title: CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Freiburg, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ahrens
authors.forename: V
authors.initials: V
authors.lastname: Assmann
authors.forename: C
authors.initials: C
authors.lastname: Fieber
authors.forename: C
authors.initials: C
authors.lastname: Termeer
authors.forename: P
authors.initials: P
authors.lastname: Herrlich
authors.forename: M
authors.initials: M
authors.lastname: Hofmann
authors.forename: J C
authors.initials: JC
authors.lastname: Simon
mesh_terms: 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
chemical_list: 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