Skip to main content
SpringerLink
Log in
Book cover

Glial Cells in Health and Disease of the CNS pp 245–261Cite as

Microglia in Cancer: For Good or for Bad?

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 949))

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.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

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

    Article  PubMed  Google Scholar 

  • Allan SM, Rothwell NJ (2001) Cytokines and acute neurodegeneration. Nat Rev Neurosci 2(10):734–744. doi:10.1038/35094583

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Bromberg J, Wang TC (2009) Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 15(2):79–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Jacobs VL, Liu Y, De Leo JA (2012b) Propentofylline targets TROY, a novel microglial signaling pathway. PLoS ONE 7(5):e37955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Klinman DM (2004) Immunotherapeutic uses of CpG oligodeoxynucleotides. Nat Rev Immunol 4(4):249–258

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Krieg AM (2004) Antitumor applications of stimulating toll-like receptor 9 with CpG oligodeoxynucleotides. Curr Oncol Rep 6(2):88–95

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Penfield W (1925) Microglia and the process of phagocytosis in gliomas. Am J Pathol 1(1):77–90

    CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6):429–439. doi:10.1038/nri2565

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sansone P, Bromberg J (2012) Targeting the interleukin-6/Jak/stat pathway in human malignancies. J Clin Oncol 30(9):10

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spencer DM (2000) Developments in suicide genes for preclinical and clinical applications. Curr Opin Mol Ther 2(4):433–440

    CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Suk K (2004) Minocycline suppresses hypoxic activation of rodent microglia in culture. Neurosci Lett 366(2):167–171

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho, 373, Rio de Janeiro, RJ, 21949-590, Brazil

    Anna Carolina Carvalho da Fonseca, Rackele Amaral, Celina Garcia, Luiz Henrique Geraldo, Diana Matias & Flavia Regina Souza Lima

Authors
  1. Anna Carolina Carvalho da Fonseca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rackele Amaral
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Celina Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luiz Henrique Geraldo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diana Matias
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Flavia Regina Souza Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Flavia Regina Souza Lima .

Editor information

Editors and Affiliations

  1. Faculty of Medicine Professor of Neurology, Pontificia Universidad Católica de Chile, Santiago, Chile

    Rommy von Bernhardi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

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

Download citation

Publish with us

Policies and ethics

Search

Navigation