Neuroblastoma is the most common extracranial childhood solid tumor with about 1/4 of cases presenting with extensive disease and a disease free survival of only 10-15% regardless of therapy. Retinoic acid (RA) is capable of inducing some neuroblastoma cells to differentiate in vitro and the regression of some neuroblastomas in vivo, however many neuroblastoma cells are resistant or become resistant to the effects of RA. The recent characterization of nuclear RA receptors has given considerable insight into the mechanisms whereby RA exerts effects on cell proliferation and differentiation. Although there have been numerous investigations into the induction of differentiation of neuroblastoma cells by RA, there have been almost no studies regarding the role of RA receptors. These receptors have been shown to play a critical central role in the RA induced differentiation of acute promyelocytic leukemia as well as in normal embryological development. The studies in this proposal will determine which RA receptors are present in neuroblastoma cells (RAR-alpha,Beta,gamma and RXR-alpha,Beta, gamma) and why some neuroblastoma cells are sensitive to RA-induced terminal differentiation while others are not. Emphasis will be placed on extensively characterizing RA receptor structure, function, and number in cultured neuroblastoma cell lines and determining the genetic basis for any observed RA receptor abnormalities. RA receptors will be retrovirally transduced into neuroblastoma cell lines that are resistant to RA to determining which RA receptors are important in RA induced differentiation of neuroblastoma cells. Finally, neuroblastoma cells that are sensitive to RA or infected with various RA receptor vectors and exhibit an in vitro response to RA, will be injected into nude mice and observed for their response to RA to see if an in vitro response translates into an in vivo response. These studies will provide insight into the molecular mechanisms of neuroblastoma cell sensitivity and resistance to RA and more clearly define the role of the activated RA receptor in neuroblastoma cell differentiation with the hope of identifying a more rational use of RA in the treatment of neuroblastoma.
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