Abstract
Glioblastoma is a malignant tumor of astrocytic origin that is highly invasive, proliferative and angiogenic. Despite current advances in multimodal therapies, such as surgery, radio- and chemotherapy, the outcome for patients with glioblastoma is nearly always fatal. The glioblastoma microenvironment has a tremendous influence over the tumor growth and spread. Microglia and macrophages are abundant cells in the tumor mass. Increasing evidence indicates that glioblastoma recruits these cell populations and signals in a way that microglia and macrophages are subverted to promote tumor progression. In this chapter, we discuss some aspects of the interaction between microglia and glioblastoma, consequences of this interaction for tumor progression and the possibility of microglial cells being used as therapeutic vectors, which opens up new alternatives for the development of GBM therapies targeting microglia.
Keywords
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- CNS:
-
Central nervous system
- IL:
-
Interleukin
- TNF:
-
Tumor necrosis factor
- GBM:
-
Glioblastoma
- MMP:
-
Matrix metalloproteinase
- VEGF:
-
Vascular endothelial growth factor
- DLL4:
-
Delta-like ligand 4
- NO:
-
Nitric oxide
- MCP-1 (CCL2):
-
Macrophage chemoattractant protein 1
- CCR2:
-
CCL2 receptor
- TNFR1:
-
TNF receptor 1
- IkBa:
-
Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha
- NF-kB:
-
Nuclear factor of kappa light polypeptide gene enhancer in B-cells
- uPA:
-
Urokinase-type plasminogen activator
- STI1:
-
Stress-inducible protein 1
- Hsp:
-
Heat shock protein
- MG CM:
-
Microglial conditioned medium
- MYD88/TLR8:
-
Myeloid Differentiation Primary Response 88/Toll-like receptor 8
- TLR:
-
Toll-like receptor
- MT1-MMP:
-
Membrane-type-1 MMP
- GDNF:
-
Glial cell-line-derived neurotrophic factor
- GFRa:
-
GDNF receptor
- EGFR:
-
Epidermal growth factor receptor
- EGF:
-
Epidermal growth factor
- poly [I:C]:
-
Polyinosinic-polycytidylic acid
- TRAIL:
-
TNF-related apoptosis inducing ligand
- mTOR:
-
Mammalian target of rapamycin
- iNOS:
-
Inducible nitric oxide synthase
- MIF:
-
Macrophage migration inhibitory factor
- STAT:
-
Signal transducer and activator of transcription
- RAGE:
-
Receptor for Advanced Glycation End products
- S100B:
-
S100 calcium binding protein B
- CpG-ODN:
-
Oligodeoxynucleotides containing CpG motifs
- TROY/TNFRSF19:
-
Tumor necrosis factor receptor of mouse embryo
- GSC:
-
Glioma stem cell
- MRI:
-
Magnetic resonance imaging
- GCV:
-
Gancyclovir
References
Albesiano E, Han JE, Lim M (2010) Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am 21(1):17–29. doi:10.1016/j.nec.2009.08.008
Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2(10):734–744. doi:10.1038/35094583
Alves TR, Lima FR, Kahn SA, Lobo D, Dubois LG, Soletti R, Borges H, Neto VM (2011) Glioblastoma cells: a heterogeneous and fatal tumor interacting with the parenchyma. Life Sci 89(15–16):532–539. doi:10.1016/j.lfs.2011.04.022
Auf G, Carpentier AF, Chen L, Le Clanche C, Delattre JY (2001) Implication of macrophages in tumor rejection induced by CpG-oligodeoxynucleotides without antigen. Clin Cancer Res 7(11):3540–3543
Badie B, Schartner JM (2000) Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 46(4):957–961; discussion 961–952
Baker BJ, Qin H, Benveniste EN (2008) Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. Glia 56(11):1250–1262. doi:10.1002/glia.20694
Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848. doi:10.1158/0008-5472.CAN-06-1010
Brada M, Stenning S, Gabe R, Thompson LC, Levy D, Rampling R, Erridge S, Saran F, Gattamaneni R, Hopkins K, Beall S, Collins VP, Lee SM (2010) Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. J Clin Oncol 28(30):4601–4608
Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15(2):79–80
Burrows FJ, Gore M, Smiley WR, Kanemitsu MY, Jolly DJ, Read SB, Nicholas T, Kruse CA (2002) Purified herpes simplex virus thymidine kinase retroviral particles: III. Characterization of bystander killing mechanisms in transfected tumor cells. Cancer Gene Ther 9(1):87–95
Carpentier AF, Xie J, Mokhtari K, Delattre JY (2000) Successful treatment of intracranial gliomas in rat by oligodeoxynucleotides containing CpG motifs. Clin Cancer Res 6(6):2469–2473
Carpentier A, Laigle-Donadey F, Zohar S, Capelle L, Behin A, Tibi A, Martin-Duverneuil N, Sanson M, Lacomblez L, Taillibert S, Puybasset L, Van Effenterre R, Delattre JY, Carpentier AF (2006) Phase 1 trial of a CpG oligodeoxynucleotide for patients with recurrent glioblastoma. Neuro Oncol 8(1):60–66
Carpentier A, Metellus P, Ursu R, Zohar S, Lafitte F, Barrié M, Meng Y, Richard M, Parizot C, Laigle-Donadey F, Gorochov G, Psimaras D, Sanson M, Tibi A, Chinot O, Carpentier AF (2010) Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. Neuro Oncol 12(4):401–408
Caruso M, Panis Y, Gagandeep S, Houssin D, Salzmann JL, Klatzmann D (1993) Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci USA 90(15):7024–7028
Carvalho da Fonseca AC, Wang H, Fan H, Chen X, Zhang I, Zhang L, Lima FR, Badie B (2014) Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages. J Neuroimmunol 274(1–2):71–77. doi:10.1016/j.jneuroim.2014.06.021
Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2011) The brain tumor microenvironment. Glia 59(8):1169–1180. doi:10.1002/glia.21136
Chen S, Smith DF (1998) Hop as an adaptor in the heat shock protein 70 (Hsp70) and hsp90 chaperone machinery. J Biol Chem 273(52):35194–35200
Cheng F, Wang HW, Cuenca A, Huang M, Ghansah T, Brayer J, Kerr WG, Takeda K, Akira S, Schoenberger SP, Yu H, Jove R, Sotomayor EM (2003) A critical role for Stat3 signaling in immune tolerance. Immunity 19(3):425–436
Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722
Chiu TL, Peng CW, Wang MJ (2011) Enhanced anti-glioblastoma activity of microglia by AAV2-mediated IL-12 through TRAIL and phagocytosis in vitro. Oncol Rep 25(5):1373–1380. doi:10.3892/or.2011.1213
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
da Fonseca AC, Badie B (2013) Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies. Clin Dev Immunol 2013:264124. doi:10.1155/2013/264124
D’Mello C, Le T, Swain MG (2009) Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factorα signaling during peripheral organ inflammation. J Neurosci 29(7):2089–2102. doi:10.1523/JNEUROSCI.3567-08.2009
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
Faria J, Romao L, Martins S, Alves T, Mendes FA, de Faria GP, Hollanda R, Takiya C, Chimelli L, Morandi V, de Souza JM, Abreu JG, Moura Neto V (2006) Interactive properties of human glioblastoma cells with brain neurons in culture and neuronal modulation of glial laminin organization. Differentiation 74(9–10):562–572. doi:10.1111/j.1432-0436.2006.00090.x
Fonseca AC, Romao L, Amaral RF, Assad Kahn S, Lobo D, Martins S, Marcondes de Souza J, Moura-Neto V, Lima FR (2012) Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neuroscience 200:130–141. doi:10.1016/j.neuroscience.2011.10.025
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
Gagliano N, Costa F, Cossetti C, Pettinari L, Bassi R, Chiriva-Internati M, Cobos E, Gioia M, Pluchino S (2009) Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model. Oncol Rep 22(6):1349–1356
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
Herrera M, Herrera A, Dominguez G, Silva J, Garcia V, Garcia JM, Gomez I, Soldevilla B, Munoz C, Provencio M, Campos-Martin Y, Garcia de Herreros A, Casal I, Bonilla F, Pena C (2013) Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci 104(4):437–444. doi:10.1111/cas.12096
Hu F, Ku MC, Markovic D, Od AD, Lehnardt S, Synowitz M, Wolf SA, Kettenmann H (2014) Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline. Int J Cancer 135 (11):2569–2578. doi:10.1002/ijc.28908
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
Hwang SY, Yoo BC, Jung JW, Oh ES, Hwang JS, Shin JA, Kim SY, Cha SH, Han IO (2009) Induction of glioma apoptosis by microglia-secreted molecules: the role of nitric oxide and cathepsin B. Biochim Biophys Acta 1793(11):1656–1668. doi:10.1016/j.bbamcr.2009.08.011
Iwamaru A, Szymanski S, Iwado E, Aoki H, Yokoyama T, Fokt I, Hess K, Conrad C, Madden T, Sawaya R, Kondo S, Priebe W, Kondo Y (2007) A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo. Oncogene 26(17):2435–2444
Jacobs VL, Landry RP, Liu Y, Romero-Sandoval EA, De Leo JA (2012a) Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro Oncol 14(2):119–131
Jacobs VL, Liu Y, De Leo JA (2012b) Propentofylline targets TROY, a novel microglial signaling pathway. PLoS ONE 7(5):e37955
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
Klinman DM (2004) Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4(4):249–258
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
Kren L, Muckova K, Lzicarova E, Sova M, Vybihal V, Svoboda T, Fadrus P, Smrcka M, Slaby O, Lakomy R, Vanhara P, Krenova Z, Michalek J (2010) Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: a role in innate immunity? J Neuroimmunol 220(1–2):131–135. doi:10.1016/j.jneuroim.2010.01.014
Krieg AM (2004) Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6(2):88–95
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
Lang R, Patel D, Morris JJ, Rutschman RL, Murray PJ (2002) Shaping gene expression in activated and resting primary macrophages by IL-10. J Immunol 169(5):2253–2263
Le DM, Besson A, Fogg DK, Choi KS, Waisman DM, Goodyer CG, Rewcastle B, Yong VW (2003) Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J Neurosci 23(10):4034–4043
Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro Oncol 14(8):958–978. doi:10.1093/neuonc/nos116
Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner JA, Harris AL (2007) Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 67(23):11244–11253. doi:10.1158/0008-5472.CAN-07-0969
Li R, Li G, Deng L, Liu Q, Dai J, Shen J, Zhang J (2010) IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol Rep 23(6):1553–1559
Lima FRS, da Fonseca ACC, Faria GP, Dubois LGF, Alves TR, Faria J, Moura Neto V (2010) The origin of microglia and the development of the brain. In: Ulrich H (ed) Perspectives of stem cells: from tools for studying mechanisms of neuronal differentiation towards therapy. Springer, Netherlands. doi:10.1007/978-90-481-3375-8_12
Lima FR, Kahn SA, Soletti RC, Biasoli D, Alves T, da Fonseca AC, Garcia C, Romao L, Brito J, Holanda-Afonso R, Faria J, Borges H, Moura-Neto V (2012) Glioblastoma: therapeutic challenges, what lies ahead. Biochim Biophys Acta 1826(2):338–349. doi:10.1016/j.bbcan.2012.05.004
Lisi L, Laudati E, Navarra P, Dello Russo C (2014) The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype. J Neuroinflammation 11:125. doi:10.1186/1742-2094-11-125
Mallat M, Marin-Teva JL, Cheret C (2005) Phagocytosis in the developing CNS: more than clearing the corpses. Curr Opin Neurobiol 15(1):101–107. doi:10.1016/j.conb.2005.01.006
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):754–762
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):5
Meng Y, Carpentier AF, Chen L, Boisserie G, Simon JM, Mazeron JJ, Delattre JY (2005) Successful combination of local CpG-ODN and radiotherapy in malignant glioma. Int J Cancer 116(6):992–997
Nadeau S, Rivest S (2000) Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor κ B activity in the brain during endotoxemia. J Neurosci 20(9):3456–3468
Ng WH, Wan GQ, Peng ZN, Too HP (2009) Glial cell-line derived neurotrophic factor (GDNF) family of ligands confer chemoresistance in a ligand-specific fashion in malignant gliomas. J Clin Neurosci 16(3):427–436. doi:10.1016/j.jocn.2008.06.002
Nolte C, Kirchhoff F, Kettenmann H (1997) Epidermal growth factor is a motility factor for microglial cells in vitro: evidence for EGF receptor expression. Eur J Neurosci 9(8):1690–1698
O’Farrell AM, Liu Y, Moore KW, Mui AL (1998) IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat-3-dependent and -independent pathways. EMBO J 17(4):1006–1018
Ohgaki H, Kleihues P (2007) Genetic pathways to primary and secondary glioblastoma. Am J Pathol 170(5):1445–1453. doi:10.2353/ajpath.2007.070011
Penfield W (1925) Microglia and the process of phagocytosis in gliomas. Am J Pathol 1(1):77–90
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):388–392. doi:10.1002/ana.10679
Prat E, Baron P, Meda L, Scarpini E, Galimberti D, Ardolino G, Catania A, Scarlato G (2000) The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with beta-amyloid protein. Neurosci Lett 283(3):177–180
Qiao J, Black ME, Caruso M (2000) Enhanced ganciclovir killing and bystander effect of human tumor cells transduced with a retroviral vector carrying a herpes simplex virus thymidine kinase gene mutant. Hum Gene Ther 11(11):1569–1576
Raychaudhuri B, Han Y, Lu T, Vogelbaum MA (2007) Aberrant constitutive activation of nuclear factor κB in glioblastoma multiforme drives invasive phenotype. J Neurooncol 85(1):39–47. doi:10.1007/s11060-007-9390-7
Ribes S, Ebert S, Regen T, Agarwal A, Tauber SC, Czesnik D, Spreer A, Bunkowski S, Eiffert H, Hanisch UK, Hammerschmidt S, Nau R (2010) Toll-like receptor stimulation enhances phagocytosis and intracellular killing of nonencapsulated and encapsulated streptococcus pneumoniae by murine microglia. Infect Immun 78(2):865–871
Ribot E, Bouzier-Sore AK, Bouchaud V, Miraux S, Delville MH, Franconi JM, Voisin P (2007) Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy. Cancer Gene Ther 14(8):724–737
Ribot EJ, Miraux S, Konsman JP, Bouchaud V, Pourtau L, Delville MH, Franconi JM, Thiaudière E, Voisin PJ (2011) In vivo MR tracking of therapeutic microglia to a human glioma model. NMR Biomed 24(10):1361–1368
Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6):429–439. doi:10.1038/nri2565
Rodero M, Marie Y, Coudert M, Blondet E, Mokhtari K, Rousseau A, Raoul W, Carpentier C, Sennlaub F, Deterre P, Delattre JY, Debré P, Sanson M, Combadière C (2008) Polymorphism in the microglial cell-mobilizing CX3CR1 gene is associated with survival in patients withglioblastoma. J Clin Oncol 26(36):5957–5964
Rolhion C, Penault-Llorca F, Kemeny JL, Lemaire JJ, Jullien C, Labit-Bouvier C, Finat-Duclos F, Verrelle P (2001) Interleukin-6 overexpression as a marker of malignancy in human gliomas. J Neurosurg 94(1):97–101. doi:10.3171/jns.2001.94.1.0097
Sangar V, Funk CC, Kusebauch U, Campbell DS, Moritz RL, Price ND (2014) Quantitative proteomic analysis reveals effects of EGFR on invasion-promoting proteins secreted by glioblastoma cells. Mol Cell Proteomics 13(10):2618–2631. doi:10.1074/mcp.M114.040428
Sansone P, Bromberg J (2012) Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol 30(9):10
Sarkar S, Döring 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
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
Schmieder A, Michel J, Schonhaar K, Goerdt S, Schledzewski K (2012) Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol 22(4):289–297. doi:10.1016/j.semcancer.2012.02.002
Si QS, Nakamura Y, Schubert P, Rudolphi K, Kataoka K (1996) Adenosine and propentofylline inhibit the proliferation of cultured microglial cells. Exp Neurol 137(2):345–349
Si Q, Nakamura Y, Ogata T, Kataoka K, Schubert P (1998) Differential regulation of microglial activation by propentofylline via cAMP signaling. Brain Res 812(1–2):97–104
Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18(5):349–355. doi:10.1016/j.semcancer.2008.03.004
Song Y, Masison DC (2005) Independent regulation of Hsp70 and Hsp90 chaperones by Hsp70/Hsp90-organizing protein Sti1 (Hop1). J Biol Chem 280(40):34178–34185. doi:10.1074/jbc.M505420200
Spencer DM (2000) Developments in suicide genes for preclinical and clinical applications. Curr Opin Mol Ther 2(4):433–440
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352 (10):987–996
Suk K (2004) Minocycline suppresses hypoxic activation of rodent microglia in culture. Neurosci Lett 366(2):167–171
Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Förster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10(1):39–49
Tchoghandjian A, Jennewein C, Eckhardt I, Rajalingam K, Fulda S (2013) Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells. Cell Death Dis 4:e564. doi:10.1038/cddis.2013.70
Tsunoda K, Kitange G, Anda T, Shabani HK, Kaminogo M, Shibata S, Nagata I (2005) Expression of the constitutively activated RelA/NF-κB in human astrocytic tumors and the in vitro implication in the regulation of urokinase-type plasminogen activator, migration, and invasion. Brain Tumor Pathol 22(2):79–87. doi:10.1007/s10014-005-0186-1
Ursu R, Carpentier A, Metellus P, Barrie M, Meng Y, Laigle-Donadey F, Tibi A, Chinot O, Carpentier AF (2009) Phase II trial of intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma. J Clin Oncol 27:15S
Vilhardt F (2005) Microglia: phagocyte and glia cell. Int J Biochem Cell Biol 37(1):17–21. doi:10.1016/j.biocel.2004.06.010
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 15(11):1457–1468. doi:10.1093/neuonc/not115
Walker PR, Calzascia T, de Tribolet N, Dietrich PY (2003) T-cell immune responses in the brain and their relevance for cerebral malignancies. Brain Res Brain Res Rev 42(2):97–122
Wang H, Lathia JD, Wu Q, Wang J, Li Z, Heddleston JM, Eyler CE, Elderbroom J, Gallagher J, Schuschu J, MacSwords J, Cao Y, McLendon RE, Wang XF, Hjelmeland AB, Rich JN (2009) Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 27(10):2393–2404. doi:10.1002/stem.188
Weissenberger J, Loeffler S, Kappeler A, Kopf M, Lukes A, Afanasieva TA, Aguzzi A, Weis J (2004) IL-6 is required for glioma development in a mouse model. Oncogene 23(19):3308–3316
Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H, Humpel C (2000) Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol 99(2):131–137
Wu Y, Zhou BP (2010) TNF-α/NF-κB/Snail pathway in cancer cell migration and invasion. Br J Cancer 102(4):639–644. doi:10.1038/sj.bjc.6605530
Yang I, Han SJ, Kaur G, Crane C, Parsa AT (2010) The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci 17(1):6–10. doi:10.1016/j.jocn.2009.05.006
Yao Y, Tsirka SE (2014) Monocyte chemoattractant protein-1 and the blood-brain barrier. Cell Mol Life Sci 71(4):683–697. doi:10.1007/s00018-013-1459-1
Yi D, Hua TX, Lin HY, Kui CL, Ning LX, Wang ZZ (2011) Antitumor treatment efficacy by targeting epidermal growth factor receptor and vascular endothelial growth factor receptor-2 in an orthotopic human glioblastoma model. J Neurooncol 104(1):93–101. doi:10.1007/s11060-010-0479-z
Yu H, Kortylewski M, Pardoll D (2007) Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 7(1):41–51
Zeiner PS, Preusse C, Blank AE, Zachskorn C, Baumgarten P, Caspary L, Braczynski AK, Weissenberger J, Bratzke H, Reiss S, Pennarz S, Winkelmann R, Senft C, Plate KH, Wischhusen J, Stenzel W, Harter PN, Mittelbronn M (2014) MIF receptor CD74 is restricted to microglia/macrophages, associated with a M1-polarized immune milieu, and prolonged patient survival in gliomas. Brain Pathol 25(4):491–504. doi:10.1111/bpa.12194
Zhang L, Alizadeh D, Van Handel M, Kortylewski M, Yu H, Badie B (2009a) Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice. Glia 57(13):1458–1467
Zhang L, Liu W, Alizadeh D, Zhao D, Farrukh O, Lin J, Badie SA, Badie B (2009b) S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway. Glia 59(3):486–498
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da Fonseca, A.C.C., Amaral, R., Garcia, C., Geraldo, L.H., Matias, D., Lima, F.R.S. (2016). Microglia in Cancer: For Good or for Bad?. In: von Bernhardi, R. (eds) Glial Cells in Health and Disease of the CNS. Advances in Experimental Medicine and Biology, vol 949. Springer, Cham. https://doi.org/10.1007/978-3-319-40764-7_12
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