Shedding of Gangliosides by Human Medulloblastoma Cells

Chang, Fumin; Li, Ruixiang; Ladisch, Stephan

doi:10.1006/excr.1997.3619

Cited by 55 publications

(39 citation statements)

References 35 publications

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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 [144]. During tumor growth and metastatization, gangliosides shed in the microenvironment [145] with a consequent increase of their serum levels (Table 1) and accumulation in the tumor microenvironment. For instance, gangliosides are highly expressed in the hyper-vascularized areas of gliomas where they regulate angiogenesis [146].…”

Section: Gangliosidesmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,130

870

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Fibroblast growth factors (FGFs) are a family of heparin-binding growth factors. FGFs exert their pro-angiogenic activity by interacting with various endothelial cell surface receptors, including tyrosine kinase receptors, heparan-sulfate proteoglycans, and integrins. Their activity is modulated by a variety of free and extracellular matrix-associated molecules. Also, the cross-talk among FGFs, vascular endothelial growth factors (VEGFs), and inflammatory cytokines/chemokines may play a role in the modulation of blood vessel growth in different pathological conditions, including cancer. Indeed, several experimental evidences point to a role for FGFs in tumor growth and angiogenesis. This review will focus on the relevance of the FGF/FGF receptor system in adult angiogenesis and its contribution to tumor vascularization. #

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Section: Gangliosidesmentioning

confidence: 99%

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Presta

Dell’Era

Mitola

et al. 2005

Cytokine & Growth Factor Reviews

1,130

870

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“…As tumor cells proliferate, gangliosides are shed into their local microenvironment both in vitro and in vivo (1)(2)(3)(4), particularly by tumors of neuroectodermal origin. Many different molecular species are shed, and generally they reflect the ganglioside complement of the tumor cells.…”

Section: Inhibition Of Tlr Activation and Up-regulation Of Il-1r-assomentioning

confidence: 99%

Inhibition of TLR Activation and Up-Regulation of IL-1R-Associated Kinase-M Expression by Exogenous Gangliosides

Shen

Stone

Jales

et al. 2008

The Journal of Immunology

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Gangliosides, sialic acid-containing glycosphingolipids present in the outer leaflet of plasma membranes, are produced at high levels by some tumors, are actively shed into the tumor microenvironment, and can be detected in high concentrations in the serum of cancer patients. These tumor-shed molecules are known to be immunosuppressive, although mechanisms remain to be fully elucidated. In this study, we show that membrane enrichment of human monocytes with purified exogenous gangliosides potently inhibits ligand-induced activation and proinflammatory cytokine production induced by a broad range of TLRs, including TLR2, TLR3, TLR6, and TLR7/8, in addition to a previously identified inhibitory effect on TLR4 and TLR5. Inhibition of TLR activation is reversible, with complete restoration of TLR signaling within 6–24 h of washout of exogenous gangliosides, and is selective for certain gangliosides (GM1, GD1a, and GD1b), whereas others (GM3) are inactive. To characterize the inhibition, we assessed the expression of the TLR signaling pathway inhibitor, IL-1 receptor associated kinase-M (IRAK-M). In response to ganglioside enrichment alone, we observed striking up-regulation of IRAK-M in monocytes, but without concomitant proinflammatory cytokine production. This contrasts with endotoxin tolerance, in which IRAK-M up-regulation follows proinflammatory cytokine expression caused by LPS exposure. We hypothesize that ganglioside treatment induces a state of tolerance to TLR signaling, leading to blunted activation of innate immune responses. In the tumor microenvironment, shed tumor ganglioside enrichment of APC membranes may likewise cause these cells to bypass the normal TLR signaling response and progress directly to the inhibitory state.

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“…synthesis has been proposed based on evidence that GSLs may modulate tumour growth, metastasis, immunity and multidrug resistance (Chang et al, 1997;Liu et al, 1999;Radin, 1999). Defects in GSL biosynthesis are found in most human cancers and may underlie the invasive and malignant properties of brain tumours (Merzak et al, 1995;Hakomori, 1996;Berra et al, 1997).…”

mentioning

confidence: 99%

“…GSLs can modulate the function of growth factor receptors and have recently been implicated as modulators of brain tumour angiogenesis and cell adhesion (Hakomori, 1996;Alessandri et al, 1997;Bai and Seyfried, 1997;Manfredi et al, 1999;Zeng et al, 2000). GSLs newly synthesized and shed by tumours can competitively bind to interleukin-2 (IL-2) receptors on T cells, hindering the proliferative response required for immunological rejection (Chang et al, 1997). Taken together, these findings suggest that the modification of GSL biosynthesis and expression could be effective in brain tumour therapy.…”

mentioning

confidence: 99%

N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours

et al. 2001

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Abnormalities in glycosphingolipid (GSL) biosynthesis have been implicated in the oncogenesis and malignancy of brain tumours. GSLs comprise the gangliosides and the neutral GSLs and are major components of the cell surface glycocalyx. N -butyldeoxynojirimycin ( N B-DNJ) is an imino sugar that inhibits the glucosyltransferase catalysing the first step in GSL biosynthesis. The influence of N B-DNJ was studied on the growth and ganglioside composition of two 20-methylcholanthrene-induced experimental mouse brain tumours, EPEN and CT-2A, which were grown in vitro and in vivo. N B-DNJ (200 μM) inhibited the proliferation of the EPEN and CT-2A cells by 50%, but did not reduce cell viability. The drug, administered in the diet (2400 mg kg −1 ) to adult syngeneic C57BL/6 mice, reduced the growth and ganglioside content of subcutaneous and intracerebral EPEN and CT-2A tumours by at least 50% compared to the untreated controls. N B-DNJ treatment also shifted the relative distribution of tumour gangliosides in accordance with the depletion of metabolic substrates. Side effects of N B-DNJ treatment were generally mild and included reductions in body and spleen weights and intestinal distension. We conclude that N B-DNJ may inhibit tumour growth through an effect on ganglioside biosynthesis and may be useful as a new chemotherapy for brain tumours. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Shedding of Gangliosides by Human Medulloblastoma Cells

Cited by 55 publications

References 35 publications

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis

Inhibition of TLR Activation and Up-Regulation of IL-1R-Associated Kinase-M Expression by Exogenous Gangliosides

N -butyldeoxynojirimycin reduces growth and ganglioside content of experimental mouse brain tumours

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