CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation

Interactions of the extracellular matrix component hyaluronic acid and its cellular receptors CD44 and RHAMM/IHABP have been linked to tumor progressi on and metastasis formation. We investigated the expression and hyaluronic- acid-dependent functions of CD44 and RHAMM/IHABP in human melanoma. Immunoh istochemistry of tumor specimens at different stages of melanoma progressio n revealed an increased expression of CD44 and RHAMM/IHABP, High mRNA expre ssion of CD44 was found in three highly tumorigenic melanoma cell lines com pared with less tumorigenic melanoma cells or nontransformed melanocytes. R HAMM/IHABP expression was upregulated in all cell lines analyzed but not in melanocytes. In contrast to the cell surface localization of CD44, RHAMM/I HABP was detected exclusively within the cytoplasm of melanoma cells. Bindi ng and adhesion of melanoma cells to hyaluronic acid is mainly CD44 depende nt as it was inhibited to 60%-80% by an anti-CD44 monoclonal antibody where as anti-RHAMM/IHABP sera had no effect, Culture of melanoma cells in the pr esence of hyaluronic acid resulted in a dose-dependent, CD44-mediated incre ase of melanoma cell proliferation and enhanced release of basic fibroblast growth factor and transforming growth factor pi. We conclude that (i) the expression of CD44 and RHAMM/IHABP is increased during melanoma progression , (ii) CD44 is the principal hyaluronic acid surface receptor on melanoma c ells, and (iii) the hyaluronic-acid-induced increase of the proliferative c apacity of melanoma cells is mainly dependent on CD44-hyaluronic acid inter actions.