Hypothesis: Are Neoplastic Macrophages/Microglia Present in Glioblastoma Multiforme?

Huysentruyt, Leanne C.; Akgoc, Zeynep; Seyfried, Thomas N.

doi:10.1042/an20110011

Cited by 53 publications

(69 citation statements)

References 118 publications

(245 reference statements)

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“…Increased expression of microglial Gfap, Vim and Serpina3n transcripts was also reported in a mouse model of ALS (Chiu et al, 2013), whilst in vivo microglial transformation into astrocyte-like cells were found in a rat model of the disease (Trias et al, 2013). Co-expression of microglia and astrocytic markers has been also found in neoplastic glioblastoma multiform cells associated with increased inflammation (Huysentruyt et al, 2011). Other studies had also shown vimentin expression in reative microglia following injury (Graeber et al, 1988; Wohl et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

Noristani

Gerber

Sabourin

et al. 2017

Front. Mol. Neurosci.

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Neurons have inherent competence to regrow following injury, although not spontaneously. Spinal cord injury (SCI) induces a pronounced neuroinflammation driven by resident microglia and infiltrating peripheral macrophages. Microglia are the first reactive glial population after SCI and participate in recruitment of monocyte-derived macrophages to the lesion site. Both positive and negative influence of microglia and macrophages on axonal regeneration had been reported after SCI, raising the issue whether their response depends on time post-lesion or different lesion severity. We analyzed molecular alterations in microglia at several time-points after different SCI severities using RNA-sequencing. We demonstrate that activation of microglia is time-dependent post-injury but is independent of lesion severity. Early transcriptomic response of microglia after SCI involves proliferation and neuroprotection, which is then switched to neuroinflammation at later stages. Moreover, SCI induces an autologous microglial expression of astrocytic markers with over 6% of microglia expressing glial fibrillary acidic protein and vimentin from as early as 72 h post-lesion and up to 6 weeks after injury. We also identified the potential involvement of DNA damage and in particular tumor suppressor gene breast cancer susceptibility gene 1 (Brca1) in microglia after SCI. Finally, we established that BRCA1 protein is specifically expressed in non-human primate spinal microglia and is upregulated after SCI. Our data provide the first transcriptomic analysis of microglia at multiple stages after different SCI severities. Injury-induced microglia expression of astrocytic markers at RNA and protein levels demonstrates novel insights into microglia plasticity. Finally, increased microglia expression of BRCA1 in rodents and non-human primate model of SCI, suggests the involvement of oncogenic proteins after CNS lesion.

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Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

Noristani

Gerber

Sabourin

et al. 2017

Front. Mol. Neurosci.

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“…We do feel that whatever the changes that occurred might offer some insight into overall cell transformation biology and perhaps to some understanding of forms of brain malignancy that may involve a microglial phenotype. Indeed, a recent review highlights a possible role of microglial transformation, in particular, in glioblastoma multiforme (Huysentruyt et al, 2011). Although our present report focused on the microglial phenotype characterization of the SIM-A9 cells, it would be of a great future interest to elucidate potential oncogenic factor(s) that prompted the transformation of the primary microglia.…”

Section: Discussionmentioning

confidence: 99%

A novel cell line from spontaneously immortalized murine microglia

Nagamoto-Combs

Kulas

Combs

2014

Journal of Neuroscience Methods

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Background Purified microglia cultures are useful tools to study microglial behavior in vitro. Microglial cell lines serve as an attractive alternative to primary microglia culture, circumventing the costly and lengthy preparation of the latter. However, immortalization by genetic or pharmacologic manipulations may show altered physiology from primary microglia. New Method A novel microglial cell line was isolated from a primary glial culture of postnatal murine cerebral cortices. The culture contained a population of spontaneously transformed microglia that continued to divide without genetic or pharmacological manipulations. After several clones were isolated, one particular clone, SIM-A9, was analyzed for its microglial characteristics. Results SIM-A9 cells expressed macrophage/microglia-specific proteins, CD68 and Iba1. SIM-A9 cells were responsive to exogenous inflammatory stimulation with lipopolysaccharide and β-amyloid, triggering tyrosine kinase-based and NFκB signaling cascades as well as TNFα secretion. SIM-A9 cells also exhibited phagocytic uptake of fluorescent labeled β-amyloid and bacterial bioparticles. Furthermore, lipopolysaccharide increased the levels of inducible nitric oxide synthase and cyclooxygenase-2, whereas IL-4 stimulation increased arginase-1 levels demonstrating that SIM-A9 cells are capable of switching their profiles to pro- or anti-inflammatory phenotypes, respectively. Comparison with Existing Methods The use of SIM-A9 cells avoids expensive and lengthy procedures required for the preparation of primary microglia. Spontaneously immortalized SIM-A9 cells are expected to behave more comparably to primary microglia than virally transformed or pharmacologically induced microglial cell lines. Conclusions SIM-A9 cells exhibit key characteristics of cultured primary microglia and may serve as a valuable model system for the investigation of microglial behavior in vitro.

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“…A further viewpoint arises from the recent finding that subpopulations of cells within human gliomas, specifically GBM, are neoplastic macrophages/microglia [33]. Metastatic cancer cells retrieved in spontaneous mouse brain tumors appear to express multiple properties of macrophages [34], thus suggesting that the most aggressive cells in GBM may be neoplastic microglia/macrophages.…”

Section: Discussionmentioning

confidence: 99%

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

Lisi¹,

Laudati²,

Navarra³

et al. 2014

J Neuroinflammation

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BackgroundIncreased activation of mammalian target of rapamycin (mTOR) is observed in numerous human cancers. Recent studies on the glioma kinome have identified several deregulated pathways that converge and activate mTOR. The available evidence on the role of microglia in CNS cancers would suggest a dual role, a tumoricidal role and -on the contrary- a role favoring tumor growth.MethodsIn the present paper, we have compared the effects of μM concentrations of rapamycin (RAPA) and its analog, RAD001 (RAD), on activated microglia; the latter was obtained by exposing cells to conditioned medium harvested either from inflammatory activated glioma cells (LI-CM) or from glioma cells kept under basal conditions (C-CM).ResultsHere we show that the inhibition of mTOR polarizes glioma-activated microglial cells towards the M1 phenotype, with cytotoxic activities, preventing the induction of the M2 status that promotes tumor growth. In fact RAPA and RAD significantly increased iNOS expression and activity, while on the same time significantly reducing IL-10 gene expression induced by C-CM, thus suggesting that the drugs prevent the acquisition of a M2 phenotype in response to glioma factors promoting a classic M1 activation. Similar results were obtained using the conditioned media obtained after glioma stimulation with LPS-IFNγ (LI-CM), which was found to induce a mixture of M1 and M2a/b polarization phenotypes. In these conditions, the inhibition of mTOR led to a significant up-regulation of iNOS, and in parallel to the down-regulation of both ARG and IL-10 gene expression.ConclusionsThese data suggest that mTOR inhibition may prevent glioma induced M2 polarization of microglial cells and increase their cytotoxic potential, possibly resulting in antitumor actions.

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Hypothesis: Are Neoplastic Macrophages/Microglia Present in Glioblastoma Multiforme?

Cited by 53 publications

References 118 publications

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

RNA-Seq Analysis of Microglia Reveals Time-Dependent Activation of Specific Genetic Programs following Spinal Cord Injury

A novel cell line from spontaneously immortalized murine microglia

The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype

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