Abstract
Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties. Disialylated gangliosides GD2 and GD3 are considered as markers of neuroectoderm origin in tumors, whereas fucosyl-GM1 is expressed in very few normal tissues but overexpressed in a variety of cancers, especially in small cell lung carcinoma. These gangliosides are absent in most normal adult tissues, making them targets of interest in immuno-oncology. Passive and active immunotherapy strategies have been developed, and have shown promising results in clinical trials. In this review, we summarized the current knowledge on GD2, GD3, and fucosyl-GM1 expression in health and cancer, their biosynthesis pathways in the Golgi apparatus, and their biological roles. We described how their overexpression can affect intracellular signaling pathways, increasing the malignant phenotypes of cancer cells, including their metastatic potential and invasiveness. Finally, the different strategies used to target these tumor-associated gangliosides for immunotherapy were discussed, including the use and development of monoclonal antibodies, vaccines, immune system modulators, and immune effector-cell therapy, with a special focus on adoptive cellular therapy with T cells engineered to express chimeric antigen receptors.
Highlights
Biosynthesis and Expression of Cancer-Associated GangliosidesGangliosides are cell surface glycosphingolipids that play important functional roles in cell-cell recognition, cell adhesion, and signal transduction
Aberrant expression of glycosphingolipids is a hallmark of cancer cells and is associated with their malignant properties
The biosynthesis of tumor-associated gangliosides starts from lactosylceramide (LacCer, Gg2Cer) by the transfer in the Golgi apparatus of a first sialic acid residue catalyzed by the GM3 synthase ST3Gal V to form GM3 (II3Neu5AcGg2Cer) (Figure 1)
Summary
Gangliosides are cell surface glycosphingolipids that play important functional roles in cell-cell recognition, cell adhesion, and signal transduction. Their carbohydrate moiety is synthesized in the Golgi apparatus by the sequential action of different glycosyltransferases. Modifications in expression patterns of gangliosides during development or diseases can be largely attributed to changes of the expression of glycosyltransferases involved in their synthesis and that are spatiotemporally regulated both at the transcriptional and posttranslational levels [1]. Regulation at the transcriptional level includes transcription factors (TF), and epigenetic modifications and can explain most of the glycolipid composition changes observed during development and cancer [2,3]. A characteristic feature of small cell lung carcinoma (SCLC) is the aberrant and abundant expression of ganglioside Fuc-GM1 (fucosylated monosialotetrahexosylganglioside or IV2FucII3Neu5AcGg4Cer), whereas the ectopic expression of b-series gangliosides and their O-acetylated derivatives is associated with cancers of neuro-ectoderm origin
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