Human neuroblastoma is a cancer of childhood with a higher incidence of spontaneous regression and differentiation than is found in other cancers. Nevertheless, many patients die of metastatic disease. Amplification of the N-myc oncogene in the tumor cells is highly correlated with metastasis and fatal outcome. In order to understand the above phenomena and to have an impact on the treatment of this disease in the future, we will investigate the cellular and molecular biology of human neuroblastoma growth, differentiation and metastasis in relation to the expression and amplification of the N-myc oncogene. The effects of humoral factors on the survival, growth and differentiation of cultured human neuroblastoma cell lines that do or do not have N-myc oncogene expression or amplification will be examined. Effects of the humoral factors on expression of the N- myc oncogene and expression of neuroblastoma differentiation genes will also be studied. Because cultured cell lines may not reflect all of the biological properties of the tumor cells from which they are derived, the effects of the factors will be examined on growth, differentiation and gene expression of neuroblastoma in primary culture. For these studies, metastatic neuroblastoma will be isolated from bone marrow by two-color immunofluorescence flow cytometry and cell sorting. The roles of N-myc expression and gene amplification in metastasis will be examined in a nude mouse model in which intravenous injection of tumor cells results in lung colonization and intraaortic injection results in bone marrow colonization. Cell lines with and without N-myc expression, N-myc gene amplification, and amplification of drug-resistance genes will be compared. Because ability of a cell to metastasize may result from a process of unstable genetic change, spontaneous and induced mutation rates will be measured in the cell lines. The proposed investigations will define the role of the N-myc oncogene in the growth, differentiation and metastasis of neuroblastoma.
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