Abstract
The focus of this review is the ganglio-series of glycosphingolipids found in neuroblastoma (NB) and the myriad of unanswered questions associated with their possible role(s) in this cancer. NB is one of the more common solid malignancies of children. Five-year survival for those diagnosed with low risk NB is 90–95%, while that for children with high-risk NB is around 40–50%. Much of the survival rate reflects age of diagnosis with children under a year having a much better prognosis than those over two. Identification of expression of GD2 on the surface of most NB cells led to studies of the effectiveness and subsequent approval of anti-GD2 antibodies as a treatment modality. Despite much success, a subset of patients, possibly those whose tumors fail to express concentrations of gangliosides such as GD1b and GT1b found in tumors from patients with a good prognosis, have tumors refractory to treatment. These observations support discussion of what is known about control of ganglioside synthesis, and their actual functions in NB, as well as their possible relationship to treatment response.
Highlights
Introduction to Neuroblastoma and the BiologicalImportance of GangliosidesWhile hundreds of glycosphingolipids have been identified [1], this review will focus on the ganglio-series of glycosphingolipids (GSLs) found in neuroblastoma (NB) and the myriad of unanswered questions still associated with their possible role(s) in this cancer
Two different systems have been developed for staging NBs: The International Neuroblastoma Staging System (INSS) [3] classifies NBs based on what is found at the time of surgery while the International Neuroblastoma Risk Group Staging System (INRGSS) [4] uses imaging, exams, and biopsies
The histone deacetylase (HDAC) inhibitor upregulated expression of ST3GAL5 and ST8SIA1, the sialyltransferases that generate GM3 and GD3 gangliosides, substrates for GD2 synthase. Together these observations indicate that the use of sialic acid analogues and HDAC inhibitors to enhance GD2 expression followed by anti-GD2 targeted immunotherapy might be effective for patients with high-risk tumors that are refractory to treatment [125]
Summary
While hundreds of glycosphingolipids have been identified [1], this review will focus on the ganglio-series of glycosphingolipids (GSLs) found in neuroblastoma (NB) and the myriad of unanswered questions still associated with their possible role(s) in this cancer. Overexpression of GM1 by pheochromocytoma cells was found to inhibit nerve growth factor signaling due to GM1-induced alterations in membrane fluidity [65] Another instance of its effect on cell proliferation was seen using mouse fibroblasts (NIH3T3 cells) where its conversion of GM3 to Lac-cer resulted in activation of the epidermal growth factor receptor (EGFR) together with the Src family of protein tyrosine kinases, thereby enhancing the tumorigenicity of the cells [66]. Their results indicated that NEU3 functioned in tumorigenesis via the EGFR/Src signaling pathway and led them to posit that inhibiting NEU3 might be a treatment option for delaying tumor growth by cells expressing GM3 as their major ganglioside. These observations emphasize that care must be taken to note the type of cells studied and their ganglioside components when looking at the effects of NEU3 and of gangliosides in general [67]
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