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      Gangliosides and Neuroblastomas

      review-article
      International Journal of Molecular Sciences
      MDPI
      ganglioside, neuroblastoma, glycosyltransferases, glycosidases

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          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.

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          Most cited references127

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          The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report.

          Because current approaches to risk classification and treatment stratification for children with neuroblastoma (NB) vary greatly throughout the world, it is difficult to directly compare risk-based clinical trials. The International Neuroblastoma Risk Group (INRG) classification system was developed to establish a consensus approach for pretreatment risk stratification. The statistical and clinical significance of 13 potential prognostic factors were analyzed in a cohort of 8,800 children diagnosed with NB between 1990 and 2002 from North America and Australia (Children's Oncology Group), Europe (International Society of Pediatric Oncology Europe Neuroblastoma Group and German Pediatric Oncology and Hematology Group), and Japan. Survival tree regression analyses using event-free survival (EFS) as the primary end point were performed to test the prognostic significance of the 13 factors. Stage, age, histologic category, grade of tumor differentiation, the status of the MYCN oncogene, chromosome 11q status, and DNA ploidy were the most highly statistically significant and clinically relevant factors. A new staging system (INRG Staging System) based on clinical criteria and tumor imaging was developed for the INRG Classification System. The optimal age cutoff was determined to be between 15 and 19 months, and 18 months was selected for the classification system. Sixteen pretreatment groups were defined on the basis of clinical criteria and statistically significantly different EFS of the cohort stratified by the INRG criteria. Patients with 5-year EFS more than 85%, more than 75% to or = 50% to < or = 75%, or less than 50% were classified as very low risk, low risk, intermediate risk, or high risk, respectively. By defining homogenous pretreatment patient cohorts, the INRG classification system will greatly facilitate the comparison of risk-based clinical trials conducted in different regions of the world and the development of international collaborative studies.
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            Sphingolipid metabolism in cancer signalling and therapy

            Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure-function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P-S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.
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              Molecular machinery for non-vesicular trafficking of ceramide.

              Synthesis and sorting of lipids are essential for membrane biogenesis; however, the mechanisms underlying the transport of membrane lipids remain little understood. Ceramide is synthesized at the endoplasmic reticulum and translocated to the Golgi compartment for conversion to sphingomyelin. The main pathway of ceramide transport to the Golgi is genetically impaired in a mammalian mutant cell line, LY-A. Here we identify CERT as the factor defective in LY-A cells. CERT, which is identical to a splicing variant of Goodpasture antigen-binding protein, is a cytoplasmic protein with a phosphatidylinositol-4-monophosphate-binding (PtdIns4P) domain and a putative domain for catalysing lipid transfer. In vitro assays show that this lipid-transfer-catalysing domain specifically extracts ceramide from phospholipid bilayers. CERT expressed in LY-A cells has an amino acid substitution that destroys its PtdIns4P-binding activity, thereby impairing its Golgi-targeting function. We conclude that CERT mediates the intracellular trafficking of ceramide in a non-vesicular manner.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                27 July 2020
                August 2020
                : 21
                : 15
                : 5313
                Affiliations
                Department of Biochemistry and Molecular Biology, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA; cxs8@ 123456psu.edu
                Article
                ijms-21-05313
                10.3390/ijms21155313
                7432824
                32726962
                19b7ddb4-3e3b-478e-b78c-57e82bb2e8b9
                © 2020 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 11 May 2020
                : 18 July 2020
                Categories
                Review

                Molecular biology
                ganglioside,neuroblastoma,glycosyltransferases,glycosidases
                Molecular biology
                ganglioside, neuroblastoma, glycosyltransferases, glycosidases

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