The long term goal of this research is to elucidate the molecular basis of immunosuppression and enhancement of tumor formation by tumor gangliosides. The overall hypothesis underlying this work is that shedding of specific gangliosides by tumor cells constitutes a mechanism, possibly immunologic, enhancing tumor formation in vivo. This hypothesis is being tested in the human tumor, neuroblastoma. The finding in the initial grant period-that structure of the ganglioside molecule is critical in determining ganglioside immunosuppressive activity - leads to the new hypothesis: tumor-derived gangliosides of abnormal structure directly influence the process of tumor formation in vivo, possibly by an immunologic mechanism. To test this hypothesis, neuroblastoma tumor ganglioside species will be separated from each other using newly developed HPLC methods. Their molecular structures will be determined using new fast atom bombardment mass spectrometric methods. The importance of structure in influencing immunosuppressive activity of gangliosides will be determined in vitro. Finally, in a newly developed model of tumor formation, the tumor-enhancing activity of selected homogenous and structurally characterized neuroblastoma gangliosides will be assessed in vivo. These studies will provide the first completely homogenous human tumor gangliosides and allow structure-activity relationships to be established. The proposed in vivo and in vitro studies will increase knowledge of the process of tumor formation and of factors (gangliosides) which modulate tumorigenicity. The results will also contribute towards achieving our long term objective-fully elucidating the biologic significance and understanding the molecular structural base of activity of tumor-derived gangliosides. Such knowledge may lead to the development of new approaches to the treatment of neuroblastoma and other tumors.
Showing the most recent 10 out of 39 publications
