title: Reduction of CD200 expression in glioma cells enhances microglia activation and tumor growth.
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.
authors.affiliation: Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Yen
authors.initials: CY
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yun-Ti
authors.initials: YT
authors.lastname: Hsieh
authors.affiliation: Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kuan-Min
authors.initials: KM
authors.lastname: Fang
authors.affiliation: Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
authors.forename: Chung-Shi
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan. stzeng@mail.ncku.edu.tw.
authors.forename: Shun-Fen
authors.initials: SF
authors.lastname: Tzeng
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D001254:Astrocytoma / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation; D008297:Male; D017628:Microglia; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015703:Antigens, CD; D034741:RNA, Small Interfering; D016753:Interleukin-10; D015847:Interleukin-4; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C042739:antigens, CD200
keywords: CD200; OX-2; glioma; inflammation; microglia