Abstract B20: Corticosteroids decrease tumor-associated microglial cell proliferation and shift its phenotype

Abstract

Abstract Dexamethasone (Dex) has been used for decades in the management of brain tumor-associated edema. Despite the numerous side-effects that are associated with corticosteroids, they are the primary choice of clinician for alleviating the neurological symptoms resulted from peritumoral edema. Additionally, equally effective therapeutics do not exist for managing neurological symptoms. In CNS, microglial cells are the prominent immune cells. Under the influence of tumor cells, microglia exhibits M2 phenotype and it is believed that this polarization could support tumor cell growth and progression partially by providing immune suppressed microenvironment. Despite the intensive usage of Dex in managing peritumoral edema, its effect on microglial or glioma cells, or how it affects glioma progression has not yet been precisely identified. We hypothesized that Dex modulates tumor-associated microglial cells phenotype and hence might interfere with the symbiotic relationship between tumor and microglial cells in the context of glioma. To address this hypothesis, PDGF-driven gliomas were generated by utilizing RCAS/Ntva system in INK4a/Arf-/- mice. In vivo studies were conducted using tumor-bearing mice treated with 10 mg/kg Dex. In vitro studies were performed using primary glioma cultures generated from tumor-bearing mice. Here, we show that Dex significantly decreased microglial cell number in the tumor microenvironment. Additionally, we investigated whether this effect is due to a reduction in microglial cell proliferation. Indeed, IHC analysis showed that Iba1 positive cells (microglia) had a significant lower PCNA staining in the Dex treated mice compared to the controls. More interestingly, QRT-PCR showed that Dex treatment decreased M2 markers of microglia in vivo and in vitro. To test whether this shift in microglial polarization could influence the proliferation of glioma cells, we quantified PCNA (proliferation marker) staining in tumor section from control and Dex treated mice. There was a significant decrease in the proliferation of tumor cells, in Dex treated tumor sections compared to the controls. However, in vitro testing did not recapitulate the anti-proliferative effect of Dex, emphasizing the importance of tumor microenvironment especially microglial cells. Taken together, this study suggests that Dex might be interfering with the symbiotic relationship between glioma and microglial cells, and hence the glioma disease, perhaps by modulating tumor-associated microglial cell number and phenotype. This study sheds light on the clinical importance of studying the mechanism of action of Dex, which might lead to the development a better therapeutic to manage neuro-symptoms. Citation Format: Amira Hosni-Ahmed, Duane Miller, Lawrence Pfeffer, Terreia Jones. Corticosteroids decrease tumor-associated microglial cell proliferation and shift its phenotype. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B20.