Advertisement

Acta Neuropathologica

, Volume 128, Issue 3, pp 347–362 | Cite as

CNS macrophages and peripheral myeloid cells in brain tumours

  • Rainer Glass
  • Michael Synowitz
Review

Abstract

Primary brain tumours (gliomas) initiate a strong host response and can contain large amounts of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages. In gliomas the course of pathology is not only controlled by the genetic make-up of the tumour cells, but also depends on the interplay with myeloid cells in the tumour microenvironment. Especially malignant gliomas such as glioblastoma multiforme (GBM) are notoriously immune-suppressive and it is now evident that GBM cells manipulate myeloid cells to support tumour expansion. The protumorigenic effects of glioma-associated myeloid cells comprise a support for angiogenesis as well as tumour cell invasion, proliferation and survival. Different strategies for inhibiting the pathological functions of myeloid cells in gliomas are explored, and blocking the tropism of microglia/macrophages to gliomas or manipulating the signal transduction pathways for immune cell activation has been successful in pre-clinical models. Hence, myeloid cells are now emerging as a promising target for new adjuvant therapies for gliomas. However, it is also becoming evident that some myeloid-directed glioma therapies may only be beneficial for distinct subclasses of gliomas and that a more cell-type-specific manipulation of either microglia or macrophages may improve therapeutic outcomes.

Keywords

Glioma Cell Microglial Cell Myeloid Cell Peripheral Immune Cell Peripheral Macrophage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Financial support for R.G. by the Deutsche Forschungsgemeinschaft (SFB824, GL691/2), Anni-Hofmann Stiftung and the German Cancer Consortium (DKTK), Heidelberg, Germany, and for M.S. by the Deutsche Forschungsgemeinschaft (SY 144/3) is gratefully acknowledged.

References

  1. 1.
    abd-el-Basset E, Fedoroff S (1995) Effect of bacterial wall lipopolysaccharide (LPS) on morphology, motility, and cytoskeletal organization of microglia in cultures. J Neurosci Res 41(2):222–237. doi: 10.1002/jnr.490410210 PubMedGoogle Scholar
  2. 2.
    Adach A, Ellert-Miklaszewska A, Kaminska B (2009) Molecular characterization of STAT signaling in inflammation and tumorigenesis. Methods Mol Biol 512:265–278. doi: 10.1007/978-1-60327-530-9_14 PubMedGoogle Scholar
  3. 3.
    Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM (2007) Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10(12):1538–1543. doi: 10.1038/nn2014 PubMedGoogle Scholar
  4. 4.
    Badhiwala J, Decker WK, Berens ME, Bhardwaj RD (2013) Clinical trials in cellular immunotherapy for brain/CNS tumors. Expert Rev Neurother 13(4):405–424. doi: 10.1586/ern.13.23 PubMedGoogle Scholar
  5. 5.
    Badie B, Schartner J (2001) Role of microglia in glioma biology. Microsc Res Tech 54(2):106–113PubMedGoogle Scholar
  6. 6.
    Badie B, Schartner J, Klaver J, Vorpahl J (1999) In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor. Neurosurgery 44 (5):1077–1082 (discussion 1082–1073)Google Scholar
  7. 7.
    Badie B, Schartner JM (2000) Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 46(4):957–961 (discussion 961–952)Google Scholar
  8. 8.
    Badie B, Schartner JM, Paul J, Bartley BA, Vorpahl J, Preston JK (2000) Dexamethasone-induced abolition of the inflammatory response in an experimental glioma model: a flow cytometry study. J Neurosurg 93(4):634–639. doi: 10.3171/jns.2000.93.4.0634 PubMedGoogle Scholar
  9. 9.
    Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103(43):16021–16026. doi: 10.1073/pnas.0607423103 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Bello L, Lucini V, Carrabba G, Giussani C, Machluf M, Pluderi M, Nikas D, Zhang J, Tomei G, Villani RM, Carroll RS, Bikfalvi A, Black PM (2001) Simultaneous inhibition of glioma angiogenesis, cell proliferation, and invasion by a naturally occurring fragment of human metalloproteinase-2. Cancer Res 61(24):8730–8736PubMedGoogle Scholar
  11. 11.
    Bettinger I, Thanos S, Paulus W (2002) Microglia promote glioma migration. Acta Neuropathol (Berl) 103(4):351–355Google Scholar
  12. 12.
    Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, Wani K, Heathcock L, James JD, Goodman LD, Conroy S, Long L, Lelic N, Wang S, Gumin J, Raj D, Kodama Y, Raghunathan A, Olar A, Joshi K, Pelloski CE, Heimberger A, Kim SH, Cahill DP, Rao G, Den Dunnen WF, Boddeke HW, Phillips HS, Nakano I, Lang FF, Colman H, Sulman EP, Aldape K (2013) Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 24(3):331–346. doi: 10.1016/j.ccr.2013.08.001 PubMedGoogle Scholar
  13. 13.
    Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, James JD, Gumin J, Diefes KL, Kim SH, Turski A, Azodi Y, Yang Y, Doucette T, Colman H, Sulman EP, Lang FF, Rao G, Copray S, Vaillant BD, Aldape KD (2011) The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev 25(24):2594–2609. doi: 10.1101/gad.176800.111 PubMedCentralPubMedGoogle Scholar
  14. 14.
    Bielamowicz K, Khawja S, Ahmed N (2013) Adoptive cell therapies for glioblastoma. Front Oncol 3:275. doi: 10.3389/fonc.2013.00275 PubMedCentralPubMedGoogle Scholar
  15. 15.
    Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57(13):2602–2605PubMedGoogle Scholar
  16. 16.
    Boche D, Perry VH, Nicoll JA (2013) Review: activation patterns of microglia and their identification in the human brain. Neuropathol Appl Neurobiol 39(1):3–18. doi: 10.1111/nan.12011 PubMedGoogle Scholar
  17. 17.
    Bradley D, Rees J (2013) Updates in the management of high-grade glioma. J Neurol. doi: 10.1007/s00415-013-7032-x PubMedGoogle Scholar
  18. 18.
    Brantley EC, Benveniste EN (2008) Signal transducer and activator of transcription-3: a molecular hub for signaling pathways in gliomas. Mol Cancer Res MCR 6(5):675–684. doi: 10.1158/1541-7786.MCR-07-2180 Google Scholar
  19. 19.
    Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, Zheng S, Chakravarty D, Sanborn JZ, Berman SH, Beroukhim R, Bernard B, Wu CJ, Genovese G, Shmulevich I, Barnholtz-Sloan J, Zou L, Vegesna R, Shukla SA, Ciriello G, Yung WK, Zhang W, Sougnez C, Mikkelsen T, Aldape K, Bigner DD, Van Meir EG, Prados M, Sloan A, Black KL, Eschbacher J, Finocchiaro G, Friedman W, Andrews DW, Guha A, Iacocca M, O’Neill BP, Foltz G, Myers J, Weisenberger DJ, Penny R, Kucherlapati R, Perou CM, Hayes DN, Gibbs R, Marra M, Mills GB, Lander E, Spellman P, Wilson R, Sander C, Weinstein J, Meyerson M, Gabriel S, Laird PW, Haussler D, Getz G, Chin L, Network TR (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. doi: 10.1016/j.cell.2013.09.034 PubMedGoogle Scholar
  20. 20.
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17(1):131–143. doi: 10.1038/nn.3599 PubMedCentralPubMedGoogle Scholar
  21. 21.
    Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, Sulman EP, Anne SL, Doetsch F, Colman H, Lasorella A, Aldape K, Califano A, Iavarone A (2010) The transcriptional network for mesenchymal transformation of brain tumours. Nature 463(7279):318–325. doi: 10.1038/nature08712 PubMedCentralPubMedGoogle Scholar
  22. 22.
    Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter JA, Tamagnone L, Mazzone M (2013) Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24(6):695–709. doi: 10.1016/j.ccr.2013.11.007 PubMedGoogle Scholar
  23. 23.
    Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149(1):36–47. doi: 10.1016/j.cell.2012.03.009 PubMedCentralPubMedGoogle Scholar
  24. 24.
    Ciechomska IA, Gabrusiewicz K, Szczepankiewicz AA, Kaminska B (2013) Endoplasmic reticulum stress triggers autophagy in malignant glioma cells undergoing cyclosporine a-induced cell death. Oncogene 32(12):1518–1529. doi: 10.1038/onc.2012.174 PubMedGoogle Scholar
  25. 25.
    Compton JJ, Laack NN, Eckel LJ, Schomas DA, Giannini C, Meyer FB (2012) Long-term outcomes for low-grade intracranial ganglioglioma: 30-year experience from the Mayo Clinic. J Neurosurg 117(5):825–830. doi: 10.3171/2012.7.JNS111260 PubMedGoogle Scholar
  26. 26.
    Coniglio SJ, Eugenin E, Dobrenis K, Stanley ER, West BL, Symons MH, Segall JE (2012) Microglial stimulation of glioblastoma invasion involves epidermal growth factor receptor (EGFR) and colony stimulating factor 1 receptor (CSF-1R) signaling. Mol Med 18:519–527. doi: 10.2119/molmed.2011.00217 PubMedCentralPubMedGoogle Scholar
  27. 27.
    Cooper LA, Gutman DA, Chisolm C, Appin C, Kong J, Rong Y, Kurc T, Van Meir EG, Saltz JH, Moreno CS, Brat DJ (2012) The tumor microenvironment strongly impacts master transcriptional regulators and gene expression class of glioblastoma. Am J Pathol 180(5):2108–2119. doi: 10.1016/j.ajpath.2012.01.040 PubMedCentralPubMedGoogle Scholar
  28. 28.
    Csoka B, Selmeczy Z, Koscso B, Nemeth ZH, Pacher P, Murray PJ, Kepka-Lenhart D, Morris SM Jr, Gause WC, Leibovich SJ, Hasko G (2012) Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J Off Publ Federation Am Soc Exp Biol 26(1):376–386. doi: 10.1096/fj.11-190934 Google Scholar
  29. 29.
    Cunningham CL, Martinez-Cerdeno V, Noctor SC (2013) Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci Off J Soc Neurosci 33(10):4216–4233. doi: 10.1523/JNEUROSCI.3441-12.2013 Google Scholar
  30. 30.
    Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758. doi: 10.1038/nn1472 PubMedGoogle Scholar
  31. 31.
    del Río-Hortega P (1921) Sobre la fagocitosis en los tumores y en otros procesos patológicos. In: Río-Hortega Pd (ed) Archivos de Cardiología y Hematología, vol 2, pp 161–220Google Scholar
  32. 32.
    Diserbo M, Agin A, Lamproglou I, Mauris J, Staali F, Multon E, Amourette C (2002) Blood-brain barrier permeability after gamma whole-body irradiation: an in vivo microdialysis study. Can J Physiol Pharmacol 80(7):670–678PubMedGoogle Scholar
  33. 33.
    Dityatev A, Seidenbecher CI, Schachner M (2010) Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain. Trends Neurosci 33(11):503–512. doi: 10.1016/j.tins.2010.08.003 PubMedGoogle Scholar
  34. 34.
    Doucette T, Rao G, Rao A, Shen L, Aldape K, Wei J, Dziurzynski K, Gilbert M, Heimberger AB (2013) Immune heterogeneity of glioblastoma subtypes: extrapolation from the cancer genome atlas. Cancer Immunol Res 1(112). doi: 10.1158/2326-6066.CIR-13-0028
  35. 35.
    Ebert S, Gerber J, Bader S, Muhlhauser F, Brechtel K, Mitchell TJ, Nau R (2005) Dose-dependent activation of microglial cells by Toll-like receptor agonists alone and in combination. J Neuroimmunol 159(1–2):87–96. doi: 10.1016/j.jneuroim.2004.10.005 PubMedGoogle Scholar
  36. 36.
    El Andaloussi A, Sonabend AM, Han Y, Lesniak MS (2006) Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors. Glia 54(6):526–535. doi: 10.1002/glia.20401 PubMedGoogle Scholar
  37. 37.
    Ellert-Miklaszewska A, Dabrowski M, Lipko M, Sliwa M, Maleszewska M, Kaminska B (2013) Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia. Glia 61(7):1178–1190. doi: 10.1002/glia.22510 PubMedGoogle Scholar
  38. 38.
    Engler JR, Robinson AE, Smirnov I, Hodgson JG, Berger MS, Gupta N, James CD, Molinaro A, Phillips JJ (2012) Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS ONE 7(8):e43339. doi: 10.1371/journal.pone.0043339 PubMedCentralPubMedGoogle Scholar
  39. 39.
    Flugel A, Labeur MS, Grasbon-Frodl EM, Kreutzberg GW, Graeber MB (1999) Microglia only weakly present glioma antigen to cytotoxic T cells. Int J Dev Neurosci Off J Int Soc Dev Neurosci 17(5–6):547–556Google Scholar
  40. 40.
    Ford AL, Foulcher E, Lemckert FA, Sedgwick JD (1996) Microglia induce CD4 T lymphocyte final effector function and death. J Exp Med 184(5):1737–1745PubMedGoogle Scholar
  41. 41.
    Franke H, Verkhratsky A, Burnstock G, Illes P (2012) Pathophysiology of astroglial purinergic signalling. Purinergic Signal 8(3):629–657. doi: 10.1007/s11302-012-9300-0 PubMedCentralPubMedGoogle Scholar
  42. 42.
    Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM (2012) Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338(6110):1080–1084. doi: 10.1126/science.1226929 PubMedCentralPubMedGoogle Scholar
  43. 43.
    Gabrusiewicz K, Ellert-Miklaszewska A, Lipko M, Sielska M, Frankowska M, Kaminska B (2011) Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS ONE 6(8):e23902. doi: 10.1371/journal.pone.0023902 PubMedCentralPubMedGoogle Scholar
  44. 44.
    Galarneau H, Villeneuve J, Gowing G, Julien JP, Vallieres L (2007) Increased glioma growth in mice depleted of macrophages. Cancer Res 67(18):8874–8881. doi: 10.1158/0008-5472.CAN-07-0177 PubMedGoogle Scholar
  45. 45.
    Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005):841–845. doi: 10.1126/science.1194637 PubMedCentralPubMedGoogle Scholar
  46. 46.
    Goldmann T, Wieghofer P, Muller PF, Wolf Y, Varol D, Yona S, Brendecke SM, Kierdorf K, Staszewski O, Datta M, Luedde T, Heikenwalder M, Jung S, Prinz M (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16(11):1618–1626. doi: 10.1038/nn.3531 PubMedGoogle Scholar
  47. 47.
    Gomez Perdiguero E, Schulz C, Geissmann F (2013) Development and homeostasis of “resident” myeloid cells: the case of the microglia. Glia 61(1):112–120. doi: 10.1002/glia.22393 PubMedGoogle Scholar
  48. 48.
    Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40(2):252–259PubMedGoogle Scholar
  49. 49.
    Grauer OM, Molling JW, Bennink E, Toonen LW, Sutmuller RP, Nierkens S, Adema GJ (2008) TLR ligands in the local treatment of established intracerebral murine gliomas. J Immunol 181(10):6720–6729PubMedGoogle Scholar
  50. 50.
    Hanisch UK (2013) Proteins in microglial activation–inputs and outputs by subsets. Curr Protein Pept Sci 14(1):3–15PubMedGoogle Scholar
  51. 51.
    Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi: 10.1038/nn1997 PubMedGoogle Scholar
  52. 52.
    Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci USA 95(18):10896–10901PubMedCentralPubMedGoogle Scholar
  53. 53.
    Hart AD, Wyttenbach A, Perry VH, Teeling JL (2012) Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav Immun 26(5):754–765. doi: 10.1016/j.bbi.2011.11.006 PubMedCentralPubMedGoogle Scholar
  54. 54.
    Hasko G, Cronstein BN (2004) Adenosine: an endogenous regulator of innate immunity. Trends Immunol 25(1):33–39PubMedGoogle Scholar
  55. 55.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. New Engl J Med 352(10):997–1003. doi: 10.1056/NEJMoa043331 PubMedGoogle Scholar
  56. 56.
    Heimberger AB, Sampson JH (2011) Immunotherapy coming of age: what will it take to make it standard of care for glioblastoma? Neuro Oncol 13(1):3–13. doi: 10.1093/neuonc/noq169 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Held-Feindt J, Hattermann K, Muerkoster SS, Wedderkopp H, Knerlich-Lukoschus F, Ungefroren H, Mehdorn HM, Mentlein R (2010) CX3CR1 promotes recruitment of human glioma-infiltrating microglia/macrophages (GIMs). Exp Cell Res 316(9):1553–1566. doi: 10.1016/j.yexcr.2010.02.018 PubMedGoogle Scholar
  58. 58.
    Herculano-Houzel S (2009) The human brain in numbers: a linearly scaled-up primate brain. Front Hum Neurosci 3:31. doi: 10.3389/neuro.09.031.2009 PubMedCentralPubMedGoogle Scholar
  59. 59.
    Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–1905. doi: 10.1038/nn.3554 PubMedGoogle Scholar
  60. 60.
    Hussain SF, Kong LY, Jordan J, Conrad C, Madden T, Fokt I, Priebe W, Heimberger AB (2007) A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Res 67(20):9630–9636. doi: 10.1158/0008-5472.CAN-07-1243 PubMedGoogle Scholar
  61. 61.
    Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8(3):261–279. doi: 10.1215/15228517-2006-008 PubMedCentralPubMedGoogle Scholar
  62. 62.
    Ishihara H, Kubota H, Lindberg RL, Leppert D, Gloor SM, Errede M, Virgintino D, Fontana A, Yonekawa Y, Frei K (2008) Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor beta2 involves matrix metalloproteinases and tight junction proteins. J Neuropathol Exp Neurol 67(5):435–448. doi: 10.1097/NEN.0b013e31816fd622 PubMedGoogle Scholar
  63. 63.
    Jack CS, Arbour N, Manusow J, Montgrain V, Blain M, McCrea E, Shapiro A, Antel JP (2005) TLR signaling tailors innate immune responses in human microglia and astrocytes. J Immunol 175(7):4320–4330PubMedGoogle Scholar
  64. 64.
    Jacobs VL, Landry RP, Liu Y, Romero-Sandoval EA, De Leo JA (2012) Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro Oncol 14(2):119–131. doi: 10.1093/neuonc/nor194 PubMedCentralPubMedGoogle Scholar
  65. 65.
    Janicki CN, Jenkinson SR, Williams NA, Morgan DJ (2008) Loss of CTL function among high-avidity tumor-specific CD8 + T cells following tumor infiltration. Cancer Res 68(8):2993–3000. doi: 10.1158/0008-5472.CAN-07-5008 PubMedGoogle Scholar
  66. 66.
    Jansen T, Tyler B, Mankowski JL, Recinos VR, Pradilla G, Legnani F, Laterra J, Olivi A (2010) FasL gene knock-down therapy enhances the antiglioma immune response. Neuro Oncol 12(5):482–489. doi: 10.1093/neuonc/nop052 PubMedCentralPubMedGoogle Scholar
  67. 67.
    Jantaratnotai N, Choi HB, McLarnon JG (2009) ATP stimulates chemokine production via a store-operated calcium entry pathway in C6 glioma cells. BMC Cancer 9:442. doi: 10.1186/1471-2407-9-442 PubMedCentralPubMedGoogle Scholar
  68. 68.
    Joseph J, Knobler RL, D’Imperio C, Lublin FD (1988) Down-regulation of interferon-gamma-induced class II expression on human glioma cells by recombinant interferon-beta: effects of dosage treatment schedule. J Neuroimmunol 20(1):39–44PubMedGoogle Scholar
  69. 69.
    Kaminska B, Kocyk M, Kijewska M (2013) TGF beta signaling and its role in glioma pathogenesis. Adv Exp Med Biol 986:171–187. doi: 10.1007/978-94-007-4719-7_9 PubMedGoogle Scholar
  70. 70.
    Kaneko YS, Ota A, Nakashima A, Mori K, Nagatsu I, Nagatsu T (2012) Regulation of oxidative stress in long-lived lipopolysaccharide-activated microglia. Clin Exp Pharmacol Physiol 39(7):599–607. doi: 10.1111/j.1440-1681.2012.05716.x PubMedGoogle Scholar
  71. 71.
    Kees T, Lohr J, Noack J, Mora R, Gdynia G, Todt G, Ernst A, Radlwimmer B, Falk CS, Herold-Mende C, Regnier-Vigouroux A (2012) Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation. Neuro Oncol 14(1):64–78. doi: 10.1093/neuonc/nor182 PubMedCentralPubMedGoogle Scholar
  72. 72.
    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91(2):461–553. doi: 10.1152/physrev.00011.2010 PubMedGoogle Scholar
  73. 73.
    Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18. doi: 10.1016/j.neuron.2012.12.023 PubMedGoogle Scholar
  74. 74.
    Kierdorf K, Erny D, Goldmann T, Sander V, Schulz C, Perdiguero EG, Wieghofer P, Heinrich A, Riemke P, Holscher C, Muller DN, Luckow B, Brocker T, Debowski K, Fritz G, Opdenakker G, Diefenbach A, Biber K, Heikenwalder M, Geissmann F, Rosenbauer F, Prinz M (2013) Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 16(3):273–280. doi: 10.1038/nn.3318 PubMedGoogle Scholar
  75. 75.
    Kim J, Hajjar KA (2002) Annexin II: a plasminogen–plasminogen activator co-receptor. Front Biosci J Virtual Libr 7:d341–d348Google Scholar
  76. 76.
    Kleihues PB, Burger PC, Scheithauer BW (1996) Histological typing of the tumours of the central nervous system. International histological classification of tumours, 2nd edn. Springer, StuttgartGoogle Scholar
  77. 77.
    Kloss CU, Bohatschek M, Kreutzberg GW, Raivich G (2001) Effect of lipopolysaccharide on the morphology and integrin immunoreactivity of ramified microglia in the mouse brain and in cell culture. Exp Neurol 168(1):32–46. doi: 10.1006/exnr.2000.7575 PubMedGoogle Scholar
  78. 78.
    Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K, Hirakawa A, Takeuchi H, Suzumura A, Ishiguro N, Kadomatsu K (2013) Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis 4:e525. doi: 10.1038/cddis.2013.54 PubMedCentralPubMedGoogle Scholar
  79. 79.
    Komohara Y, Ohnishi K, Kuratsu J, Takeya M (2008) Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 216(1):15–24. doi: 10.1002/path.2370 PubMedGoogle Scholar
  80. 80.
    Kortylewski M, Kujawski M, Wang T, Wei S, Zhang S, Pilon-Thomas S, Niu G, Kay H, Mule J, Kerr WG, Jove R, Pardoll D, Yu H (2005) Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11(12):1314–1321. doi: 10.1038/nm1325 PubMedGoogle Scholar
  81. 81.
    Ku MC, Wolf SA, Respondek D, Matyash V, Pohlmann A, Waiczies S, Waiczies H, Niendorf T, Synowitz M, Glass R, Kettenmann H (2013) GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis. Acta Neuropathol 125(4):609–620. doi: 10.1007/s00401-013-1079-8 PubMedGoogle Scholar
  82. 82.
    Kurpad SN, Wikstrand CJ, Bigner DD (1994) Immunobiology of malignant astrocytomas. Semin Oncol 21(2):149–161PubMedGoogle Scholar
  83. 83.
    Lakka SS, Gondi CS, Rao JS (2005) Proteases and glioma angiogenesis. Brain Pathol 15(4):327–341PubMedGoogle Scholar
  84. 84.
    Lawson LJ, Perry VH, Dri P, Gordon S (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–170PubMedGoogle Scholar
  85. 85.
    Li B, Senbabaoglu Y, Peng W, Yang ML, Xu J, Li JZ (2012) Genomic estimates of aneuploid content in glioblastoma multiforme and improved classification. Clinical Cancer Res Off J Am Assoc Cancer Res 18(20):5595–5605. doi: 10.1158/1078-0432.CCR-12-1427 Google Scholar
  86. 86.
    Linden J (2006) Adenosine metabolism and cancer. Focus on “Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatases and reducing ERK1/2 activity via a novel pathway”. Am J Physiol Cell Physiol 291(3):C405–C406. doi: 10.1152/ajpcell.00242.2006 PubMedGoogle Scholar
  87. 87.
    Liu C, Luo D, Streit WJ, Harrison JK (2008) CX3CL1 and CX3CR1 in the GL261 murine model of glioma: CX3CR1 deficiency does not impact tumor growth or infiltration of microglia and lymphocytes. J Neuroimmunol 198(1–2):98–105. doi: 10.1016/j.jneuroim.2008.04.016 PubMedCentralPubMedGoogle Scholar
  88. 88.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. doi: 10.1007/s00401-007-0243-4 PubMedCentralPubMedGoogle Scholar
  89. 89.
    Luongo L, Guida F, Imperatore R, Napolitano F, Gatta L, Cristino L, Giordano C, Siniscalco D, Di Marzo V, Bellini G, Petrelli R, Cappellacci L, Usiello A, de Novellis V, Rossi F, Maione S (2014) The A1 adenosine receptor as a new player in microglia physiology. Glia 62(1):122–132. doi: 10.1002/glia.22592 PubMedGoogle Scholar
  90. 90.
    Machein MR, Renninger S, de Lima-Hahn E, Plate KH (2003) Minor contribution of bone marrow-derived endothelial progenitors to the vascularization of murine gliomas. Brain Pathol 13(4):582–597PubMedGoogle Scholar
  91. 91.
    Mark R. Gilbert JD, Minhee Won, Deborah T. Blumenthal, Michael A. Vogelbaum, Kenneth D. Aldape, Howard Colman, Arnab Chakravarti, Robert Jeraj, Terri S. Armstrong, Jeffrey Scott Wefel, Paul D. Brown, Kurt A. Jaeckle, David Schiff, James Norman Atkins, David Brachman, Maria Werner-Wasik, Ritsuko Komaki, Erik P. Sulman, Minesh P. Mehta; University of Texas MD Anderson Cancer Center Department of Neuro-Oncology, Houston, TX; Radiation Therapy Oncology Group, Philadelphia, PA; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Cleveland Clinic Foundation, Cleveland, OH; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Utah, Huntsman Cancer Institute, Salt Lake City, UT; Arthur G. James Cancer Center, The Ohio State University, Columbus, OH; Department of Medical Physics, University of Wisconsin, Madison, WI; University of Texas Health Science Center School of Nursing, Houston, TX; Mayo Clinic, Jacksonville, FL; University of Virginia Medical Center, Charlottesville, VA; National Surgical Adjuvant Breast and Bowel Project and SCCC-CCOP, Goldboro, NC; Arizona Oncology Services Foundation, Phoenix, AZ; Thomas Jefferson University Hospital, Philadelphia, PA; University of Maryland, Baltimore, MD (2013) RTOG 0825: Phase III double-blind, placebo-controlled trial evaluating bevacizumab in patiens with newly diagnosed glioblastoma. Paper presented at the ASCO Annual MeetingGoogle Scholar
  92. 92.
    Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H (2005) Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol 64(9):754–762PubMedGoogle Scholar
  93. 93.
    Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kalin R, van Rooijen N, Holmbeck K, Heppner FL, Kiwit J, Matyash V, Lehnardt S, Kaminska B, Glass R, Kettenmann H (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA 106(30):12530–12535. doi: 10.1073/pnas.0804273106 PubMedCentralPubMedGoogle Scholar
  94. 94.
    Markovic DS, Vinnakota K, van Rooijen N, Kiwit J, Synowitz M, Glass R, Kettenmann H (2011) Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression. Brain Behav Immun 25(4):624–628. doi: 10.1016/j.bbi.2011.01.015 PubMedGoogle Scholar
  95. 95.
    Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M (2007) Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 10(12):1544–1553. doi: 10.1038/nn2015 PubMedGoogle Scholar
  96. 96.
    Morioka T, Baba T, Black KL, Streit WJ (1992) Response of microglial cells to experimental rat glioma. Glia 6(1):75–79. doi: 10.1002/glia.440060110 PubMedGoogle Scholar
  97. 97.
    Mosieniak G, Figiel I, Kaminska B (1997) Cyclosporin A, an immunosuppressive drug, induces programmed cell death in rat C6 glioma cells by a mechanism that involves the AP-1 transcription factor. J Neurochem 68(3):1142–1149PubMedGoogle Scholar
  98. 98.
    Naganuma H, Sasaki A, Satoh E, Nagasaka M, Nakano S, Isoe S, Nukui H (1998) Down-regulation of transforming growth factor-beta and interleukin-10 secretion from malignant glioma cells by cytokines and anticancer drugs. J Neurooncol 39(3):227–236PubMedGoogle Scholar
  99. 99.
    Nakano Y, Kuroda E, Kito T, Uematsu S, Akira S, Yokota A, Nishizawa S, Yamashita U (2008) Induction of prostaglandin E2 synthesis and microsomal prostaglandin E synthase-1 expression in murine microglia by glioma-derived soluble factors. Laboratory investigation. J Neurosurg 108(2):311–319. doi: 10.3171/JNS/2008/108/2/0311 PubMedGoogle Scholar
  100. 100.
    Nieto MA (2011) The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 27:347–376. doi: 10.1146/annurev-cellbio-092910-154036 PubMedGoogle Scholar
  101. 101.
    Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. doi: 10.1126/science.1110647 PubMedGoogle Scholar
  102. 102.
    Nishie A, Ono M, Shono T, Fukushi J, Otsubo M, Onoue H, Ito Y, Inamura T, Ikezaki K, Fukui M, Iwaki T, Kuwano M (1999) Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas. Clin Cancer Res Off J Am Assoc Cancer Res 5(5):1107–1113Google Scholar
  103. 103.
    Norden AD, Drappatz J, Wen PY (2009) Antiangiogenic therapies for high-grade glioma. Nat Rev Neurol 5(11):610–620. doi: 10.1038/nrneurol.2009.159 PubMedGoogle Scholar
  104. 104.
    Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453PubMedCentralPubMedGoogle Scholar
  105. 105.
    Ohnishi T, Matsumura H, Izumoto S, Hiraga S, Hayakawa T (1998) A novel model of glioma cell invasion using organotypic brain slice culture. Cancer Res 58(14):2935–2940PubMedGoogle Scholar
  106. 106.
    Okada M, Saio M, Kito Y, Ohe N, Yano H, Yoshimura S, Iwama T, Takami T (2009) Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1. Int J Oncol 34(6):1621–1627PubMedGoogle Scholar
  107. 107.
    Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA J Am Med Assoc 310(17):1842–1850. doi: 10.1001/jama.2013.280319 Google Scholar
  108. 108.
    Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, Stroup NE, Kruchko C, Barnholtz-Sloan JS (2013) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol 15(Suppl 2):ii1–ii56. doi: 10.1093/neuonc/not151 Google Scholar
  109. 109.
    Pagano M, Reboud-Ravaux M (2011) Cryptic activities of fibronectin fragments, particularly cryptic proteases. Front Biosci (Landmark Ed) 16:698–706Google Scholar
  110. 110.
    Paolicelli RC, Gross CT (2011) Microglia in development: linking brain wiring to brain environment. Neuron Glia Biol 7(1):77–83. doi: 10.1017/S1740925X12000105 PubMedGoogle Scholar
  111. 111.
    Parney IF, Waldron JS, Parsa AT (2009) Flow cytometry and in vitro analysis of human glioma-associated macrophages. Laboratory investigation. J Neurosurg 110(3):572–582. doi: 10.3171/2008.7.JNS08475 PubMedCentralPubMedGoogle Scholar
  112. 112.
    Penfield W (1925) Microglia and the process of phagocytosis in gliomas. Am J Pathol 1(1):77–90PubMedCentralPubMedGoogle Scholar
  113. 113.
    Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, Cuartas I, Garcia-Dorado D, Poca MA, Sahuquillo J, Baselga J, Seoane J (2009) TGF-beta increases glioma-initiating cell self-renewal through the induction of LIF in human glioblastoma. Cancer Cell 15(4):315–327. doi: 10.1016/j.ccr.2009.02.011 PubMedGoogle Scholar
  114. 114.
    Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9(3):157–173PubMedGoogle Scholar
  115. 115.
    Piao Y, Liang J, Holmes L, Henry V, Sulman E, de Groot JF (2013) Acquired resistance to anti-VEGF therapy in glioblastoma is associated with a mesenchymal transition. Clin Cancer Res Off J Am Assoc Cancer Res 19(16):4392–4403. doi: 10.1158/1078-0432.CCR-12-1557 Google Scholar
  116. 116.
    Piao Y, Liang J, Holmes L, Zurita AJ, Henry V, Heymach JV, de Groot JF (2012) Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol 14(11):1379–1392. doi: 10.1093/neuonc/nos158 PubMedCentralPubMedGoogle Scholar
  117. 117.
    Platten M, Kretz A, Naumann U, Aulwurm S, Egashira K, Isenmann S, Weller M (2003) Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas. Ann Neurol 54(3):388–392PubMedGoogle Scholar
  118. 118.
    Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U (2001) Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 7(12):1356–1361. doi: 10.1038/nm1201-1356 PubMedGoogle Scholar
  119. 119.
    Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, Olson OC, Quick ML, Huse JT, Teijeiro V, Setty M, Leslie CS, Oei Y, Pedraza A, Zhang J, Brennan CW, Sutton JC, Holland EC, Daniel D, Joyce JA (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19(10):1264–1272. doi: 10.1038/nm.3337 PubMedGoogle Scholar
  120. 120.
    Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51. doi: 10.1016/j.cell.2010.03.014 PubMedGoogle Scholar
  121. 121.
    Qin H, Yeh WI, De Sarno P, Holdbrooks AT, Liu Y, Muldowney MT, Reynolds SL, Yanagisawa LL, Fox TH 3rd, Park K, Harrington LE, Raman C, Benveniste EN (2012) Signal transducer and activator of transcription-3/suppressor of cytokine signaling-3 (STAT3/SOCS3) axis in myeloid cells regulates neuroinflammation. Proc Natl Acad Sci USA 109(13):5004–5009. doi: 10.1073/pnas.1117218109 PubMedCentralPubMedGoogle Scholar
  122. 122.
    Raivich G (2005) Like cops on the beat: the active role of resting microglia. Trends Neurosci 28(11):571–573. doi: 10.1016/j.tins.2005.09.001 PubMedGoogle Scholar
  123. 123.
    Ramanathan M, Pinhal-Enfield G, Hao I, Leibovich SJ (2007) Synergistic up-regulation of vascular endothelial growth factor (VEGF) expression in macrophages by adenosine A2A receptor agonists and endotoxin involves transcriptional regulation via the hypoxia response element in the VEGF promoter. Mol Biol Cell 18(1):14–23. doi: 10.1091/mbc.E06-07-0596 PubMedCentralPubMedGoogle Scholar
  124. 124.
    Ransohoff RM, Engelhardt B (2012) The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol 12(9):623–635. doi: 10.1038/nri3265 PubMedGoogle Scholar
  125. 125.
    Ribes S, Adam N, Schutze S, Regen T, Redlich S, Janova H, Borisch A, Hanisch UK, Nau R (2012) The nucleotide-binding oligomerization domain-containing-2 ligand muramyl dipeptide enhances phagocytosis and intracellular killing of Escherichia coli K1 by Toll-like receptor agonists in microglial cells. J Neuroimmunol 252(1–2):16–23. doi: 10.1016/j.jneuroim.2012.07.012 PubMedGoogle Scholar
  126. 126.
    Roggendorf W, Strupp S, Paulus W (1996) Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol (Berl) 92(3):288–293Google Scholar
  127. 127.
    Rolle CE, Sengupta S, Lesniak MS (2012) Mechanisms of immune evasion by gliomas. Adv Exp Med Biol 746:53–76. doi: 10.1007/978-1-4614-3146-6_5 PubMedGoogle Scholar
  128. 128.
    Rutka JT, Apodaca G, Stern R, Rosenblum M (1988) The extracellular matrix of the central and peripheral nervous systems: structure and function. J Neurosurg 69(2):155–170. doi: 10.3171/jns.1988.69.2.0155 PubMedGoogle Scholar
  129. 129.
    Sahm F, Oezen I, Opitz CA, Radlwimmer B, von Deimling A, Ahrendt T, Adams S, Bode HB, Guillemin GJ, Wick W, Platten M (2013) The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer Res 73(11):3225–3234. doi: 10.1158/0008-5472.CAN-12-3831 PubMedGoogle Scholar
  130. 130.
    Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11(11):775–787. doi: 10.1038/nri3086 PubMedGoogle Scholar
  131. 131.
    Sanai N, Berger MS (2012) Recent surgical management of gliomas. Adv Exp Med Biol 746:12–25. doi: 10.1007/978-1-4614-3146-6_2 PubMedGoogle Scholar
  132. 132.
    Sarkar S, Doring A, Zemp FJ, Silva C, Lun X, Wang X, Kelly J, Hader W, Hamilton M, Mercier P, Dunn JF, Kinniburgh D, van Rooijen N, Robbins S, Forsyth P, Cairncross G, Weiss S, Yong VW (2014) Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nat Neurosci 17(1):46–55. doi: 10.1038/nn.3597 PubMedGoogle Scholar
  133. 133.
    Schartner JM, Hagar AR, Van Handel M, Zhang L, Nadkarni N, Badie B (2005) Impaired capacity for upregulation of MHC class II in tumor-associated microglia. Glia 51(4):279–285. doi: 10.1002/glia.20201 PubMedGoogle Scholar
  134. 134.
    Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J, Liu KJ, Geissmann F (2012) A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336(6077):86–90. doi: 10.1126/science.1219179 PubMedGoogle Scholar
  135. 135.
    Schwaighofer H, Kernan NA, O’Reilly RJ, Brankova J, Nachbaur D, Herold M, Eibl B, Niederwieser D (1996) Serum levels of cytokines and secondary messages after T-cell-depleted and non-T-cell-depleted bone marrow transplantation: influence of conditioning and hematopoietic reconstitution. Transplantation 62(7):947–953PubMedGoogle Scholar
  136. 136.
    Seiki M (2003) Membrane-type 1 matrix metalloproteinase: a key enzyme for tumor invasion. Cancer Lett 194(1):1–11. S0304383502006997 [pii]Google Scholar
  137. 137.
    Sengupta S, Marrinan J, Frishman C, Sampath P (2012) Impact of temozolomide on immune response during malignant glioma chemotherapy. Clin Dev Immunol 2012:831090. doi: 10.1155/2012/831090 PubMedCentralPubMedGoogle Scholar
  138. 138.
    Shechter R, Schwartz M (2013) Harnessing monocyte-derived macrophages to control central nervous system pathologies: no longer ‘if’ but ‘how’. J Pathol 229(2):332–346. doi: 10.1002/path.4106 PubMedGoogle Scholar
  139. 139.
    Shinonaga M, Chang CC, Suzuki N, Sato M, Kuwabara T (1988) Immunohistological evaluation of macrophage infiltrates in brain tumors. Correlation with peritumoral edema. J Neurosurg 68(2):259–265. doi: 10.3171/jns.1988.68.2.0259 PubMedGoogle Scholar
  140. 140.
    Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42(6):717–727. doi: 10.1016/j.ejca.2006.01.003 PubMedGoogle Scholar
  141. 141.
    Sielska M, Przanowski P, Wylot B, Gabrusiewicz K, Maleszewska M, Kijewska M, Zawadzka M, Kucharska J, Vinnakota K, Kettenmann H, Kotulska K, Grajkowska W, Kaminska B (2013) Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. J Pathol 230(3):310–321. doi: 10.1002/path.4192 PubMedGoogle Scholar
  142. 142.
    Sliwa M, Markovic D, Gabrusiewicz K, Synowitz M, Glass R, Zawadzka M, Wesolowska A, Kettenmann H, Kaminska B (2007) The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A. Brain J Neurol 130(Pt 2):476–489Google Scholar
  143. 143.
    Sonabend AM, Rolle CE, Lesniak MS (2008) The role of regulatory T cells in malignant glioma. Anticancer Res 28(2B):1143–1150PubMedGoogle Scholar
  144. 144.
    Streit WJ (1994) Cellular immune response in brain tumors. Neuropathol Appl Neurobiol 20(2):205–206PubMedGoogle Scholar
  145. 145.
    Suzumura A, Sawada M, Yamamoto H, Marunouchi T (1993) Transforming growth factor-beta suppresses activation and proliferation of microglia in vitro. J Immunol 151(4):2150–2158PubMedGoogle Scholar
  146. 146.
    Synowitz M, Glass R, Farber K, Markovic D, Kronenberg G, Herrmann K, Schnermann J, Nolte C, van Rooijen N, Kiwit J, Kettenmann H (2006) A1 adenosine receptors in microglia control glioblastoma-host interaction. Cancer Res 66(17):8550–8557PubMedGoogle Scholar
  147. 147.
    Tabatabai G, Bahr O, Mohle R, Eyupoglu IY, Boehmler AM, Wischhusen J, Rieger J, Blumcke I, Weller M, Wick W (2005) Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain J Neurol 128(Pt 9):2200–2211. doi: 10.1093/brain/awh563 Google Scholar
  148. 148.
    Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, Zheng W, Franco CA, Murtomaki A, Aranda E, Miura N, Yla-Herttuala S, Fruttiger M, Makinen T, Eichmann A, Pollard JW, Gerhardt H, Alitalo K (2011) VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 13(10):1202–1213. doi: 10.1038/ncb2331 PubMedCentralPubMedGoogle Scholar
  149. 149.
    Tatter SB (2002) Recurrent malignant glioma in adults. Curr Treat Options Oncol 3(6):509–524PubMedGoogle Scholar
  150. 150.
    van Hinsbergh VW, Koolwijk P (2008) Endothelial sprouting and angiogenesis: matrix metalloproteinases in the lead. Cardiovasc Res 78(2):203–212. doi: 10.1093/cvr/cvm102 PubMedGoogle Scholar
  151. 151.
    Veeravagu A, Jiang B, Ludwig C, Chang SD, Black KL, Patil CG (2013) Biopsy versus resection for the management of low-grade gliomas. Cochrane Database Systematic Rev 4:CD009319. doi: 10.1002/14651858.CD009319.pub2
  152. 152.
    Vega EA, Graner MW, Sampson JH (2008) Combating immunosuppression in glioma. Future Oncol 4(3):433–442. doi: 10.2217/14796694.4.3.433 PubMedCentralPubMedGoogle Scholar
  153. 153.
    Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110. doi: 10.1016/j.ccr.2009.12.020 PubMedCentralPubMedGoogle Scholar
  154. 154.
    Vince GH, Wagner S, Pietsch T, Klein R, Goldbrunner RH, Roosen K, Tonn JC (1999) Heterogeneous regional expression patterns of matrix metalloproteinases in human malignant gliomas. Int J Dev Neurosci Off J Int Soc Dev Neurosci 17(5–6):437–445Google Scholar
  155. 155.
    Vinnakota K, Hu F, Ku MC, Georgieva PB, Szulzewsky F, Pohlmann A, Waiczies S, Waiczies H, Niendorf T, Lehnardt S, Hanisch UK, Synowitz M, Markovic D, Wolf SA, Glass R, Kettenmann H (2013) Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion. Neuro Oncol. doi: 10.1093/neuonc/not115 PubMedGoogle Scholar
  156. 156.
    Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839. doi: 10.1161/01.RES.0000070112.80711.3D PubMedGoogle Scholar
  157. 157.
    Vukovic J, Colditz MJ, Blackmore DG, Ruitenberg MJ, Bartlett PF (2012) Microglia modulate hippocampal neural precursor activity in response to exercise and aging. J Neurosci Off J Soc Neurosci 32(19):6435–6443. doi: 10.1523/JNEUROSCI.5925-11.2012 Google Scholar
  158. 158.
    Wagner S, Czub S, Greif M, Vince GH, Suss N, Kerkau S, Rieckmann P, Roggendorf W, Roosen K, Tonn JC (1999) Microglial/macrophage expression of interleukin 10 in human glioblastomas. Int J Cancer J 82(1):12–16Google Scholar
  159. 159.
    Wainwright DA, Dey M, Chang A, Lesniak MS (2013) Targeting tregs in malignant brain cancer: overcoming IDO. Front Immunol 4:116. doi: 10.3389/fimmu.2013.00116 PubMedCentralPubMedGoogle Scholar
  160. 160.
    Walker C, Baborie A, Crooks D, Wilkins S, Jenkinson MD (2011) Biology, genetics and imaging of glial cell tumours. Br J Radiol 84 Spec No 2:S90–S106. doi: 10.1259/bjr/23430927
  161. 161.
    Wang SC, Hong JH, Hsueh C, Chiang CS (2012) Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model. Lab Investig J Tech Methods Pathol 92(1):151–162. doi: 10.1038/labinvest.2011.128 Google Scholar
  162. 162.
    Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81(3):447–455PubMedGoogle Scholar
  163. 163.
    Wei J, Gabrusiewicz K, Heimberger A (2013) The controversial role of microglia in malignant gliomas. Clin Dev Immunol 2013:285246. doi: 10.1155/2013/285246 PubMedCentralPubMedGoogle Scholar
  164. 164.
    Wei J, Wang F, Kong LY, Xu S, Doucette T, Ferguson SD, Yang Y, McEnery K, Jethwa K, Gjyshi O, Qiao W, Levine NB, Lang FF, Rao G, Fuller GN, Calin GA, Heimberger AB (2013) miR-124 inhibits STAT3 signaling to enhance T cell-mediated immune clearance of glioma. Cancer Res 73(13):3913–3926. doi: 10.1158/0008-5472.CAN-12-4318 PubMedCentralPubMedGoogle Scholar
  165. 165.
    Wesolowska A, Kwiatkowska A, Slomnicki L, Dembinski M, Master A, Sliwa M, Franciszkiewicz K, Chouaib S, Kaminska B (2008) Microglia-derived TGF-beta as an important regulator of glioblastoma invasion—an inhibition of TGF-beta-dependent effects by shRNA against human TGF-beta type II receptor. Oncogene 27(7):918–930. doi: 10.1038/sj.onc.1210683 PubMedGoogle Scholar
  166. 166.
    Wessels PH, Weber WE, Raven G, Ramaekers FC, Hopman AH, Twijnstra A (2003) Supratentorial grade II astrocytoma: biological features and clinical course. Lancet Neurol 2(7):395–403PubMedGoogle Scholar
  167. 167.
    Wick W, Naumann U, Weller M (2006) Transforming growth factor-beta: a molecular target for the future therapy of glioblastoma. Curr Pharm Des 12(3):341–349PubMedGoogle Scholar
  168. 168.
    Ye XZ, Xu SL, Xin YH, Yu SC, Ping YF, Chen L, Xiao HL, Wang B, Yi L, Wang QL, Jiang XF, Yang L, Zhang P, Qian C, Cui YH, Zhang X, Bian XW (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-beta1 signaling pathway. J Immunol 189(1):444–453. doi: 10.4049/jimmunol.1103248 PubMedGoogle Scholar
  169. 169.
    Yi L, Xiao H, Xu M, Ye X, Hu J, Li F, Li M, Luo C, Yu S, Bian X, Feng H (2011) Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J Neuroimmunol 232(1–2):75–82. doi: 10.1016/j.jneuroim.2010.10.011 PubMedGoogle Scholar
  170. 170.
    Yuan H, Gaber MW, McColgan T, Naimark MD, Kiani MF, Merchant TE (2003) Radiation-induced permeability and leukocyte adhesion in the rat blood-brain barrier: modulation with anti-ICAM-1 antibodies. Brain Res 969(1–2):59–69PubMedGoogle Scholar
  171. 171.
    Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B (2009) Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia 57(13):1458–1467. doi: 10.1002/glia.20863 PubMedGoogle Scholar
  172. 172.
    Zhang L, Handel MV, Schartner JM, Hagar A, Allen G, Curet M, Badie B (2007) Regulation of IL-10 expression by upstream stimulating factor (USF-1) in glioma-associated microglia. J Neuroimmunol 184(1–2):188–197. doi: 10.1016/j.jneuroim.2006.12.006 PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Neurosurgical Research, Department of NeurosurgeryUniversity Clinics MunichMunichGermany
  2. 2.Department of NeurosurgeryCharité-University Medicine BerlinBerlinGermany
  3. 3.Max Delbrueck Center for Molecular Medicine Berlin-Buch (MDC)BerlinGermany
  4. 4.Neurosurgical Research, Department of NeurosurgeryLudwig Maximilians University (LMU)MunichGermany

Personalised recommendations