title: A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis.
abstract: Glioma cells in situ are surrounded by microglia, suggesting the potential of glioma-microglia interactions to produce various outcomes. As chemokines are important mediators of cell-cell communication, we sought first to identify commonly expressed chemokines in 16 human glioma lines. We found CCL2 (macrophage chemoattractant protein-1) messenger RNA to be expressed by the majority of glioma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. Next, we overexpressed CCL2 in the U87 glioma line, which has low basal level of CCL2, to investigate the hypothesis that glioma-secreted CCL2 interacts with microglia to affect glioma growth. Stable clones with 10- to 12-fold elevation of CCL2 have similar growth rate and invasive capacity as vector controls when cultured in isolation. However, in coculture with microglia in a three-dimensional collagen gel matrix, the invasiveness of CCL2-overexpressing clones was increased. Gene array analyses were then undertaken and they revealed that interleukin (IL)-6 was consistently increased in the coculture. Recombinant IL-6 enhanced the invasiveness of glioma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated glioma invasiveness. Finally, we found that human glioma specimens in situ contained IL-6 immunoreactivity that was expressed on CD68+ cells. This study has uncovered a mechanism by which glioma cells exploit microglia for increased invasiveness. Specifically, glioma-derived CCL2 acts upon CCR2-bearing microglia, which then produces IL-6 to stimulate gliomas. The CCL2/CCR2/IL-6 loop is a potential therapeutic target for the currently incurable malignant gliomas.
authors.affiliation: Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Susobhan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Rowena
authors.initials: R
authors.lastname: Cua
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Walter
authors.initials: W
authors.lastname: Hader
authors.forename: V Wee
authors.initials: VW
authors.lastname: Yong
mesh_terms: D057134:Antibodies, Neutralizing; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment; D000093242:Interleukin-6 Inhibitors; D000097382:CD68 Molecule
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D018932:Chemokine CCL2; D018925:Chemokines; D051523:Fibroblast Growth Factor 7; D015850:Interleukin-6; D012333:RNA, Messenger; D054390:Receptors, CCR2; D000093242:Interleukin-6 Inhibitors; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C496453:FGF7 protein, human