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

Abstract

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.

Cocaine-mediated microglial activation involves the ER stress-autophagy axis

“…However, the effects of rapamycin-induced autophagy on microglial activation remain elusive and controversial. Rapamycin has been reported to inhibit microglial activation for functional recovery after spinal cord injury, 67 contribute to glioma-induced microglial activation through polarizing its M1 phenotype, 68 or have no effect at all on microglial activation in rat models of temporal lobe epilepsy. 69 These inconsistencies could be attributable to the different disease models or the different doses of rapamycin used.…”

The role of microglia and macrophages in glioma maintenance and progression

“…As such, glioma-derived M-CSF induces a shift of microglia and macrophages toward the M2 phenotype, which increases tumor growth 56 . Similarly, mTOR 57 or CSF-1 (ref. 56) inhibition shifts to the M1 phenotype.…”

Human glioblastoma‐associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples

“…GAMs actively support tumor growth, e.g. In addition, recent studies using glioma mouse models have shown that GAMs-directed therapeutic approaches can be beneficial for disease intervention (Kees et al, 2012;Lisi et al, 2014;Markovic et al, 2011;Pyonteck et al, 2013;Sarkar et al, 2014;Xu et al, 2014). In addition, recent studies using glioma mouse models have shown that GAMs-directed therapeutic approaches can be beneficial for disease intervention (Kees et al, 2012;Lisi et al, 2014;Markovic et al, 2011;Pyonteck et al, 2013;Sarkar et al, 2014;Xu et al, 2014).…”