VITRONECTIN EXPRESSION IN DIFFERENTIATING NEUROBLASTIC TUMORS - INTEGRIN ALPHA-V-BETA-5 MEDIATES VITRONECTIN-DEPENDENT ADHESION OF RETINOIC-ACID-DIFFERENTIATED NEUROBLASTOMA-CELLS

The metastatic potential of undifferentiated neuroblastomas is typical ly lost when differentiation into ganglioneuroblastomas occurs spontan eously or is induced. Cell adhesion may play a role in metastasis, and we have shown recently that expression of integrin alpha upsilon beta 5 protein and mRNA is up-regulated in ganglioneuroblastomas in vivo. To investigate whether interactions of alpha upsilon beta 5 with matri x components play a role in the loss of metastatic potential, we used immunohistochemical and in situ hybridization to analyze neuroblastic tumors at various stages of differentiation for expression of the alph a upsilon beta 5 ligands, vitronectin and osteopontin, and determined the ability of vitronectin to promote attachment and neurite outgrowth in vitro in a retinoic-acid-differentiated neuroblastoma cell model. We found that vitronectin, but not osteopontin, was expressed in 5 of 5 ganglioneuroblastomas but was absent or weakly expressed in 6 of 6 u ndifferentiated neuroblastomas. Neuronal cell vitronectin was detected in 7 of 9 ganglioneuromas, 5 of 8 peripheral ganglia, and 14 of 21 ad renal gland medullae, confirming expression of vitronectin in mature p eripheral neurons. In vitro, vitronectin promoted attachment of both u ndifferentiated and retinoic-acid-differentiated neuroblastoma cells, which was inhibited 20 and 60%, respectively, by monoclonal antibody a nti-integrin alpha upsilon beta 5. Vitronectin-promoted neurite out-gr owth of retinoic-acid-differentiated neuroblastoma cells was not inhib ited by monoclonal antibody anti-alpha upsilon beta 5. These data sugg est that the synthesis of vitronectin and the ability of integrin alph a upsilon beta 5 to mediate vitronectin adhesion on retinoic-acid-diff erentiated neuroblastoma cells may promote differentiation of neurobla stoma cells in vivo.