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Schwannian Cell Differentiation of Human Neuroblastoma Cell Lines in Vitro Induced by Bromodeoxyuridine¹

Children's Research Hospital [T. Su.], Department of Pediatrics [T. Sa., Y. H., T. H., H. H.] and Laboratory of Electron Microscope [H. M.], Kyoto Prefectural University of Medicine, Kyoto 602, Japan; Department of Biochemistry [T. K.], Nagoya City University Medical School, Nagoya 467, Japan; and Institute of Child Health [J. T. K.], London WC1 1EH, England

In normal development the neural crest gives rise to sympathetic neuroblasts, sensory and autonomic ganglia, as well as Schwann cells. One tumor arising from this tissue is the neuroblastoma (NB), a malignancy of the adrenergic component of the sympathetic nervous system. Recent histological studies have shown that neuroblastomas can present with a schwannian cell component, rich in S100 protein.

We have investigated the differentiation of NB cell lines, GOTO and RT-LN-1, into a schwannian cell phenotype using bromodeoxyuridine (BrdU). This agent induced morphological changes in these cell lines. Flat-epithelial cells were identified in the GOTO cell line and both flat-epithelial and neuronal phenotypes were found in the RT-LN-1 cell line. S100 protein (ß-Subunit) was induced in both cell lines after 18–25 days of BrdU treatment as determined by enzyme-linked immunoassay. In addition increase in the ß-subunit of S100 protein was identified in BrdU-treated flat-epithelial cells by indirect immunofluorescence using a monoclonal antibody specific for the ß-subunit of the protein. Cyclic nucleotide phosphodiesterase activity significantly increased in both BrdU-treated NB cell lines, as compared with nontreated cells. However no significant increase of glial fibrillary acidic protein in BrdU-treated cells was found either by enzyme-linked immunoassay or indirect immunofluorescence using a monoclonal antibody to glial fibrillary acidic protein. Thus, cells with Schwann cell characteristics can clearly be identified in the neuroblastoma cell lines after BrdU treatment. Fluorescence-activated cell sorting analysis revealed no quantitative changes in cell membrane antigens recognized by monoclonal antibodies UJ-13A (neuroectodermal associated antigen) and anti-Thy-1 (Thy-1) on BrdU treatment. In contrast, UJ-127-11 (neuroectodermal associated) decreased, and W6/32 and BB7.7 (HLA-ABC) and BBM.1 (ß₂-microglobulin) markedly increased in both BrdU-treated cell lines. No induction of L243 (HLA-DR), B7/21 (HLA-DP), and Genox 3.55 (HLA-DQ) was noted. The increased HLA-ABC (HLA class I) antigen may enable BrdU-treated NB cells to be recognized by cytotoxic T-cells. This may be related to the pathological evidence that NB patients whose tumors are rich in S100 protein have a better prognosis. Further studies on the potential of differentiation agents to induce a phenotypic change, that is associated with an improved prognosis for NB patients, are required.

¹ This work was supported in part by grants for cancer research from the Ministry of Health and Welfare of Japan.

² To whom requests for reprints should be addressed, at Department of Pediatrics, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyoku, Kyoto 602, Japan.

Received 6/22/87. Revised 1/28/88. Accepted 2/ 4/88.