Activated hyaluronan metabolism in the tumor matrix — Causes and consequences

Hyaluronan accumulates in the stroma of several solid tumors and promotes their progression. Both enhanced synthesis and fragmentation of hyaluronan are required as a part of this inflammatory process resembling wound healing. Increased expression of the genes of hyaluronan synthases (HAS1-3) are infrequent in human tumors, while posttranslational modifications that activate the HAS enzymes, and glucose shunted to the UDP-sugar substrates HASs, can have crucial contributions to tumor hyaluronan synthesis. The pericellular hyaluronan influences virtually all cell-cell and cell-matrix interactions, controlling migration, proliferation, apoptosis, epithelial to mesenchymal transition, and stem cell functions. The catabolism by hyaluronidases and free radicals appears to be as important as synthesis for the inflammation that promotes tumor growth, since the receptors mediating the signals create specific responses to hyaluronan fragments. Targeting hyaluronan metabolism shows therapeutic efficiency in animal experiments and early clinical trials. •Hyaluronan contributes to most aspects of the malignant phenotype.•Factors in both hyaluronan synthesis and catabolism contribute to tumor progression.•Cancer glucose uptake and Warburg metabolism stimulate hyaluronan synthesis.•Posttranslational regulation rather than expression of HAS enzymes is important.•Hyaluronan synthesis, degradation and signaling are potential targets of therapy.