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Published on: November 28, 2015
Reduction of CD200 expression in glioma cells enhances microglia activation and tumor growth
Chih-Yen Wang1, Yun-Ti Hsieh1, Kuan-Min Fang1
1Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Abstract:
CD200, a type I transmembrane glycoprotein, can interact with its receptor CD200R, which plays an inhibitory role in the activation of microglia-the resident macrophages of the central nervous system. In this study, the rat C6 glioma cell line (C6-1) that was previously characterized with high in vivo tumorigenicity was found to generate CD200 mRNA abundantly. However, CD200 expression was barely detected in another C6 glioma cell clone (C6-2) that was previously found to display low tumorigenic behavior. The results from CD200 immunohistochemistry on human glioma tissue array also showed that tumor cells in Grade I-II astrocytoma expressed a lower level of CD200 immunoreactivity than those detected in Grade III-IV glioblastoma multiforme. C6-1 transfectants with stable downregulation of CD200 gene expression using lentivirus knockdown approach were generated (C6-KD). Microglia and iNOS+ cells were increased when microglia were co-cultured with C6-KD cells. The colony formation of C6-KD was also augmented when those cells were co-cultured with microglia. Yet, increased colony formation of C6-KD transfectants in the co-culture with microglia was effectively suppressed by interleukin (IL)-4 and IL-10. The in vivo results indicated that the tumor formation of C6-1 cells in rat brain was promoted after CD200 gene knockdown. Moreover, CD11b+ activated microglia and iNOS+ microglia were highly accumulated in the tumor site formed by C6-KD. In conclusion, our findings demonstrate that the downregulation of CD200 expression in CD200-rich glioma cells could foster the formation of an activated microglia-associated tumor microenvironment, leading to glioma progression. © 2016 Wiley Periodicals, Inc.
Insights
Downregulating CD200 in glioma cells promotes tumor growth by activating microglia. Interleukin-4 and IL-10 can suppress this effect, suggesting therapeutic potential for glioma progression.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- CD200, a glycoprotein, interacts with CD200R to inhibit microglia activation in the central nervous system.
- Glioma cells express varying levels of CD200, correlating with tumorigenicity and grade.
- Microglia, the brain's resident macrophages, play a critical role in the tumor microenvironment.
Purpose of the Study:
- To investigate the role of CD200 expression in glioma progression and its interaction with microglia.
- To determine how CD200 downregulation affects glioma cell behavior and the tumor microenvironment.
- To explore potential therapeutic strategies targeting the CD200-microglia axis in glioma.
Main Methods:
- Utilized rat C6 glioma cell lines (C6-1 and C6-2) with differing CD200 expression and tumorigenicity.
- Generated CD200-downregulated C6-1 cells (C6-KD) using lentivirus-mediated knockdown.
- Performed co-culture experiments with C6-KD cells and microglia, including treatments with IL-4 and IL-10.
- Analyzed human glioma tissue arrays for CD200 expression across different grades.
- Assessed in vivo tumor formation and microglia activation in rat brains after C6-KD cell implantation.
Main Results:
- CD200 expression was abundant in highly tumorigenic C6-1 cells and human glioblastoma, but low in less tumorigenic C6-2 cells and lower-grade astrocytomas.
- CD200 knockdown in C6-1 cells (C6-KD) increased microglia and iNOS+ cell presence and augmented colony formation in co-culture.
- Interleukin-4 and IL-10 suppressed the increased colony formation of C6-KD cells co-cultured with microglia.
- In vivo, CD200 knockdown promoted tumor formation of C6-1 cells and led to increased accumulation of activated CD11b+ and iNOS+ microglia at the tumor site.
Conclusions:
- Downregulation of CD200 in glioma cells promotes tumor progression by fostering an activated microglia-associated tumor microenvironment.
- The CD200-microglia interaction is a critical factor in glioma development and progression.
- Targeting the CD200-microglia axis, potentially with IL-4 and IL-10, may offer a novel therapeutic strategy for glioma.
