Skip to main content
SpringerLink
Log in

Microglia in Gliomas: Friend or Foe?

  • Chapter
  • First Online:
Glioma Cell Biology

Abstract

Microglia are myeloid cells residing in the central nervous system that regulate innate and adaptive immune responses in development, infections, and neuropathological disorders. Clinical and experimental data show that microglia constitute the dominant immune infiltrate in malignant gliomas. The clinical significance of the mononuclear infiltrate in gliomas remains the subject of controversy. Despite accumulation of these immune cells in both low and high grade gliomas, the antitumor immune response is defective in glioblastomas. Some evidence shows the immunosuppressive and pro-invasive action of glioblastoma-infiltrating microglia. Molecular mechanisms responsible for dual and likely opposite role of these cells are being recently unraveled. This chapter summarizes the latest findings on the heterogeneity of glioma-infiltrating microglia/macrophages, functional characterization of their phenotype, and contribution to glioma pathology. Recent attempts to determine a profile of cytokine/chemokine production and gene expression profiling in CD11b+ cells isolated from patients or rodent gliomas revealed their similarity to alternatively activated, the M2-type macrophages observed in other tissues. Glioma-infiltrating microglia/macrophages acquire the alternative, pro-invasive phenotype in which their phagocytic, trophic, and tissue remodeling functions are enhanced. Cell culture and organotypic brain slice culture studies demonstrated the pro-invasive activity of microglia, and their polarization into tumor supportive cells. This is supported by studies of rodent experimental gliomas which reproduce glioblastoma pathology. Genetic or pharmacological ablation of microglia/macrophages impairs glioma growth, extends survival, and in some cases restores to some extent antitumor immune responses. The potential for targeting interactions between glioma and infiltrating microglia/macrophages in therapeutic interventions is discussed. Small molecule inhibitors of mitogen-activated protein kinase (MAPK)-signaling with immunosuppressive or anti-inflammatory properties, such as cyclosporine A and minocycline, were shown to block infiltration and activation of microglia in vitro and in organotypic brain slices. These molecules reduce infiltration of microglia/macrophages, angiogenesis, and tumor growth of experimental gliomas providing a rationale for blocking pro-invasive functions of microglia/macrophages as a new therapeutic strategy in glioblastomas.

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

Access this chapter

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

Institutional subscriptions

Abbreviations

BM:

Bone marrow

G-CM:

Glioma-conditioned medium

GDNF:

Glial cell-derived neurotrophic factor

GFP:

Green fluorescent protein

GLUT5:

Glucose transporter 5

GM-CSF:

Granulocyte-macrophage colony stimulating factor

HO:

Heme oxygenase

IFN:

Interferon

IL:

Interleukin

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase (ERK1 and ERK2)

MCP-1:

Monocyte chemoattractant protein-1 (CCL2)

M-CSF:

Macrophage colony stimulating factor

MMP:

Matrix metalloproteinase

MT1-MMP:

Membrane type 1-MMP (=MMP14)

RANTES:

Regulated on activation normal T cell expressed and secreted, CCL5

TGF:

Transforming growth factor

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

Treg:

Regulatory T cell

TREM2:

Triggering receptor expressed on myeloid cells 2

References

  • Aharinejad S, Paulus P, Sioud M, Hofmann M, Zins K, Schäfer R, Stanley ER, Abraham D (2004) Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice. Cancer Res 64(15):5378–5384

    CAS  PubMed  Google Scholar 

  • Akira S, Takeda K, Kaisho T (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680

    CAS  PubMed  Google Scholar 

  • Albesiano E, Han JE, Lim M (2010) Mechanisms of local immunoresistance in glioma. Neurosurg Clin N Am 21(1):17–29

    PubMed  Google Scholar 

  • Alizadeh D, Zhang L, Hwang J, Schluep T, Badie B (2010) Tumor-associated macrophages are predominant carriers of cyclodextrin-based nanoparticles into gliomas. Nanomedicine 6(2):382–390

    CAS  PubMed Central  PubMed  Google Scholar 

  • Armstrong A, Ravichandran KS (2011) Phosphatidylserine receptors: what is the new RAGE? EMBO Rep 12(4):287–288

    CAS  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Badie B, Schartner J, Prabakaran S, Paul J, Vorpahl J (2001) Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol 120(1–2):19–24

    CAS  PubMed  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9(7):917–924

    CAS  PubMed  Google Scholar 

  • Cecchini MG, Dominguez MG, Mocci S, Wetterwald A, Felix R, Fleisch H, Chisholm O, Hofstetter W, Pollard JW, Stanley ER (1994) Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. Development 120(6):1357–1372

    CAS  PubMed  Google Scholar 

  • Chang GH, Barbaro NM, Pieper RO (2000) Phosphatidylserine-dependent phagocytosis of apoptotic glioma cells by normal human microglia, astrocytes, and glioma cells. Neuro Oncol 2(3):174–183

    CAS  PubMed Central  PubMed  Google Scholar 

  • Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2012) The brain tumor microenvironment. Glia 60(3):502–514

    PubMed  Google Scholar 

  • Chen C, Xu T, Chen J, Zhou J, Yan Y, Lu Y, Wu S (2011) Allergy and risk of glioma: a meta-analysis. Eur J Neurol 18(3):387–395

    CAS  PubMed  Google Scholar 

  • Combadiere C, Feumi C, Raoul W, Keller N, Rodero M, Pezard A, Lavalette S, Houssier M, Jonet L, Picard E, Debre P, Sirinyan M, Deterre P, Ferroukhi T, Cohen SY, Chauvaud D, Jeanny JC, Chemtob S, Behar-Cohen F, Sennlaub F (2007) CX3CR1-dependent subretinal microglia cell accumulation is associated with cardinal features of age-related macular degeneration. J Clin Invest 117(10):2920–2928

    CAS  PubMed Central  PubMed  Google Scholar 

  • Crane CA, Ahn BJ, Han SJ, Parsa AT (2012) Soluble factors secreted by glioblastoma cell lines facilitate recruitment, survival, and expansion of regulatory T cells: implications for immunotherapy. Neuro Oncol 14(5):584–595

    CAS  PubMed Central  PubMed  Google Scholar 

  • Davies LC, Rosas M, Smith PJ, Fraser DJ, Jones SA, Taylor PR (2011) A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation. Eur J Immunol 41(8):2155–2164

    CAS  PubMed  Google Scholar 

  • Davoust N, Vuaillat C, Androdias G, Nataf S (2008) From bone marrow to microglia: barriers and avenues. Trends Immunol 29(5):227–234

    CAS  PubMed  Google Scholar 

  • Deininger MH, Meyermann R, Trautmann K, Morgalla M, Duffner F, Grote EH, Wickboldt J, Schluesener HJ (2000) Cyclooxygenase (COX)-1 expressing macrophages/microglial cells and COX-2 expressing astrocytes accumulate during oligodendroglioma progression. Brain Res 885(1):111–116

    CAS  PubMed  Google Scholar 

  • Dick AD, Ford AL, Forrester JV, Sedgwick JD (1995) Flow cytometric identification of a minority population of MHC class II positive cells in the normal rat retina distinct from CD45lowCD11b/c+ CD4low parenchymal microglia. Br J Ophthalmol 79(9):834–840

    CAS  PubMed Central  PubMed  Google Scholar 

  • Donson AM, Birks DK, Schittone SA, Kleinschmidt-DeMasters BK, Sun DY, Hemenway MF, Handler MH, Waziri AE, Wang M, Foreman NK (2012) Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors. J Immunol 189(4):1920–1927

    CAS  PubMed Central  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

    PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Färber K, Synowitz M, Zahn G, Vossmeyer D, Stragies R, van Rooijen N, Kettenmann H (2008) An alpha5beta1 integrin inhibitor attenuates glioma growth. Mol Cell Neurosci 39(4):579–585

    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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Galarneau H, Villeneuve J, Gowing G, Julien JP, Vallières L (2007) Increased glioma growth in mice depleted of macrophages. Cancer Res 67(18):8874–8881

    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

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goodridge HS, Underhill DM, Touret N (2012) Mechanisms of Fc receptor and dectin-1 activation for phagocytosis. Traffic 13(8):1062–1071

    CAS  PubMed  Google Scholar 

  • Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119(1):89–105

    PubMed  Google Scholar 

  • Graeber MB, Scheithauer BW, Kreutzberg GW (2002) Microglia in brain tumors. Glia 40(2):252–259

    PubMed  Google Scholar 

  • Graf MR, Sauer JT, Merchant RE (2005) Tumor infiltration by myeloid suppressor cells in response to T cell activation in rat gliomas. J Neurooncol 73(1):29–36

    PubMed  Google Scholar 

  • 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):6720–6729

    CAS  PubMed  Google Scholar 

  • Grauer OM, Wesseling P, Adema GJ (2009) Immunotherapy of diffuse gliomas: biological background, current status and future developments. Brain Pathol 19(4):674–693

    CAS  PubMed  Google Scholar 

  • Guillemin GJ, Brew BJ (2004) Microglia, macrophages, perivascular macrophages, and pericytes: a review of function and identification. J Leukoc Biol 75(3):388–397

    CAS  PubMed  Google Scholar 

  • Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8(7):533–544

    CAS  PubMed  Google Scholar 

  • Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Hibbs ML, Quilici C, Kountouri N, Seymour JF, Armes JE, Burgess AW, Dunn AR (2007) Mice lacking three myeloid colony-stimulating factors (G-CSF, GM-CSF, and M-CSF) still produce macrophages and granulocytes and mount an inflammatory response in a sterile model of peritonitis. J Immunol 178(10):6435–6443

    CAS  PubMed  Google Scholar 

  • Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, Leboeuf M, Low D, Oller G, Almeida F, Choy SH, Grisotto M, Renia L, Conway SJ, Stanley ER, Chan JK, Ng LG, Samokhvalov IM, Merad M, Ginhoux F (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209(6):1167–1181

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang H, Hara A, Homma T, Yonekawa Y, Ohgaki H (2005) Altered expression of immune defense genes in pilocytic astrocytomas. J Neuropathol Exp Neurol 64(10):891–901

    CAS  PubMed  Google Scholar 

  • Hussain SF, Heimberger AB (2005) Immunotherapy for human glioma: innovative approaches and recent results. Expert Rev Anticancer Ther 5(5):777–790

    CAS  PubMed  Google Scholar 

  • Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006a) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8(3):261–279

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hussain SF, Yang D, Suki D, Grimm E, Heimberger AB (2006b) Innate immune functions of microglia isolated from human glioma patients. J Transl Med 4:15

    PubMed Central  PubMed  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

    CAS  PubMed  Google Scholar 

  • Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77(1):10–18

    CAS  PubMed  Google Scholar 

  • Kierdorf K, Prinz M (2013) Factors regulating microglia activation. Front Cell Neurosci 7:44

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim HS, Suh YH (2009) Minocycline and neurodegenerative diseases. Behav Brain Res 196(2):168–179

    CAS  PubMed  Google Scholar 

  • Kleber S, Sancho-Martinez I, Wiestler B, Beisel A, Gieffers C, Hill O, Thiemann M, Mueller W, Sykora J, Kuhn A, Schreglmann N, Letellier E, Zuliani C, Klussmann S, Teodorczyk M, Gröne HJ, Ganten TM, Sültmann H, Tüttenberg J, von Deimling A, Regnier-Vigouroux A, Herold-Mende C, Martin-Villalba A (2008) Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13(3):235–248

    CAS  PubMed  Google Scholar 

  • Klein R, Roggendorf W (2001) Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study. Acta Neuropathol 101(3):245–248

    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

    CAS  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

    CAS  PubMed  Google Scholar 

  • Kulprathipanja NV, Kruse CA (2004) Microglia phagocytose alloreactive CTL-damaged 9L gliosarcoma cells. J Neuroimmunol 153(1–2):76–82

    CAS  PubMed  Google Scholar 

  • Lambertsen KL, Deierborg T, Gregersen R, Clausen BH, Wirenfeldt M, Nielsen HH, Dalmau I, Diemer NH, Dagnaes-Hansen F, Johansen FF, Keating A, Finsen B (2011) Differences in origin of reactive microglia in bone marrow chimeric mouse and rat after transient global ischemia. J Neuropathol Exp Neurol 70(6):481–494

    PubMed  Google Scholar 

  • Li MO, Flavell RA (2008) Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28(4):468–476

    PubMed  Google Scholar 

  • Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro Oncol 14(8):958–978

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193(6):727–740

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW (2002) The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia 7(2):147–162

    PubMed  Google Scholar 

  • Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, Qian H, Xue XN, Pollard JW (2006) Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66(23):11238–11246

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed Central  PubMed  Google Scholar 

  • London A, Cohen M, Schwartz M (2013) Microglia and monocyte-derived macrophages: functionally distinct populations that act in concert in CNS plasticity and repair. Front Cell Neurosci 7:34

    CAS  PubMed Central  PubMed  Google Scholar 

  • Maes W, Van Gool SW (2011) Experimental immunotherapy for malignant glioma: lessons from two decades of research in the GL261 model. Cancer Immunol Immunother 60(2):153–160

    CAS  PubMed  Google Scholar 

  • Mantovani A, Sica A (2010) Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 22(2):231–237

    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

    CAS  PubMed  Google Scholar 

  • Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kälin 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 U S A 106(30):12530–12535

    CAS  PubMed Central  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):624–628

    CAS  PubMed  Google Scholar 

  • Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci 13:453–461

    CAS  PubMed  Google Scholar 

  • Morantz RA, Wood GW, Foster M, Clark M, Gollahon K (1979) Macrophages in experimental and human brain tumors. Part 2: studies of the macrophage content of human brain tumors. J Neurosurg 50(3):305–311

    CAS  PubMed  Google Scholar 

  • Morford LA, Elliott LH, Carlson SL, Brooks WH, Roszman TL (1997) T cell receptor-mediated signaling is defective in T cells obtained from patients with primary intracranial tumors. J Immunol 159(9):4415–4425

    CAS  PubMed  Google Scholar 

  • Morimura T, Neuchrist C, Kitz K, Budka H, Scheiner O, Kraft D, Lassmann H (1990) Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumor proliferation. Acta Neuropathol 80(3):287–294

    CAS  PubMed  Google Scholar 

  • Morioka T, Baba T, Black KL, Streit WJ (1992a) Immunophenotypic analysis of infiltrating leukocytes and microglia in an experimental rat glioma. Acta Neuropathol 83(6):590–597

    CAS  PubMed  Google Scholar 

  • Morioka T, Baba T, Black KL, Streit WJ (1992b) Inflammatory cell infiltrates vary in experimental primary and metastatic brain tumors. Neurosurgery 30(6):891–896

    CAS  PubMed  Google Scholar 

  • Morris CS, Esiri MM (1991) Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease. 1. Gliomas. J Neurol Sci 101(1):47–58

    CAS  PubMed  Google Scholar 

  • Mroczko B, Groblewska M, Wereszczyńska-Siemiatkowska U, Okulczyk B, Kedra B, Łaszewicz W, Dabrowski A, Szmitkowski M (2007) Serum macrophage-colony stimulating factor levels in colorectal cancer patients correlate with lymph node metastasis and poor prognosis. Clin Chim Acta 380(1–2):208–212

    CAS  PubMed  Google Scholar 

  • Neumann H, Kotter MR, Franklin RJ (2009) Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 132(Pt 2):288–295

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID (2007) Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC)alpha/betaII. J Biol Chem 282(20):15208–15216

    CAS  PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318

    CAS  PubMed  Google Scholar 

  • 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 5(5):1107–1113

    CAS  PubMed  Google Scholar 

  • Nowicki A, Szenajch J, Ostrowska G, Wojtowicz A, Wojtowicz K, Kruszewski AA, Maruszynski M, Aukerman SL, Wiktor-Jedrzejczak W (1996) Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma. Int J Cancer 65(1):112–119

    CAS  PubMed  Google Scholar 

  • 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):1621–1627

    CAS  PubMed  Google Scholar 

  • Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924

    CAS  PubMed  Google Scholar 

  • Pollard JW (2009) Trophic macrophages in development and disease. Nat Rev Immunol 9(4):259–270

    CAS  PubMed Central  PubMed  Google Scholar 

  • Prins RM, Liau LM (2004) Cellular immunity and immunotherapy of brain tumors. Front Biosci 9:3124–3136

    CAS  PubMed  Google Scholar 

  • Prins RM, Scott GP, Merchant RE, Graf MR (2002) Irradiated tumor cell vaccine for treatment of an established glioma. II. Expansion of myeloid suppressor cells that promote tumor progression. Cancer Immunol Immunother 51(4):190–199

    PubMed  Google Scholar 

  • Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, Lang RA, Pollard JW (2009) A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4(8):e6562

    PubMed Central  PubMed  Google Scholar 

  • Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207(9):1807–1817

    CAS  PubMed Central  PubMed  Google Scholar 

  • Raychaudhuri B, Rayman P, Ireland J, Ko J, Rini B, Borden EC, Garcia J, Vogelbaum MA, Finke J (2011) Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol 13(6):591–599

    PubMed Central  PubMed  Google Scholar 

  • Revoltella RP, Menicagli M, Campani D (2012) Granulocyte-macrophage colony-stimulating factor as an autocrine survival-growth factor in human gliomas. Cytokine 57(3):347–359

    CAS  PubMed  Google Scholar 

  • Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, Lin Y, Dietz AB, Forsyth PA, Yong VW, Parney IF (2010) Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol 12(4):351–365

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roggendorf W, Strupp S, Paulus W (1996) Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol 92(3):288–293

    CAS  PubMed  Google Scholar 

  • Rolle CE, Sengupta S, Lesniak MS (2012) Mechanisms of immune evasion by gliomas. Adv Exp Med Biol 746:53–76

    CAS  PubMed  Google Scholar 

  • Sapi E, Kacinski BM (1999) The role of CSF-1 in normal and neoplastic breast physiology. Proc Soc Exp Biol Med 220(1):1–8

    CAS  PubMed  Google Scholar 

  • Sasaki A, Yamaguchi H, Horikoshi Y, Tanaka G, Nakazato Y (2004) Expression of glucose transporter 5 by microglia in human gliomas. Neuropathol Appl Neurobiol 30(5):447–455

    CAS  PubMed  Google Scholar 

  • Sasaki A, Yokoo H, Tanaka Y, Homma T, Nakazato Y, Ohgaki H (2013) Characterization of microglia/macrophages in gliomas developed in S-100β-v-erbB transgenic rats. Neuropathology 33(5):505–514

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Schwartz M (2010) “Tissue-repairing” blood-derived macrophages are essential for healing of the injured spinal cord: from skin-activated macrophages to infiltrating blood-derived cells? Brain Behav Immun 24(7):1054–1057

    CAS  PubMed  Google Scholar 

  • Schwartzbaum JA, Huang K, Lawler S, Ding B, Yu J, Chiocca EA (2010) Allergy and inflammatory transcriptome is predominantly negatively correlated with CD133 expression in glioblastoma. Neuro Oncol 12(4):320–327

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sedgwick JD, Schwender S, Imrich H, Dörries R, Butcher GW, ter Meulen V (1991) Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A 88(16):7438–7442

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sedgwick JD, Schwender S, Gregersen R, Dörries R, ter Meulen V (1993) Resident macrophages (ramified microglia) of the adult brown Norway rat central nervous system are constitutively major histocompatibility complex class II positive. J Exp Med 177(4):1145–1152

    CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Sierra A, Abiega O, Shahraz A, Neumann H (2013) Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front Cell Neurosci 7:6

    CAS  PubMed Central  PubMed  Google Scholar 

  • Simmons GW, Pong WW, Emnett RJ, White CR, Gianino SM, Rodriguez FJ, Gutmann DH (2011) Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth. J Neuropathol Exp Neurol 70(1):51–62

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 130(Pt 2):476–489

    PubMed  Google Scholar 

  • Solinas G, Germano G, Mantovani A, Allavena P (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86(5):1065–1073

    CAS  PubMed  Google Scholar 

  • Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Panina Bordignon P, Meldolesi J (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 110(1):284–294

    CAS  PubMed  Google Scholar 

  • Szatmári T, Lumniczky K, Désaknai S, Trajcevski S, Hídvégi EJ, Hamada H, Sáfrány G (2006) Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy. Cancer Sci 97(6):546–553

    PubMed  Google Scholar 

  • Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4):e124

    PubMed Central  PubMed  Google Scholar 

  • Tran Thang NN, Derouazi M, Philippin G, Arcidiaco S, Di Berardino-Besson W, Masson F, Hoepner S, Riccadonna C, Burkhardt K, Guha A, Dietrich PY, Walker PR (2010) Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development. Cancer Res 70(12):4829–4839

    PubMed  Google Scholar 

  • Umemura N, Saio M, Suwa T, Kitoh Y, Bai J, Nonaka K, Ouyang GF, Okada M, Balazs M, Adany R, Shibata T, Takami T (2008) Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics. J Leukoc Biol 83(5):1136–1144

    CAS  PubMed  Google Scholar 

  • Voisin P, Bouchaud V, Merle M, Diolez P, Duffy L, Flint K, Franconi JM, Bouzier-Sore AK (2010) Microglia in close vicinity of glioma cells: correlation between phenotype and metabolic alterations. Front Neuroenergetics 2:131

    PubMed Central  PubMed  Google Scholar 

  • 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 Invest 92(1):151–162

    CAS  PubMed  Google Scholar 

  • Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81(3):447–455

    CAS  PubMed  Google Scholar 

  • Wei J, Barr J, Kong LY, Wang Y, Wu A, Sharma AK, Gumin J, Henry V, Colman H, Priebe W, Sawaya R, Lang FF, Heimberger AB (2010) Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol Cancer Ther 9(1):67–78

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Wierzba-Bobrowicz T, Kuchna I, Matyja E (1994) Reaction of microglial cells in human astrocytomas (preliminary report). Folia Neuropathol 32(4):251–252

    CAS  PubMed  Google Scholar 

  • Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci U S A 87(12):4828–4832

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wiktor-Jedrzejczak W, Ratajczak MZ, Ptasznik A, Sell KW, Ahmed-Ansari A, Ostertag W (1992) CSF-1 deficiency in the op/op mouse has differential effects on macrophage populations and differentiation stages. Exp Hematol 20(8):1004–1010

    CAS  PubMed  Google Scholar 

  • Wisniewski P, Ellert-Miklaszewska A, Kwiatkowska A, Kaminska B (2010) Non-apoptotic Fas signaling regulates invasiveness of glioma cells and modulates MMP-2 activity via NFkappaB-TIMP-2 pathway. Cell Signal 22(2):212–220

    CAS  PubMed  Google Scholar 

  • Wu A, Wei J, Kong LY, Wang Y, Priebe W, Qiao W, Sawaya R, Heimberger AB (2010) Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol 12(11):1113–1125

    CAS  PubMed Central  PubMed  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

    PubMed Central  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345(6274):442–444

    CAS  PubMed  Google Scholar 

  • Zawadzka M, Dabrowski M, Gozdz A, Szadujkis B, Sliwa M, Lipko M, Kaminska B (2012) Early steps of microglial activation are directly affected by neuroprotectant FK506 in both in vitro inflammation and in rat model of stroke. J Mol Med (Berl) 90(12):1459–1471

    CAS  Google Scholar 

  • Zhai H, Heppner FL, Tsirka SE (2011) Microglia/macrophages promote glioma progression. Glia 59(3):472–485

    PubMed Central  PubMed  Google Scholar 

  • 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

    PubMed  Google Scholar 

  • Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26(16):2707–2716

    PubMed  Google Scholar 

Download references

Acknowledgments

I would like to thank Dr. Aleksandra Ellert-Miklaszewska and Malgorzata Sielska for reading and help with editing of the manuscript. This work was supported by a grant 2012/04/A/NZ3/00630 from The National Science Centre Poland.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, 3 Pasteur Str., 02-093, Warsaw, Poland

    Bozena Kaminska

Authors
  1. Bozena Kaminska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bozena Kaminska .

Editor information

Editors and Affiliations

  1. Biochemistry and Experimental Oncology, Charles University Prague 1st Faculty of Medicine, Prague, Czech Republic

    Aleksi Sedo

  2. Anatomisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

    Rolf Mentlein

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer-Verlag Wien

About this chapter

Cite this chapter

Kaminska, B. (2014). Microglia in Gliomas: Friend or Foe?. In: Sedo, A., Mentlein, R. (eds) Glioma Cell Biology. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1431-5_9

Download citation

Publish with us

Policies and ethics

Search

Navigation