Tumor microenvironment modulates hyaluronan expression: the lactate effect.

Hyaluronan (HA) synthesis is a tightly regulated process and is partly controlled by the microenvironment (e.g., lactate concentration). Experimental evidence has indicated that the melanoma cells that synthesize large amounts of HA exhibit enhanced tumor cell growth and increased metastatic capacity compared to those expressing smaller amounts. Because most studies have examined HA expression on melanoma cells in vitro, we compared the patterns of HA expression by B16-F1 and B16-F10 melanoma cells in vitro and in situ. Cell surface HA expression was assessed with the HA-binding peptide Pep-1. B16-F1 melanoma cells showed significantly higher levels of Pep-1 binding compared with B16-F10 cells in vitro. On the other hand, expression levels of HA were comparable between B16-F1 and B16-F10 melanoma cells in cryostat sections. These results show that B16-F1 cells express high levels of HA in vitro and in vivo, while B16-F10 cells express high concentrations of HA only in the context of skin tumors. Finally, B16-F10 melanoma cells, but not B16-F1 cells, expressed high concentrations of HA after stimulation with lactate. We propose that components of the tumor microenvironment (e.g., lactate) can induce melanoma cells to express HA and thus acquire an aggressive phenotype.