Detection of a Tumour-Associated Ganglioside in Plasma of Patients With Neuroblastoma

Ladisch, Stephan; Wu, Zi‐Liang

doi:10.1016/s0140-6736(85)91906-3

Cited by 97 publications

(58 citation statements)

References 23 publications

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“…It seems possible, however, for the following reasons: (a) Gangliosides inhibit the in vitro function oflymphocytes (8,9,(25)(26)(27)(28), monocytes (29), and natural killer cells (30 (8,9,(25)(26)(27)(28)(29)(30) will form a tumor in a normal syngeneic host and may constitute a mechanism contributing to tumor progression. Our findings may be directly relevant to human cancer since it has already been shown that one aggressive human tumor, neuroblastoma, sheds significant quantities of gangliosides in vivo (33,34) and that these gangliosides are immunosuppressive in vitro (manuscript in preparation). Understanding exactly how tumor-derived molecules affect the extracellular environment of tumor cells may explain how tumor cells are (at the crucial initial stages of tumor formation) able to escape host defense mechanisms.…”

Section: Discussionmentioning

confidence: 76%

Gangliosides shed by tumor cells enhance tumor formation in mice.

Ladisch¹,

Kitada²,

Hays³

1987

J. Clin. Invest.

129

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The role of tumor cell membrane gangliosides in tumor formation was probed using a series of cloned murine AKR lymphoma cell lines. Tumor formation was directly related to high expression and shedding of membrane gangliosides. In vivo, as little as I pmol of purified total gangliosides of highly tumorigenic cells, injected intradermally with poorly tumorigenic cells (which lacked and did not shed gangliosides), markedly increased the tumorigenicity of these cells in syngeneic normal mice. Thus, gangliosides shed by tumor cells are a previously unrecognized, extremely potent enhancer of tumor formation in vivo.

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Section: Discussionmentioning

confidence: 76%

Gangliosides shed by tumor cells enhance tumor formation in mice.

Ladisch¹,

Kitada²,

Hays³

1987

J. Clin. Invest.

129

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“…They are present in the outer leaflet of all plasma membranes, with the highest concentrations being present in the CNS. They also are abundant in certain types of tumors, particularly tumors of neuroectodermal origin, which exhibit tumor-specific ganglioside expression profiles (5). Tumor cells shed these molecules at a high rate into their local microenvironment, and highly efficient transfer of shed gangliosides from tumor cells to target cells has been documented (47), an important point with respect to the biological activity of tumor gangliosides.…”

Section: Discussionmentioning

confidence: 99%

“…Many different molecular species are shed, and generally they reflect the ganglioside complement of the tumor cells. Shed tumor gangliosides have been detected in the circulation of some patients, and in neuroblastoma, for example, serve both qualitatively as tumor markers (5) and quantitatively as prognostic indicators of subsequent outcome (6).…”

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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“…By inhibiting APC function and thus the early stages of an immune response, tumor cells may prevent later immune effector responses, such as the activation of Th cells (11,18), without which the host immune system is unlikely to be able to eliminate tumor cells (19,20). This possibility is supported, for example, by our previous work showing that addition of exogenous gangliosides down-regulates the surface expression of costimulatory molecules induced by LPS on dendritic cells (DCs) 3 , the principal and most potent APC involved in activation of naive T cells (11). To assess the consequence of ganglioside enrichment of DCs in the tumor microenvironment on the development of the cellular immune response, we have traced the maturation of DCs and the development of Th cells after exposure of DCs to exogenous gangliosides.…”

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confidence: 93%

Modulation of CD4 Th Cell Differentiation by Ganglioside GD1a In Vitro

Shen

Falahati

Stark

et al. 2005

The Journal of Immunology

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Cell surface gangliosides are shed by tumors into their microenvironment. In this study they inhibit cellular immune responses, including APC development and function, which is critical for Th1 and Th2 cell development. Using human dendritic cells (DCs) and naive CD4+ T cells, we separately evaluated Th1 and Th2 development under the selective differentiating pressures of DC1-inducing pertussis toxin (PT) and DC2-inducing cholera toxin (CT). High DC IL-12 production after PT exposure and high DC IL-10 production after CT exposure were observed, as expected. However, when DCs were first preincubated with highly purified GD1a ganglioside, up-regulation of costimulatory molecules was blunted, and PT-induced IL-12 production was reduced, whereas CT-induced IL-10 production was increased. The combination of these effects could contribute to a block in the Th1 response. In fact, when untreated naive T cells were coincubated with ganglioside-preincubated, Ag-exposed DCs, naive Th cell differentiation into Th effector cells was reduced. Both the subsequent DC1-induced T cell production of IFN-γ (Th1 marker) and DC2-induced T cell IL-4 production (Th2) were inhibited. Thus, ganglioside exposure of DC impairs, by at least two distinct mechanisms, the ability to induce Th differentiation, which could adversely affect the development of an effective cellular antitumor immune response.

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Detection of a Tumour-Associated Ganglioside in Plasma of Patients With Neuroblastoma

Cited by 97 publications

References 23 publications

Gangliosides shed by tumor cells enhance tumor formation in mice.

Gangliosides shed by tumor cells enhance tumor formation in mice.

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

Modulation of CD4 Th Cell Differentiation by Ganglioside GD1a In Vitro

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