The Controversial Role of Microglia in Malignant Gliomas

Wei, Jun; Gabrusiewicz, Konrad; Heimberger, Amy B.

doi:10.1155/2013/285246

Cited by 182 publications

(172 citation statements)

References 132 publications

(100 reference statements)

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“…By secreting cytokines like IL-6, IL-10 and immune suppressive molecules, gliomas can polarize microglia into tumor supporting M2 phenotypes that participate in matrix remodeling and cell invasion. [125][126][127] In a recent study, PAM signaling was upregulated in microglial cells that were exposed to glioma derived factors, indicating that PAM signaling is needed to force microglial cells into a tumor supportive M2 state. [128] This result was supported by a report showing that mTOR inhibition with rapamycin polarizes microglia cells to express a tumor suppressive M1 phenotype.…”

Section: Pi3ks In Inflammation/ Microenvironmentmentioning

confidence: 99%

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Crespo¹,

Kind²,

Arcaro³

2016

JCMT

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The PI3K/AKT/mTOR (PAM) pathway is involved in a variety of cellular functions and often contributes to oncogenesis and cancer progression. It has been recognized that this pathway is frequently activated in the most common central nervous system cancers of adults and children, malignant gliomas and medulloblastomas (MB). In these tumors, the PAM network controls key functions necessary for cell invasion and metastasis, such as cell motility. This review summarizes the current knowledge about the role of PAM signaling in cell invasion and metastasis in gliomas and MB. Current approaches to inhibit cell invasion and metastasis by targeting the PAM pathway will also be discussed.

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Section: Pi3ks In Inflammation/ Microenvironmentmentioning

confidence: 99%

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

Crespo¹,

Kind²,

Arcaro³

2016

JCMT

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“…Microglia and bone-marrow-derived monocytes/macrophages have largely overlapping marker profiles and to date there is no unequivocal method to distinguish both cell types in samples resected from human GBM [162]. This matter is not trivial since monocytes of the peripheral blood and microglia have different developmental origin and may have distinct function in physiology and pathology [129].…”

Section: Microglia Developmentmentioning

confidence: 99%

“…Differential activation of STAT3 in TAM can control multiple immunosuppressive pathways in high-grade gliomas [162]. STAT3 activation in TAM is induced by different cytokines of the tumour microenvironment such as IL-10, IL-6, epidermal growth factor (EGF) and fibroblast growth factor.…”

Section: Adaptive Immune Functions In Gliomasmentioning

confidence: 99%

CNS macrophages and peripheral myeloid cells in brain tumours

2014

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However, it is also becoming evident that some myeloid-directed glioma therapies may only be beneficial for distinct subclasses of gliomas and that a more cell-type specific manipulation of either microglia or macrophages may improve therapeutic outcome. 2 Neuropathological features of gliomasGlial tumours constitute approximately 50% of all newly diagnosed primary brain tumours, with low-grade gliomas accounting for roughly 15% of all brain tumours in adults [106]. The morphology and the cellular markers for gliomas share some similarities with the main macroglial cell-types (i.e. astrocytes, oligodendrocytes) [75].Histopathologically, gliomas are divided into four different grades (according to the classification scheme by the world health organization, WHO), in which low-grade tumours are defined as grade-I/-II and high-grade gliomas as grade-III and-IV [87]. The presence of mitotic activity is a key feature for distinguishing low-grade from high-grade gliomas [75]. Statistically, low-grade astrocytomas arise roughly in proportion to the relative mass of the different lobes with most common location within the frontal lobes, followed by temporal and parietal lobe lesions [107]. Overall, 5-and 10-year survival rates of ~70% and 50% for grade-I and grade-II gliomas, respectively, have been reported in the literature [25]. The tumour tissue has no obvious signs of neoangiogenesis, infiltrative invasion or inflammation [75]. On the contrary, the outlook for patients with high-grade gliomas is grim. The majority of individuals diagnosed with a grade-IV glioma, which are very heterogeneous tumours and therefore also named glioblastoma multiforme (GBM), have a median progression-free survival of just over half a year and median overall survival of 15-18 months [17], only some subpopulations of patients show median survivals of almost 2 years [54]. GBM is a fast growing, highly angiogenic and invasive tumour and the diffuse growth is a major obstacle for GBM therapy. Other hallmarks of malignant gliomas are break-down of the blood-brain barrier (BBB), many hypoxic areas and necrotic centres [75]. Gliomas are usually diagnosed by neurorimaging (i.e. magnetic resonance imaging) and visualisation of the uptake of a contrast-enhancing agent within the tissue indicates BBB-leakage/breakdown [159]. GBM typically presents as a ragged contrast-enhanced and complex multi-cystic structure. GBM may be diagnosed de novo, i.e. in patients without a clinical history for brain tumours (then named primary GBM) or may evolve from lower grade gliomas (secondary GBM) [103].3 Multi-modal glioma therapyGlioma therapy comprises very different strategies. For patients with deep-seated lesions or lesions located in eloquent regions which are clinically and radiographically indicated as low-grade glioma a conservative management including regular neuroimaging (after obtaining a histological diagnosis) [165], see also [130,150]. Individuals with high-grade gliomas undergo multi-modal treatment combining cytoreductive surgery, radiation-and ch...

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“…20,21 We therefore examined their roles in our GIC transplantation model. Using anti-IL12 p40 subunit and TNFa depletion antibodies, we found that neither factors had apparent effects on GIC elimination (Fig.…”

Section: Ecrg4 Prevented Gic Tumorigenesis Through the Activation Ofmentioning

confidence: 99%

Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling

et al. 2016

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Esophageal cancer-related gene 4 (Ecrg4), a hormone-like peptide, is thought to be a tumor suppressor, however, little is known about the mechanism of how Ecrg4 suppresses tumorigenesis. Here, we show that the ecrg4 null glioma-initiating cell (GIC) line, which was generated from neural stem cells of ecrg4 knockout (KO) mice, effectively formed tumors in the brains of immunocompetent mice, whereas the transplanted ecrg4 wild type-GIC line GIC(C/C) was frequently eliminated. This was caused by host immune system including adaptive T cell responses, since depletion of CD4 C , CD8 C , or NK cells by specific antibodies in vivo recovered tumorigenicity of GIC(C/C). We demonstrate that Ecrg4 fragments, amino acid residues 71-132 and 133-148, which are produced by the proteolitic cleavage, induced the expression of pro-inflammatory cytokines in microglia in vitro. Moreover, blockades of type-I interferon (IFN) signaling in vivo, either depleting IFN-a/b receptor 1 or using stat1 KO mice, abrogated the Ecrg4-dependent antitumor activity. Together, our findings indicate a major antitumor function of Ecrg4 in enhancing host immunity via type-I IFN signaling, and suggest its potential as a clinical candidate for cancer immunotherapy.

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The Controversial Role of Microglia in Malignant Gliomas

Cited by 182 publications

References 132 publications

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

CNS macrophages and peripheral myeloid cells in brain tumours

Ecrg4 contributes to the anti-glioma immunosurveillance through type-I interferon signaling

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