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 progression and metastasis formation. We investigated the expression and hyaluronic-acid-dependent functions of CD44 and RHAMM/IHABP in human melanoma. Immunohistochemistry of tumor specimens at different stages of melanoma progression revealed an increased expression of CD44 and RHAMM/IHABP. High mRNA expression of CD44 was found in three highly tumorigenic melanoma cell lines compared with less tumorigenic melanoma cells or nontransformed melanocytes. RHAMM/IHABP expression was upregulated in all cell lines analyzed but not in melanocytes. In contrast to the cell surface localization of CD44, RHAMM/IHABP was detected exclusively within the cytoplasm of melanoma cells. Binding and adhesion of melanoma cells to hyaluronic acid is mainly CD44 dependent as it was inhibited to 60%--80% by an anti-CD44 monoclonal antibody whereas anti-RHAMM/IHABP sera had no effect. Culture of melanoma cells in the presence of hyaluronic acid resulted in a dose-dependent, CD44-mediated increase of melanoma cell proliferation and enhanced release of basic fibroblast growth factor and transforming growth factor beta 1. 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 cells, and (iii) the hyaluronic-acid-induced increase of the proliferative capacity of melanoma cells is mainly dependent on CD44--hyaluronic acid interactions.
Ahrens
T
T
Department of Dermatology, University of Freiburg, Freiburg, Germany.
Assmann
V
V
Fieber
C
C
Termeer
C
C
Herrlich
P
P
Hofmann
M
M
Simon
J C
JC
D000954:Antigens, Surface / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000235:genetics; D006133:Growth Substances / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000502:physiology*; D006820:Hyaluronic Acid / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000473:pathology* / Q000556:secondary*; D012333:RNA, Messenger / Q000378:metabolism
D000954:Antigens, Surface; D016326:Extracellular Matrix Proteins; D006133:Growth Substances; D018960:Hyaluronan Receptors; D012333:RNA, Messenger; C098946:hyaluronan-mediated motility receptor; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid