About this Journal Submit a Manuscript Table of Contents
Clinical and Developmental Immunology
Volume 2013 (2013), Article ID 285246, 12 pages
http://dx.doi.org/10.1155/2013/285246
Review Article

The Controversial Role of Microglia in Malignant Gliomas

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-1402, USA

Received 16 April 2013; Accepted 19 June 2013

Academic Editor: Anirban Ghosh

Copyright © 2013 Jun Wei et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. Kettenmann, U. K. Hanisch, M. Noda, and A. Verkhratsky, “Physiology of microglia,” Physiological Reviews, vol. 91, no. 2, pp. 461–553, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. V. H. Perry, J. A. R. Nicoll, and C. Holmes, “Microglia in neurodegenerative disease,” Nature Reviews Neurology, vol. 6, no. 4, pp. 193–201, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. K. C. Williams and W. F. Hickey, “Traffic of hematogenous cells through the central nervous system,” Current Topics in Microbiology and Immunology, vol. 202, pp. 221–245, 1995. View at Scopus
  4. F. Ginhoux, M. Greter, M. Leboeuf et al., “Fate mapping analysis reveals that adult microglia derive from primitive macrophages,” Science, vol. 330, no. 6005, pp. 841–845, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. T. Aizawa, S. Haga, and K. Yoshikawa, “Neural differentiation-associated generation of microglia-like phagocytes in murine embryonal carcinoma cell line,” Developmental Brain Research, vol. 59, no. 1, pp. 89–97, 1991. View at Publisher · View at Google Scholar · View at Scopus
  6. B. Badie and J. M. Schartner, “Flow cytometric characterization of tumor-associated macrophages in experimental gliomas,” Neurosurgery, vol. 46, no. 4, pp. 957–962, 2000. View at Scopus
  7. T. Morimura, C. Neuchrist, K. Kitz et al., “Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation,” Acta Neuropathologica, vol. 80, no. 3, pp. 287–294, 1990. View at Publisher · View at Google Scholar · View at Scopus
  8. W. Roggendorf, S. Strupp, and W. Paulus, “Distribution and characterization of microglia/macrophages in human brain tumors,” Acta Neuropathologica, vol. 92, no. 3, pp. 288–293, 1996. View at Publisher · View at Google Scholar · View at Scopus
  9. M. B. Graeber, B. W. Scheithauer, and G. W. Kreutzberg, “Microglia in brain tumors,” GLIA, vol. 40, no. 2, pp. 252–259, 2002. View at Publisher · View at Google Scholar · View at Scopus
  10. T. Wierzba-Bobrowicz, I. Kuchna, and E. Matyja, “Reaction of microglial cells in human astrocytomas (preliminary report),” Folia Neuropathologica, vol. 32, no. 4, pp. 251–252, 1994. View at Scopus
  11. T. Morioka, T. Baba, K. L. Black, and W. J. Streit, “Response of microglial cells to experimental rat glioma,” GLIA, vol. 6, no. 1, pp. 75–79, 1992. View at Scopus
  12. B. Badie, J. Schartner, J. Klaver, and J. Vorpahl, “In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor,” Neurosurgery, vol. 44, no. 5, pp. 1077–1083, 1999. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Okada, M. Saio, Y. Kito et al., “Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1,” International Journal of Oncology, vol. 34, no. 6, pp. 1621–1627, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. J. Villeneuve, P. Tremblay, and L. Vallières, “Tumor necrosis factor reduces brain tumor growth by enhancing macrophage recruitment and microcyst formation,” Cancer Research, vol. 65, no. 9, pp. 3928–3936, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. R. L. Alterman and E. R. Stanley, “Colony stimulating factor-1 expression in human glioma,” Molecular and Chemical Neuropathology, vol. 21, no. 2-3, pp. 177–188, 1994. View at Scopus
  16. S. J. Coniglio, E. Eugenin, K. Dobrenis et al., “Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling,” Molecular Medicine, vol. 18, pp. 519–527, 2012. View at Publisher · View at Google Scholar
  17. Y. Komohara, K. Ohnishi, J. Kuratsu, and M. Takeya, “Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas,” Journal of Pathology, vol. 216, no. 1, pp. 15–24, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. M. C. Ku, S. A. Wolf, D. Respondek et al., “GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis,” Acta Neuropathologica, vol. 125, no. 4, pp. 609–620, 2013. View at Publisher · View at Google Scholar
  19. M. Sielska, P. Przanowski, B. Wylot et al., “Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response,” Journal of Pathology, vol. 230, no. 3, pp. 310–321, 2013. View at Publisher · View at Google Scholar
  20. K. Frei, D. Piani, U. V. Malipiero, E. Van Meir, N. De Tribolet, and A. Fontana, “Granulocyte-macrophage colony-stimulating factor (GM-CSF) production by glioblastoma cells: despite the presence of inducing signals GM-CSF is not expressed in vivo,” Journal of Immunology, vol. 148, no. 10, pp. 3140–3146, 1992. View at Scopus
  21. T. Nitta, K. Sato, M. Allegretta et al., “Expression of granulocyte colony stimulating factor and granulocyte-macrophage colony stimulating factor genes in human astrocytoma cell lines and glioma specimens,” Brain Research, vol. 571, no. 1, pp. 19–25, 1992. View at Publisher · View at Google Scholar · View at Scopus
  22. Z. Ahmed, G. Shaw, V. P. Sharma, C. Yang, E. McGowan, and D. W. Dickson, “Actin-binding proteins coronin-1a and IBA-1 are effective microglial markers for immunohistochemistry,” Journal of Histochemistry and Cytochemistry, vol. 55, no. 7, pp. 687–700, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. R. H. Hoek, S. R. Ruuls, C. A. Murphy et al., “Down-regulation of the macrophage lineage through interaction with OX2 (CD200),” Science, vol. 290, no. 5497, pp. 1768–1771, 2000. View at Publisher · View at Google Scholar · View at Scopus
  24. L. H. Guo, K. Trautmann, and H. J. Schluesener, “Expression of P2X4 receptor in rat C6 glioma by tumor-associated macrophages and activated microglia,” Journal of Neuroimmunology, vol. 152, no. 1-2, pp. 67–72, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. M. H. Deininger, R. Meyermann, K. Trautmann et al., “Heme oxygenase (HO)-1 expressing macrophages/microglial cells accumulate during oligodendroglioma progression,” Brain Research, vol. 882, no. 1-2, pp. 1–8, 2000. View at Publisher · View at Google Scholar · View at Scopus
  26. M. H. Deininger, K. Seid, S. Engel, R. Meyermann, and H. J. Schluesener, “Allograft inflammatory factor-1 defines a distinct subset of infiltrating macrophages/microglial cells in rat and human gliomas,” Acta Neuropathologica, vol. 100, no. 6, pp. 673–680, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. B. Badie and J. Schartner, “Role of microglia in glioma biology,” Microscopy Research and Technique, vol. 54, no. 2, pp. 106–113, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. A. L. Ford, A. L. Goodsall, W. F. Hickey, and J. D. Sedgwick, “Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting: phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared,” Journal of Immunology, vol. 154, no. 9, pp. 4309–4321, 1995. View at Scopus
  29. J. D. Sedgwick, S. Schwender, H. Imrich, R. Dorries, G. W. Butcher, and V. Ter Meulen, “Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 16, pp. 7438–7442, 1991. View at Scopus
  30. D. I. Gabrilovich, S. Ostrand-Rosenberg, and V. Bronte, “Coordinated regulation of myeloid cells by tumours,” Nature Reviews Immunology, vol. 12, no. 4, pp. 253–268, 2012. View at Publisher · View at Google Scholar · View at Scopus
  31. N. Umemura, M. Saio, T. Suwa et al., “Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics,” Journal of Leukocyte Biology, vol. 83, no. 5, pp. 1136–1144, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. B. Badie, J. Schartner, S. Prabakaran, J. Paul, and J. Vorpahl, “Expression of Fas ligand by microglia: possible role in glioma immune evasion,” Journal of Neuroimmunology, vol. 120, no. 1-2, pp. 19–24, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. S. F. Hussain, D. Yang, D. Suki, K. Aldape, E. Grimm, and A. B. Heimberger, “The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses,” Neuro-Oncology, vol. 8, no. 3, pp. 261–279, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. W. Jia, C. Jackson-Cook, and M. R. Graf, “Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma+vaccination model,” Journal of Neuroimmunology, vol. 223, no. 1-2, pp. 20–30, 2010. View at Publisher · View at Google Scholar · View at Scopus
  35. F. O. Martinez, A. Sica, A. Mantovani, and M. Locati, “Macrophage activation and polarization,” Frontiers in Bioscience, vol. 13, no. 2, pp. 453–461, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. J. W. Pollard, “Tumour-educated macrophages promote tumour progression and metastasis,” Nature Reviews Cancer, vol. 4, no. 1, pp. 71–78, 2004. View at Scopus
  37. K. Gabrusiewicz, A. Ellert-Miklaszewska, M. Lipko, M. Sielska, M. Frankowska, and B. Kaminska, “Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas,” PLoS ONE, vol. 6, no. 8, Article ID e23902, 2011. View at Publisher · View at Google Scholar · View at Scopus
  38. J. Wei, J. Barr, L. Y. Kong et al., “Glioma-associated cancer-initiating cells induce immunosuppression,” Clinical Cancer Research, vol. 16, no. 2, pp. 461–473, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. J. P. Zou, L. A. Morford, C. Chougnet et al., “Human glioma-induced immunosuppression involves soluble factor(s) that alters monocyte cytokine profile and surface markers,” Journal of Immunology, vol. 162, no. 8, pp. 4882–4892, 1999. View at Scopus
  40. J. P. Bach, O. Deuster, M. Balzer-Geldsetzer, B. Meyer, R. Dodel, and M. Bacher, “The role of macrophage inhibitory factor in tumorigenesis and central nervous system tumors,” Cancer, vol. 115, no. 10, pp. 2031–2040, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. N. A. Charles, E. C. Holland, R. Gilbertson, R. Glass, and H. Kettenmann, “The brain tumor microenvironment,” GLIA, vol. 59, no. 8, pp. 1169–1180, 2011. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Qiu, D. Zhang, C. Wang et al., “IL-10 and TGF-β2 are overexpressed in tumor spheres cultured from human gliomas,” Molecular Biology Reports, vol. 38, no. 5, pp. 3585–3591, 2011. View at Publisher · View at Google Scholar · View at Scopus
  43. L. Zhang, M. V. Handel, J. M. Schartner et al., “Regulation of IL-10 expression by upstream stimulating factor (USF-1) in glioma-associated microglia,” Journal of Neuroimmunology, vol. 184, no. 1-2, pp. 188–197, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. A. Wu, J. Wei, L. Y. Kong et al., “Glioma cancer stem cells induce immunosuppressive macrophages/microglia,” Neuro-Oncology, vol. 12, no. 11, pp. 1113–1125, 2010. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Sica, T. Schioppa, A. Mantovani, and P. Allavena, “Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy,” European Journal of Cancer, vol. 42, no. 6, pp. 717–727, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. G. G. Gomez and C. A. Kruse, “Mechanisms of malignant glioma immune resistance and sources of immunosuppression,” Gene Therapy and Molecular Biology, vol. 10, no. 1, pp. 133–146, 2006. View at Scopus
  47. L. Kren, K. Muckova, E. Lzicarova et al., “Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: a role in innate immunity?” Journal of Neuroimmunology, vol. 220, no. 1-2, pp. 131–135, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. B. C. Kennedy, L. M. Maier, R. D'Amico et al., “Dynamics of central and peripheral immunomodulation in a murine glioma model,” BMC Immunology, vol. 10, article 11, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. B. P. He, J. J. Wang, X. Zhang et al., “Differential reactions of microglia to brain metastasis of lung cancer,” Molecular Medicine, vol. 12, no. 7-8, pp. 161–170, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. T. Pukrop, F. Dehghani, H. N. Chuang et al., “Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way,” GLIA, vol. 58, no. 12, pp. 1477–1489, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. S. F. Hussain, D. Yang, D. Suki, E. Grimm, and A. B. Heimberger, “Innate immune functions of microglia isolated from human glioma patients,” Journal of Translational Medicine, vol. 4, article 15, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. J. M. Schartner, A. R. Hagar, M. Van Handel, L. Zhang, N. Nadkarni, and B. Badie, “Impaired capacity for upregulation of MHC class II in tumor-associated microglia,” GLIA, vol. 51, no. 4, pp. 279–285, 2005. View at Publisher · View at Google Scholar · View at Scopus
  53. R. Mora and A. Régnier-Vigouroux, “Autophagy-driven cell fate decision maker: activated microglia induce specific death of glioma cells by a blockade of basal autophagic flux and secondary apoptosis/necrosis,” Autophagy, vol. 5, no. 3, pp. 419–421, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. J. J. Bright, C. Natarajan, S. Sriram, and G. Muthian, “Signaling through JAK2-STAT5 pathway is essential for IL-3-induced activation of microglia,” GLIA, vol. 45, no. 2, pp. 188–196, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. D. Askew and W. S. Walker, “Alloantigen presentation to naive CD8+ T cells by mouse microglia: evidence for a distinct phenotype based on expression of surface-associated and soluble costimulatory molecules,” GLIA, vol. 18, no. 2, pp. 118–128, 1996.
  56. A. Nishie, M. Ono, T. Shono et al., “Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas,” Clinical Cancer Research, vol. 5, no. 5, pp. 1107–1113, 1999. View at Scopus
  57. C. L. Mariani, J. G. Kouri, and W. J. Streit, “Rejection of RG-2 gliomas is mediated by microglia and T lymphocytes,” Journal of Neuro-Oncology, vol. 79, no. 3, pp. 243–253, 2006. View at Publisher · View at Google Scholar · View at Scopus
  58. T. Watanabe, R. Tanaka, Y. Taniguchi, K. Yamamoto, K. Ono, and S. Yoshida, “The role of microglia and tumor-primed lymphocytes in the interaction between T lymphocytes and brain endothelial cells,” Journal of Neuroimmunology, vol. 81, no. 1-2, pp. 90–97, 1998. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Sutter, A. Hekmat, and G. A. Luckenbach, “Antibody-mediated tumor cytotoxicity of microglia,” Pathobiology, vol. 59, no. 4, pp. 254–258, 1991. View at Scopus
  60. M. Synowitz, R. Glass, K. Färber et al., “A1 adenosine receptors in microglia control glioblastoma-host interaction,” Cancer Research, vol. 66, no. 17, pp. 8550–8557, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. K. Färber, M. Synowitz, G. Zahn et al., “An α5β1 integrin inhibitor attenuates glioma growth,” Molecular and Cellular Neuroscience, vol. 39, no. 4, pp. 579–585, 2008. View at Publisher · View at Google Scholar · View at Scopus
  62. D. S. Markovic, K. Vinnakota, S. Chirasani et al., “Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 30, pp. 12530–12535, 2009. View at Publisher · View at Google Scholar · View at Scopus
  63. D. S. Markovic, R. Glass, M. Synowitz, N. Van Rooijen, and H. Kettenmann, “Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2,” Journal of Neuropathology and Experimental Neurology, vol. 64, no. 9, pp. 754–762, 2005. View at Scopus
  64. J. Held-Feindt, K. Hattermann, S. S. Müerköster et al., “CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs),” Experimental Cell Research, vol. 316, no. 9, pp. 1553–1566, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. A. C. C. da Fonseca, L. Romão, R. F. Amaral et al., “Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells,” Neuroscience, vol. 200, pp. 130–141, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics, vol. 7, no. 4, pp. 354–365, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. T. A. Doucette, L. Y. Kong, Y. Yang et al., “Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma,” Neuro-Oncology, vol. 14, no. 9, pp. 1136–1145, 2012. View at Publisher · View at Google Scholar
  68. P. Bezzi, M. Domercq, L. Brambilla et al., “CXCR4-activated astrocyte glutamate release via TNFa: amplification by microglia triggers neurotoxicity,” Nature Neuroscience, vol. 4, no. 7, pp. 702–710, 2001. View at Publisher · View at Google Scholar · View at Scopus
  69. M. H. Deininger and H. J. Schluesener, “Cyclooxygenases-1 and -2 are differentially localized to microglia and endothelium in rat EAE and glioma,” Journal of Neuroimmunology, vol. 95, no. 1-2, pp. 202–208, 1999. View at Publisher · View at Google Scholar · View at Scopus
  70. M. H. Deininger, R. Meyermann, K. Trautmann et al., “Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression,” Brain Research, vol. 885, no. 1, pp. 111–116, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. S. G. Temel and Z. Kahveci, “Cyclooxygenase-2 expression in astrocytes and microglia in human oligodendroglioma and astrocytoma,” Journal of Molecular Histology, vol. 40, no. 5-6, pp. 369–377, 2009. View at Publisher · View at Google Scholar · View at Scopus
  72. G. C. Daginakatte, S. M. Gianino, N. W. Zhao, A. S. Parsadanian, and D. H. Gutmann, “Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation,” Cancer Research, vol. 68, no. 24, pp. 10358–10366, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. G. C. Daginakatte and D. H. Gutmann, “Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth,” Human Molecular Genetics, vol. 16, no. 9, pp. 1098–1112, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. O. Butovsky, Y. Ziv, A. Schwartz et al., “Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells,” Molecular and Cellular Neuroscience, vol. 31, no. 1, pp. 149–160, 2006. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Bao, Q. Wu, R. E. McLendon et al., “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response,” Nature, vol. 444, no. 7120, pp. 756–760, 2006. View at Publisher · View at Google Scholar · View at Scopus
  76. L. Yi, H. Xiao, M. Xu et al., “Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma,” Journal of Neuroimmunology, vol. 232, no. 1-2, pp. 75–82, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. X. Z. Ye, S. L. Xu, Y. H. Xin et al., “Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway,” Journal of Immunology, vol. 189, no. 1, pp. 444–453, 2012. View at Publisher · View at Google Scholar
  78. R. A. Morantz, G. W. Wood, and M. Foster, “Macrophages in experimental and human brain tumors. Part I. Studies of the macrophage content of experimental rat brain tumors of varying immunogenicity,” Journal of Neurosurgery, vol. 50, no. 3, pp. 298–304, 1979. View at Scopus
  79. B. Badie, B. Bartley, and J. Schartner, “Differential expression of MHC class II and B7 costimulatory molecules by microglia in rodent gliomas,” Journal of Neuroimmunology, vol. 133, no. 1-2, pp. 39–45, 2002. View at Publisher · View at Google Scholar · View at Scopus
  80. P. Voisin, V. Bouchaud, M. Merle et al., “Microglia in close vicinity of glioma cells: correlation between phenotype and metabolic alterations,” Front Neuroenergetics, vol. 2, article 131, 2010. View at Publisher · View at Google Scholar
  81. K. M. Fang, Y. L. Wang, M. C. Huang, S. H. Sun, H. Cheng, and S. F. Tzeng, “Expression of macrophage inflammatory protein-1α and monocyte chemoattractant protein-1 in glioma-infiltrating microglia: involvement of ATP and P2X7 receptor,” Journal of Neuroscience Research, vol. 89, no. 2, pp. 199–211, 2011. View at Publisher · View at Google Scholar · View at Scopus
  82. S. Engel, S. Isenmann, M. Ständer, J. Rieger, M. Bähr, and M. Weller, “Inhibition of experimental rat glioma growth by decorin gene transfer is associated with decreased microglial infiltration,” Journal of Neuroimmunology, vol. 99, no. 1, pp. 13–18, 1999. View at Publisher · View at Google Scholar · View at Scopus
  83. H. Zhai, F. L. Heppner, and S. E. Tsirka, “Microglia/macrophages promote glioma progression,” GLIA, vol. 59, no. 3, pp. 472–485, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. T. Nagai, M. Tanaka, Y. Tsuneyoshi et al., “Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta,” Cancer Immunology, Immunotherapy, vol. 58, no. 10, pp. 1577–1586, 2009. View at Publisher · View at Google Scholar · View at Scopus
  85. D. Barba, J. Hardin, M. Sadelain, and F. H. Gage, “Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 10, pp. 4348–4352, 1994. View at Scopus
  86. G. Fulci, N. Dmitrieva, D. Gianni et al., “Depletion of peripheral macrophages and brain microglia increases brain tumor titers of oncolytic viruses,” Cancer Research, vol. 67, pp. 9398–9406, 2007.
  87. A. F. Carpentier, J. Xie, K. Mokhtari, and J. Y. Delattre, “Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs,” Clinical Cancer Research, vol. 6, no. 6, pp. 2469–2473, 2000. View at Scopus
  88. A. H. Dalpke, M. K. H. Scháfer, M. Frey et al., “Immunostimulatory CpG-DNA activates murine microglia,” Journal of Immunology, vol. 168, no. 10, pp. 4854–4863, 2002. View at Scopus
  89. A. El Andaloussi, A. M. Sonabend, Y. Han, and M. S. Lesniak, “Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors,” GLIA, vol. 54, no. 6, pp. 526–535, 2006. View at Publisher · View at Google Scholar · View at Scopus
  90. T. Kees, J. Lohr, J. Noack et al., “Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation,” Neuro-Oncology, vol. 14, no. 1, pp. 64–78, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. T. L. Chiu, C. W. Peng, and M. J. Wang, “Enhanced anti-glioblastoma activity of microglia by AAV2-mediated IL-12 through TRAIL and phagocytosis in vitro,” Oncology Reports, vol. 25, no. 5, pp. 1373–1380, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. T. L. Chiu, M. J. Wang, and C. C. Su, “The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model,” Journal of Biomedical Science, vol. 19, article 45, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Nakagawa, M. Saio, N. Tamakawa et al., “TNF expressed by tumor-associated macrophages, but not microglia, can eliminate glioma,” International Journal of Oncology, vol. 30, no. 4, pp. 803–811, 2007. View at Scopus
  94. T. Dutta, A. Spence, and L. A. Lampson, “Robust ability of IFN-γ to upregulate class II MHC antigen expression in tumor bearing rat brains,” Journal of Neuro-Oncology, vol. 64, no. 1-2, pp. 31–44, 2003. View at Publisher · View at Google Scholar · View at Scopus
  95. N. V. Kulprathipanja and C. A. Kruse, “Microglia phagocytose alloreactive CTL-damaged 9L gliosarcoma cells,” Journal of Neuroimmunology, vol. 153, no. 1-2, pp. 76–82, 2004. View at Publisher · View at Google Scholar · View at Scopus
  96. H. Lauterbach, E. I. Zuniga, P. Truong, M. B. A. Oldstone, and D. B. McGavern, “Adoptive immunotherapy induces CNS dendritic cell recruitment and antigen presentation during clearance of a persistent viral infection,” Journal of Experimental Medicine, vol. 203, no. 8, pp. 1963–1975, 2006. View at Publisher · View at Google Scholar · View at Scopus
  97. K. Färber, G. Cheung, D. Mitchell et al., “C1q, the recognition subcomponent of the classical pathway of complement, drives microglial activation,” Journal of Neuroscience Research, vol. 87, no. 3, pp. 644–652, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. D. P. Schafer, E. K. Lehrman, A. G. Kautzman et al., “Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner,” Neuron, vol. 74, no. 4, pp. 691–705, 2012. View at Publisher · View at Google Scholar
  99. Z. Begum, A. Ghosh, S. Sarkar et al., “Documentation of immune profile of microglia through cell surface marker study in glioma model primed by a novel cell surface glycopeptide T11TS/SLFA-3,” Glycoconjugate Journal, vol. 20, no. 9, pp. 515–523, 2004. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Sarkar, A. Ghosh, J. Mukherjee, S. Chaudhuri, and S. Chaudhuri, “CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis,” Cancer Biology and Therapy, vol. 3, no. 11, pp. 1121–1128, 2004. View at Scopus
  101. K. Nakajima, Y. Tohyama, S. Kohsaka, and T. Kurihara, “Ceramide activates microglia to enhance the production/secretion of brain-derived neurotrophic factor (BDNF) without induction of deleterious factors in vitro,” Journal of Neurochemistry, vol. 80, no. 4, pp. 697–705, 2002. View at Publisher · View at Google Scholar · View at Scopus
  102. K. J. Min, H. K. Pyo, M. S. Yang, K. A. Ji, I. Jou, and E. H. Joe, “Gangliosides activate microglia via protein kinase C and NADPH oxidase,” GLIA, vol. 48, no. 3, pp. 197–206, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. K. Takahashi, C. D. P. Rochford, and H. Neumann, “Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2,” Journal of Experimental Medicine, vol. 201, no. 4, pp. 647–657, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. J. Ryu, K. J. Min, T. Y. Rhim et al., “Prothrombin kringle-2 activates cultured rat brain microglia,” Journal of Immunology, vol. 168, no. 11, pp. 5805–5810, 2002. View at Scopus
  105. V. L. Jacobs, R. P. Landry, Y. Liu, E. A. Romero-Sandoval, and J. A. De Leo, “Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia,” Neuro-Oncology, vol. 14, no. 2, pp. 119–131, 2012. View at Publisher · View at Google Scholar · View at Scopus
  106. D. S. Markovic, K. Vinnakota, N. van Rooijen et al., “Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression,” Brain, Behavior, and Immunity, vol. 25, no. 4, pp. 624–628, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. M. Sliwa, D. Markovic, K. Gabrusiewicz et al., “The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A,” Brain, vol. 130, part 2, pp. 476–489, 2007. View at Publisher · View at Google Scholar · View at Scopus
  108. P. A. Meyers, C. L. Schwartz, M. D. Krailo et al., “Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the children's oncology group,” Journal of Clinical Oncology, vol. 26, no. 4, pp. 633–638, 2008. View at Publisher · View at Google Scholar · View at Scopus
  109. J. Huuskonen, T. Suuronen, T. Nuutinen, S. Kyrylenko, and A. Salminen, “Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids,” British Journal of Pharmacology, vol. 141, no. 5, pp. 874–880, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. J. Julow, G. T. Szeifert, K. Bálint, I. Nyáry, and Z. Nemes, “The role of microglia/macrophage system in the tissue response to I-125 interstitial brachytherapy of cerebral gliomas,” Neurological Research, vol. 29, no. 3, pp. 233–238, 2007. View at Publisher · View at Google Scholar · View at Scopus
  111. P. A. Lodge and S. Sriram, “Regulation of microglial activation by TGF-β, IL-10, and CSF-1,” Journal of Leukocyte Biology, vol. 60, no. 4, pp. 502–508, 1996. View at Scopus
  112. A. Wesolowska, A. Kwiatkowska, L. Slomnicki et al., “Microglia-derived TGF-β as an important regulator of glioblastoma invasion—an inhibition of TGF-β-dependent effects by shRNA against human TGF-β type II receptor,” Oncogene, vol. 27, no. 7, pp. 918–930, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. Y. Kitamura, T. Taniguchi, H. Kimura, Y. Nomura, and P. J. Gebicke-Haerter, “Interleukin-4-inhibited mRNA expression in mixed rat glial and in isolated microglial cultures,” Journal of Neuroimmunology, vol. 106, no. 1-2, pp. 95–104, 2000. View at Publisher · View at Google Scholar · View at Scopus
  114. M. Liebrich, L. H. Guo, H. J. Schluesener et al., “Expression of interleukin-16 by tumor-associated macrophages/activated microglia in high-grade astrocytic brain tumors,” Archivum Immunologiae et Therapiae Experimentalis, vol. 55, no. 1, pp. 41–47, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. S. Y. Leung, M. P. Wong, L. P. Chung, A. S. Y. Chan, and S. T. Yuen, “Monocyte chemoattractant protein-1 expression and macrophage infiltration in gliomas,” Acta Neuropathologica, vol. 93, no. 5, pp. 518–527, 1997. View at Publisher · View at Google Scholar · View at Scopus
  116. M. Delgado, J. Leceta, and D. Ganea, “Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia,” Journal of Leukocyte Biology, vol. 73, no. 1, pp. 155–164, 2003. View at Publisher · View at Google Scholar · View at Scopus
  117. S. F. Hussain, L. Y. Kong, J. Jordan et al., “A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients,” Cancer Research, vol. 67, no. 20, pp. 9630–9636, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. L. Zhang, D. Alizadeh, M. van Handel, M. Kortylewski, H. Yu, and B. Badie, “Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice,” GLIA, vol. 57, no. 13, pp. 1458–1467, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. L. Zhang, W. Liu, D. Alizadeh et al., “S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway,” GLIA, vol. 59, no. 3, pp. 486–498, 2011. View at Publisher · View at Google Scholar · View at Scopus
  120. G. Fulci, L. Breymann, D. Gianni et al., “Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 34, pp. 12873–12878, 2006. View at Publisher · View at Google Scholar · View at Scopus
  121. B. Badie, J. M. Schartner, J. Paul, B. A. Bartley, J. Vorpahl, and J. K. Preston, “Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study,” Journal of Neurosurgery, vol. 93, no. 4, pp. 634–639, 2000. View at Scopus
  122. C. Lambert, A. R. Ase, P. Séguéla, and J. P. Antel, “Distinct migratory and cytokine responses of human microglia and macrophages to ATP,” Brain, Behavior, and Immunity, vol. 24, no. 8, pp. 1241–1248, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. M. H. Deininger, S. Pater, H. Strik, and R. Meyermann, “Macrophage/microglial cell subpopulations in glioblastoma multiforme relapses are differentially altered by radiochemotherapy,” Journal of Neuro-Oncology, vol. 55, no. 3, pp. 141–147, 2001. View at Publisher · View at Google Scholar · View at Scopus
  124. S. S. Kim, C. Ye, P. Kumar et al., “Targeted delivery of sirna to macrophages for anti-inflammatory treatment,” Molecular Therapy, vol. 18, no. 5, pp. 993–1001, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. J. D. Weingart, E. P. Sipos, and H. Brem, “The role of minocycline in the treatment of intracranial 9L glioma,” Journal of Neurosurgery, vol. 82, no. 4, pp. 635–640, 1995. View at Scopus
  126. A. Ghosh, J. Mukherjee, M. Bhattacharjee et al., “The other side of the coin: beneficiary effect of 'oxidative burst' upsurge with T11TS facilitates the elimination of glioma cells,” Cellular and Molecular Biology, vol. 53, no. 5, pp. 53–62, 2007. View at Publisher · View at Google Scholar · View at Scopus
  127. S. Y. Hwang, B. C. Yoo, J. W. Jung et al., “Induction of glioma apoptosis by microglia-secreted molecules: the role of nitric oxide and cathepsin B,” Biochimica et Biophysica Acta, vol. 1793, no. 11, pp. 1656–1668, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. Y. J. Kim, S. Y. Hwang, J. S. Hwang, J. W. Lee, E. S. Oh, and I. O. Han, “C6 glioma cell insoluble matrix components enhance interferon-γ-stimulated inducible nitric-oxide synthase/nitric oxide production in BV2 microglial cells,” Journal of Biological Chemistry, vol. 283, no. 5, pp. 2526–2533, 2008. View at Publisher · View at Google Scholar · View at Scopus
  129. Y. J. Kim, S. Y. Hwang, E. S. Oh, S. Oh, and I. O. Han, “IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways,” Journal of Neuroscience Research, vol. 84, no. 5, pp. 1037–1046, 2006. View at Publisher · View at Google Scholar · View at Scopus
  130. E. Ribot, A. K. Bouzier-Sore, V. Bouchaud et al., “Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy,” Cancer Gene Therapy, vol. 14, no. 8, pp. 724–737, 2007. View at Publisher · View at Google Scholar · View at Scopus
  131. R. Tréhin, J. L. Figueiredo, M. J. Pittet, R. Weissleder, L. Josephson, and U. Mahmood, “Fluorescent nanoparticle uptake for brain tumor visualization,” Neoplasia, vol. 8, no. 4, pp. 302–311, 2006. View at Publisher · View at Google Scholar · View at Scopus
  132. D. Alizadeh, L. Zhang, J. Hwang, T. Schluep, and B. Badie, “Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas,” Nanomedicine, vol. 6, no. 2, pp. 382–390, 2010.
  133. B. Kateb, M. Van Handel, L. Zhang, M. J. Bronikowski, H. Manohara, and B. Badie, “Internalization of MWCNTs by microglia: possible application in immunotherapy of brain tumors,” NeuroImage, vol. 37, supplement 1, pp. S9–S17, 2007. View at Publisher · View at Google Scholar · View at Scopus
  134. H. Jackson, O. Muhammad, H. Daneshvar et al., “Quantum dots are phagocytized by macrophages and colocalize with experimental gliomas,” Neurosurgery, vol. 60, no. 3, pp. 524–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  135. G. Fleige, C. Nolte, M. Synowitz, F. Seeberger, H. Kettenmann, and C. Zimmer, “Magnetic labeling of activated microglia in experimental gliomas,” Neoplasia, vol. 3, no. 6, pp. 489–499, 2001. View at Publisher · View at Google Scholar · View at Scopus
  136. M. J. Smyth, G. P. Dunn, and R. D. Schreiber, “Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity,” Advances in Immunology, vol. 90, pp. 1–50, 2006. View at Publisher · View at Google Scholar · View at Scopus