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Inhibitors of glioma growth that reveal the tumour to the immune system

Inhibitors of glioma growth that reveal the tumour to the immune system
Inhibitors of glioma growth that reveal the tumour to the immune system
Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.

The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 ?M or higher.

At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.
glioma, immunosuppression, chemotherapy, neurostatin, antigen presentation
1179-5549
265-314
Nieto-Sampedro, Manuel
6d62c63e-e900-4219-b596-447dae4b0c2d
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Gómez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Fernández-Mayoralas, Alfonso
45d0fa50-0677-4a00-a92a-2f54ee159e51
Nieto-Díaz, Manuel
a4c8cf85-8855-4a0c-a6da-13201207aa2d
Nieto-Sampedro, Manuel
6d62c63e-e900-4219-b596-447dae4b0c2d
Valle-Argos, Beatriz
4fddaa71-c0aa-4b95-b464-8bdb592428a2
Gómez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Fernández-Mayoralas, Alfonso
45d0fa50-0677-4a00-a92a-2f54ee159e51
Nieto-Díaz, Manuel
a4c8cf85-8855-4a0c-a6da-13201207aa2d

Nieto-Sampedro, Manuel, Valle-Argos, Beatriz, Gómez-Nicola, Diego, Fernández-Mayoralas, Alfonso and Nieto-Díaz, Manuel (2011) Inhibitors of glioma growth that reveal the tumour to the immune system. Clinical Medicine Insights Oncology, 5, 265-314. (doi:10.4137/CMO.S7685). (PMID:22084619)

Record type: Article

Abstract

Treated glioblastoma patients survive from 6 to 14 months. In the first part of this review, we describe glioma origins, cancer stem cells and the genomic alterations that generate dysregulated cell division, with enhanced proliferation and diverse response to radiation and chemotherapy. We review the pathways that mediate tumour cell proliferation, neo-angiogenesis, tumor cell invasion, as well as necrotic and apoptotic cell death. Then, we examine the ability of gliomas to evade and suppress the host immune system, exhibited at the levels of antigen recognition and immune activation, limiting the effective signaling between glioma and host immune cells.

The second part of the review presents current therapies and their drawbacks. This is followed by a summary of the work of our laboratory during the past 20 years, on oligosaccharide and glycosphingolipid inhibitors of astroblast and astrocytoma division. Neurostatins, the O-acetylated forms of gangliosides GD1b and GT1b naturally present in mammalian brain, are cytostatic for normal astroblasts, but cytotoxic for rat C6 glioma cells and human astrocytoma grades III and IV, with ID50 values ranging from 200 to 450 nM. The inhibitors do not affect neurons or fibroblasts up to concentrations of 4 ?M or higher.

At least four different neurostatin-activated, cell-mediated antitumoral processes, lead to tumor destruction: (i) inhibition of tumor neovascularization; (ii) activation of microglia; (iii) activation of natural killer (NK) cells; (iv) activation of cytotoxic lymphocytes (CTL). The enhanced antigenicity of neurostatin-treated glioma cells, could be related to their increased expression of connexin 43. Because neurostatins and their analogues show specific activity and no toxicity for normal cells, a clinical trial would be the logical next step.

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More information

e-pub ahead of print date: 21 September 2011
Published date: 2011
Keywords: glioma, immunosuppression, chemotherapy, neurostatin, antigen presentation
Organisations: Biomedicine

Identifiers

Local EPrints ID: 333228
URI: https://eprints.soton.ac.uk/id/eprint/333228
ISSN: 1179-5549
PURE UUID: a5d47cfc-9010-4def-acf1-976efbf872b2
ORCID for Diego Gómez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

Catalogue record

Date deposited: 02 Mar 2012 16:29
Last modified: 06 Jun 2018 12:33

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