| Origin of brain tumor glycosphingolipids (1998) | |||||||||
Abstract | |||||||||
| Certain glycosphingolipid (GSL) biosynthetic genes, which were expressed in solid tumors, were not expressed in tumor cell lines. In addition, previous studies showed that some GSLs present in solid brain tumors decrease or disappear from tumors cells grown in culture. It was suggested that the loss of GSLs and GSL biosynthetic gene expression results from the loss of tumor-infiltrating host cells during the formation of tumor cell lines. To test the hypothesis that tumor-infiltrating host cells, and in particular tumor-infiltrating macrophages (TIMs), contribute to the increased GSL complexity in solid brain tumors, a procedure was developed for the analysis of TIM GSLs. The procedure entailed the dissociation of brain tumors into single cell suspensions with a concurrent metabolic labeling of GSLs using $\rm\sp{14}C$-galactose. The TIMs were then separated from neoplastic tumor cells and other host cells by magnetic activated cell sorting and CD11b microbeads (a macrophage specific antibody conjugated to a metallic particle). The ganglioside distribution of TIMs was extremely complex and consisted of more than 30 distinct structures. GSLs enriched in TIMs, relative to the tumors, included GM1b, GD1$\alpha,$ and Gg4Cer (asialoGM1). The TIM-enriched GSLs appeared as minor components in the whole tumor and were depleted in the neoplastic cell fraction. The GSL composition of TIMs was similar in different tumors and in TIMs isolated from tumors grown intracranially or subcutaneously. Furthermore, TIM GSLs were similar to those in activated peritoneal macrophages, although differences in ceramide structure were observed. TIMs also influence the GSLs of human brain tumor xenografts. Lastly, these studies showed that N-glycolylneuraminic acid (NeuGc) comprised approximately 66% of the ganglioside sialic acid in a human glioma xenograft grown in SCID mice. Since human cells do not synthesize NeuGc, it is likely that this sialic acid derived in part from mouse serum gangliosides. The research presented in this thesis was designed to elucidate the origin and cellular location of brain tumor GSLs which may improve GSL directed tumor prognosis and therapy. | |||||||||
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