Hyaluronan acts as a major extracellular matrix component in regulation of tissue organization and cellular functions, and its production is markedly increased with cancer progression. Since the discovery of hyaluronan synthase (HAS) genes, manipulation of HAS gene expression has led to better understanding of the altered hyaluronan biosynthesis in cancer. We have demonstrated that hyaluronan overproduction promotes cancer progression by modulating tumor microenvironment. Furthermore, we recently discovered that hyaluronan production regulates cancer stem cell (CSC) properties via the metabolic reprogramming of glycolysis and hexosamine biosynthetic pathway. These findings strongly suggest that hyaluronan plays a regulatory role in cellular metabolism coupled with its biosynthesis, in addition to its function as a conventional extracellular signal. In this review, I discuss multifaceted roles of hyaluronan in CSC regulation.
