Shedding of Gangliosides by Human Medulloblastoma Cells

Children's Research Institute, and Department of Pediatrics, The George Washington University School of Medicine, Washington, DC 20010, USA.
Experimental Cell Research (Impact Factor: 3.25). 09/1997; 234(2):341-6. DOI: 10.1006/excr.1997.3619
Source: PubMed


Shedding of immunosuppressive gangliosides is an important characteristic of both experimental and human tumors. Using a medulloblastoma cell line, Daoy, with a very high ganglioside expression (141 +/- 13 nmol/10(8) cells) and a well-characterized ganglioside complement, we have now studied ganglioside shedding by human brain tumor cells. Shedding of gangliosides, quantified by metabolic radiolabeling, was significant (169 pmol/10(8) cells/h) and was generalized with respect to the major ganglioside carbohydrate structures (G(M2), G(M3), and G(D1a)). For each ganglioside, however, shedding was selective for ceramide structures containing shorter fatty acyl chains. Rapid and ceramide-selective shedding was confirmed in two additional human medulloblastoma cell lines, D341 Med and D283 Med (112 and 59 pmol/10(8) cells/h). Significant ganglioside shedding is therefore a common characteristic of human medulloblastoma cells and may influence the biological behavior of this tumor, in view of immunosuppressive and other biological properties of shed gangliosides.

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    • "Under physiological conditions, gangliosides are mainly associated to the membrane of different cell types, including endothelium, where they modulate cell growth, adhesion, and cell-cell interaction (Birkle et al. 2003). During tumor growth, gangliosides shed in the microenvironment (Chang et al. 1997a), with a consequent increase of their serum levels and accumulation in the tumor microenvironment. For instance, gangliosides are highly expressed in the hypervascularized areas of gliomas where they regulate angiogenesis (Koochekpour et al. 1996). "
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    ABSTRACT: Angiogenesis plays a key role in various physiological and pathological processes, including inflammation and tumor growth. Numerous angiogenic growth factors (AGFs) have been identified. Usually, the angiogenic process is assumed to represent the outcome of a straightforward interaction of AGFs with specific signalling receptors of the endothelial cell (EC) surface. Actually, the mechanisms by which AGFs induce neovascularization are much more complex. Indeed, angiogenesis is the result of the simultaneous actions of various AGFs and angiogenesis modulators; multiple EC surface receptors with different structure and biological properties are engaged by AGFs to exert a full angiogenic response; AGFs bind a variety of free and immobilized proteins, polysaccharides, and complex lipids of the extracellular milieu that affect AGF integrity, stability, and bioavailability; some of the AGF-binding molecules interact also with AGF receptors. In this review the authors summarize literature data and discuss the current knowledge about the extracellular molecules able to interact with AGFs, thus representing possible key regulators of the angiogenesis process and targets/templates for the development of novel antiangiogenic drugs. This work represents an attempt to highlight common theme in the AGF interactome that occurs at the extracellular level during neovascularization.
    Endothelium 05/2006; 13(2):93-111. DOI:10.1080/10623320600698011 · 1.91 Impact Factor
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    • "A certain degree of specificity was reported to exist in both shedding and uptake. Young and colleagues reported preferential release of glycosphingolipids with shorter fatty acyl chains, over the corresponding glycosphingolipids with longer fatty acyl chains [106] [107]. Shorter forms of ceramide apparently also enables more efficient uptake of gangliosides from the medium as reported by Ladisch and Olson [108]. "
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    ABSTRACT: Gangliosides and glycosylphosphatidylinositol (GPI)-anchored proteins have very different biosynthetic origin, but they have one thing in common: they are both comprised of a relatively large hydrophilic moiety tethered to a membrane by a relatively small lipid tail. Both gangliosides and GPI-anchored proteins can be actively shed from the membrane of one cell and taken up by other cells by insertion of their lipid anchors into the cell membrane. The process of shedding and uptake of gangliosides and GPI-anchored proteins has been independently discovered in several disciplines during the last few decades, but these discoveries were largely ignored by people working in other areas of science. By bringing together results from these, sometimes very distant disciplines, in this review, we give an overview of current knowledge about shedding and uptake of gangliosides and GPI-anchored proteins. Tumor cells and some pathogens apparently misuse this process for their own advantage, but its real physiological functions remain to be discovered.
    Biochimica et Biophysica Acta 05/2006; 1760(4):584-602. DOI:10.1016/j.bbagen.2005.11.014 · 4.66 Impact Factor
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    • "They are frequently present in high concentrations in the membranes of tumor cells and are actively shed into their microenvironment (Ladisch et al., 1983, 1987; Young et al., 1986; Portoukalian et al., 1993; Chang et al., 1997), in the form of micelles, monomers, and membrane vesicles (Kong et al., 1998; Dolo et al., 2000). Gangliosides have a range of biological properties. "
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    ABSTRACT: MEB4 murine melanoma cells synthesize G(M3) as the major ganglioside. Inhibition of G(M3) synthesis by a specific glucosylceramide synthase inhibitor resulted in reduced tumorigenicity and metastatic potential of these cells. We used a molecular approach--antisense transfection targeting the glucosylceramide synthase gene--to regulate glycosphingolipid synthesis by MEB4 cells and examine the influence on tumor formation. Antisense transfection inhibited the synthesis of the direct product of glucosylceramide synthase, glucosylceramide, and consequently G(M3) ganglioside, by MEB4 cells, reducing the concentration of G(M3) in the transfectants by up to 58%. Although neither morphology nor proliferation kinetics of the cultured cells was affected, the inhibition of glycosphingolipid synthesis and reduction of total ganglioside content caused a striking reduction in melanoma formation in mice. Only 1/60 (2%) of mice injected ID with 10(4) antisense-transfected MA173 cells formed a tumor, compared to 31/60 (52%) of mice receiving MEB4 cells and 7/15 (47%) of mice receiving the MS2 sense-transfected cells (p < 0.001 and p = 0.005, respectively). These findings demonstrate that stable transfection of glucosylceramide synthase antisense reduces cellular glycosphingolipid levels and reduces tumorigenicity, providing further experimental support for an enhancing role of gangliosides in tumor formation.
    Glycobiology 03/2002; 12(3):145-52. DOI:10.1093/glycob/12.3.145 · 3.15 Impact Factor
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