAS isoforms to maximize their survival. Studies are now in progress to identify exactly which HAS proteins are associated with cancer progression. This will provide an opportunity to develop new strategies for cancer therapy targeting specific cancer-associated HAS species.

This chapter presents an introduction to the formation of the serum-derived hyaluronan-associated protein (SHAP)–hyaluronan complex and the related physiological significance. This chapter discusses its possible roles in pathological processes. The main point is that the association of SHAP changes the properties of hyaluronan. Mass spectrometry revealed a unique protein–glycosaminoglycan linkage in both IαI family molecules and the SHAP–hyaluronan complex, where an ester bond is formed between the carboxyl group of the asparate residue at the C-terminus of the heavy chains/SHAPs, and the C-6 hydroxyl group of an internal N-acetylgalactosamine residue of the bikunin chondroitin sulfate or an N-acetylglucosamine residue of hyaluronan. Based on the similarity of the protein–glycosaminoglycan linkage and the homology of both the N- and C-terminus between the heavy chain and corresponding SHAP, it is concluded that the SHAP–hyaluronan complex is formed via a trans-esterification reaction in which hyaluronan substitutes for bikunin chondroitin sulfate to form the same type of ester bond with the heavy chains, accompanied by the release of the bikunin proteoglycan.