Abstract
Despite the fact that accumulation of microglia, the resident macrophages of the central nervous system (CNS) are the main feature of glioblastoma, the role of microglia in the progression of glioma is still arguable. Based on the correlation of inflammation with tumor progression, in this study, we attempt to determine if peripheral inflammation aggravates glioma expansion and the activation of microglia associated with the tumor. Experimental animals were administered intraperitoneally by inflammagen lipopolysaccharide (LPS) for 7 days (LPS priming) before intracerebral implantation of glioma cells. Moreover, a reduced level of tumor necrosis factor receptor type 2 (TNFR2) that is restricted to immune cells, neurons, and microglia has been found in patients with glioblastoma through the clinic analysis of monocyte receptor expression. Thus, in addition to wildtype (WT) mice, heterogeneous TNFR2 gene deficiency (TNFR2+/−) mice and homogeneous TNFR2 gene knockout (TNFR2−/−) mice were used in this study. The results show that peripheral challenge by LPS, Iba1+- or CD11b+-microglia increase in numbers in the cortex and hippocampus of TNFR2−/− mice, when compared to WT or TNFR2+/− mice. We further conducted the intracerebral implantation of rodent glioma cells into the animals and found that the volumes of tumors formed by rat C6 glioma cells or mouse GL261 glioma cells were significantly larger in the cortex of TNFR2−/− mice when compared to that measured in LPS-primed WT or LPS-primed TNFR2+/− mice. Ki67+-cells were exclusively clustered in the tumor of LPS-primed TNFR2−/− mice. Microglia were also extensively accumulated in the tumor formed in LPS-primed TNFR2−/− mice. Accordingly, our findings demonstrate that aggravation of microglia activation by peripheral inflammatory challenge and a loss of TNFR2 function might lead to the promotion of glioma growth.
Highlights
IntroductionAstrocytoma WHO grade IV or Glioblastoma are the most common and aggressive form of the tumors in the central nervous system (CNS) and account for over 50% of primary
To determine if glioma cells increased by co-culture with LPS-activated microglia with TNFR2 downregulation, we were first to conduct the in vitro study using a co-culture system of C6 glioma cells with a mouse BV2 cell line
The findings indicate that TNFR2KD promoted microglia invasive capability and proliferation, and increased glioma cell proliferation
Summary
Astrocytoma WHO grade IV or Glioblastoma are the most common and aggressive form of the tumors in the central nervous system (CNS) and account for over 50% of primary. Based on the development of current therapies, the survival time of most patients with glioblastoma has been significantly improved up to 21 months on average [4,5]. This life expectancy is considerably short because the efficacy remains limited for high-grade glioma. Microglia and macrophages that can promote tumor growth have been reported to exist in gliomas [15]. In addition, the presence of microglia and macrophages with M2 markers predicts a poor survival factor in gliomas
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