The in Vivo Antitumoral Effects of Lipopolysaccharide Against Glioblastoma Multiforme Are Mediated in Part by Toll-Like Receptor 4

Chicoine, Michael R.; Zahner, Michael C.; Won, Eun Kyung; Kalra, Ricky; Kitamura, Tatsuya; Perry, Arie; Higashikubo, Ryuji

doi:10.1227/01.neu.0000249280.61761.2e

Cited by 82 publications

(60 citation statements)

References 34 publications

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“…Moreover, as previously demonstrated in a different murine glioma model, even higher amounts of LPS (100 g/mouse) only showed modest antitumoral effects after local administration and failed to induce long-term survivors (52). Finally, it should be noted that CpG-ODN has been optimized to improve in vivo stability, while poly(I:C) and R848 are not and therefore may have unfavourable pharmacokinetics in vivo.…”

Section: Discussionmentioning

confidence: 66%

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Grauer

Molling

Bennink

et al. 2008

The Journal of Immunology

121

102

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Local TLR stimulation is an attractive approach to induce antitumor immunity. In this study, we compared various TLR ligands for their ability to affect murine GL261 cells in vitro and to eradicate established intracerebral murine gliomas in vivo. Our data show that GL261 cells express TLR2, TLR3, and TLR4 and respond to the corresponding TLR ligands with increasing MHC class I expression and inducing IL-6 secretion in vitro, while TLR5, TLR7, and TLR9 are essentially absent. Remarkably, CpG-oligonucleotides (CpG-ODN, TLR9) appeared to inhibit GL261 cell proliferation in a cell-type specific, but CpG-motif and TLR9-independent manner. A single intratumoral injection of CpG-ODN most effectively inhibited glioma growth in vivo and cured 80% of glioma-bearing C57BL/6 mice. Intratumoral injection of Pam3Cys-SK4 (TLR1/2) or R848 (TLR7) also produced a significant survival benefit, whereas poly(I:C) (TLR3) or purified LPS (TLR4) stimulation alone was not effective. Additional studies using TLR9+/+ wild-type and TLR9−/− knockout mice revealed that the efficacy of local CpG-ODN treatment in vivo required TLR9 expression on nontumor cells. Additional experiments demonstrated increased frequencies of tumor-infiltrating IFN-γ producing CD4+ and CD8+ effector T cells and a marked increase in the ratio of CD4+ effector T cells to CD4+FoxP3+ regulatory T cells upon CpG-ODN treatment. Surviving CpG-ODN treated mice were also protected from a subsequent tumor challenge without further addition of CpG-ODN. In summary, this study underlines the potency of local TLR treatment in antiglioma therapy and demonstrates that local CpG-ODN treatment most effectively restores antitumor immunity in a therapeutic murine glioma model.

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Section: Discussionmentioning

confidence: 66%

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

Grauer

Molling

Bennink

et al. 2008

The Journal of Immunology

121

102

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“…The effect might also occur in vivo since intratumoral application of lipopolysaccharide to mice implanted with intracranial glioblastomas, increased the survival times modestly. This benefit was abrogated in mice deficient for lipopolysaccharide receptor Tlr-4-indicating that lipopolysaccharide does not affect the tumor cells, but the intrinsic macrophage/ microglia population (Chicoine et al, 2007). Another indication that the antitumorigenic effect of microglia is due to their specific glioma associated phenotype came from experiments interfering with the signaling pathway involving signal transducers and activators of transcription 3 (Stat3).…”

Section: Microglia Promote Glioma Migration and Tumor Growthmentioning

confidence: 99%

The brain tumor microenvironment

Charles

Holland

Gilbertson

et al. 2011

Glia

693

327

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High-grade brain tumors are heterogeneous with respect to the composition of bona fide tumor cells and with respect to a range of intermingling parenchymal cells. Glioblastomas harbor multiple cell types, some with increased tumorigenicity and stem cell-like capacity. The stem-like cells may be the cells of origin for tumor relapse. However, the tumor-associated parenchymal cells such as vascular cells, microglia, peripheral immune cells, and neural precursor cells also play a vital role in controlling the course of pathology. In this review, we describe the multiple interactions of bulk glioma cells and glioma stem cells with parenchymal cell populations and highlight the pathological impact as well as signaling pathways known for these types of cell-cell communication. The tumor-vasculature not only nourishes glioblastomas, but also provides a specialized niche for these stem-like cells. In addition, microglial cells, which can contribute up to 30% of a brain tumor mass, play a role in glioblastoma cell invasion. Moreover, non-neoplastic astrocytes can be converted into a reactive phenotype by the glioma microenvironment and can then secrete a number of factors which influences tumor biology. The young brain may have the capacity to inhibit gliomagenesis by the endogenous neural precursor cells, which secrete tumor suppressive factors. The factors, pathways, and interactions described in this review provide a new prospective on the cell biology of primary brain tumors, which may ultimately generate new treatment modalities. However, our picture of the multiple interactions between parenchymal and tumor cells is still incomplete. V

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“…Recently, functional TLRs were found to be expressed in cancer cells, but their significance remains controversial (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Whereas most of the therapeutic strategies using microbial products were designed with the idea of activating TLRs present on innate immune system cells (3)(4)(5)(6)(7)(8)(9)(10), clear distinction about the separate contribution of immune and cancer cells to the immune response has yet to be done. Stimulation of TLR4, the main receptor of bacterial lipopolysaccharide (LPS), on tumor cells has been shown to have a positive role in tumorigenesis in in vivo (13)(14)(15), but mainly in in vitro settings (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

IFNβ Produced by TLR4-Activated Tumor Cells Is Involved in Improving the Antitumoral Immune Response

et al. 2012

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Toll-like receptor (TLR) ligands may be a valuable tool to promote antitumor responses by reinforcing antitumor immunity. In addition to their expression in immune cells, functional TLRs are also expressed by many cancer cells, but their significance has been controversial. In this study, we examined the action of TLR ligands on tumor pathophysiology as a result of direct tumor cell effects. B16 murine melanoma cells were stimulated in vitro with a TLR4 ligand (LPS-B16) prior to inoculation into TLR4-deficient mice (Tlr4

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The in Vivo Antitumoral Effects of Lipopolysaccharide Against Glioblastoma Multiforme Are Mediated in Part by Toll-Like Receptor 4

Abstract: LPS-induced antitumoral effects on glioblastoma multiforme are mediated, in part, by the Tlr-4 receptor. Further understanding of this process may lead to novel treatment strategies for this uniformly fatal disease.

Cited by 82 publications

References 34 publications

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

TLR Ligands in the Local Treatment of Established Intracerebral Murine Gliomas

The brain tumor microenvironment

IFNβ Produced by TLR4-Activated Tumor Cells Is Involved in Improving the Antitumoral Immune Response

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