Abstract
The paper wants to be a tracking shot of the main recent acquisitions on the function and significance of microglia/macrophages in gliomas. The observations have been principally carried out on in vitro cultures and on tumor transplants in animals. Contrary to what is deduced from microglia in non-neoplastic pathologic conditions of central nervous system (CNS), most conclusions indicate that microglia acts favoring tumor proliferation through an immunosuppression induced by glioma cells. By immunohistochemistry, different microglia phenotypes are recognized in gliomas, from ramified microglia to frank macrophagic aspect. One wonders whether the functional conclusions drawn from many microglia studies, but not in conditions of human pathology, apply to all the phenotypes recognizable in them. It is difficult to verify in human pathology a prognostic significance of microglia. Only CD163-positive microglia/macrophages inversely correlate with glioma patients' survival, whereas the total number of microglia does not change with the malignancy grade.
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References
Graeber MB, Streit WJ (2010) Microglia: biology and pathology. Acta Neuropathol 119:89–105
Shaked I, Porat Z, Gersner R, Kipnis J, Schwartz M (2004) Early activation of microglia as antigen-presenting cells correlates with T cell-mediated protection and repair of the injured central nervous system. J Neuroimmunol 146:84–93
Ulvestad E, Williams K, Bjerkvig R, Tiekotter K, Antel J, Matre R (1994) Human microglial cells have phenotypic and functional characteristics in common with both macrophages and dendritic antigen-presenting cells. J Leukoc Biol 56:732–740
Miescher S, Whiteside TL, de Tribolet N, von Fliedner V (1988) In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers. J Neurosurg 68:438–448
Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro-Oncology 14:958–978
Badie B, Schartner J (2001) Role of microglia in glioma biology. Microsc Res Tech 54:106–113
Kennedy BC, Maier LM, D'Amico R et al (2009) Dynamics of central and peripheral immunomodulation in a murine glioma model. BMC Immunol 10:11
Markovic DS, Vinnakota K, Chirasani S et al (2009) Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci U S A 106:12530–12535
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:e23902
Vinnakota K, Hu F, Ku MC et al (2013) Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion. Neuro-Oncology 15:1457–1468
Perry VH, Teeling J (2013) Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin Immunopathol 35:601–612
Glass R, Synowitz M (2014) CNS macrophages and peripheral myeloid cells in brain tumours. Acta Neuropathol 128:347–362
Lisi L, Stigliano E, Lauriola L, Navarra P, Dello Russo C (2014) Proinflammatory-activated glioma cells induce a switch in microglial polarization and activation status, from a predominant M2b phenotype to a mixture of M1 and M2a/B polarized cells. ASN Neuro 6:171–183
Szulzewsky F, Pelz A, Feng X et al (2015) Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PLoS One 10:e0116644
Qin T, Wang C, Chen X et al (2015) Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma. Toxicol Appl Pharmacol 286:112–123
Xu S, Wei J, Wang F et al (2014) Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma. J Natl Cancer Inst 106. pii:dju162.
Shen X, Burguillos MA, Osman AM et al (2016) Glioma-induced inhibition of caspase-3 in microglia promotes a tumor-supportive phenotype. Nat Immunol 17:1282–1290
Grauwet K, Chiocca EA (2016) Glioma and microglia, a double entendre. Nat Immunol 17:1240–1242
Kennedy BC, Showers CR, Anderson DE et al (2013) Tumor-associated macrophages in glioma: friend or foe? J Oncol 2013:486912
da Fonseca AC, Badie B (2013) Microglia and macrophages in malignant gliomas: recent discoveries and implications for promising therapies. Clin Dev Immunol 2013:264124
Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20–27
Magaña-Maldonado R, Chávez-Cortez EG, Olascoaga-Arellano NK et al (2016) Immunological Evasion in Glioblastoma. Biomed Res Int 2016:7487313
Watters JJ, Schartner JM, Badie B (2005) Microglia function in brain tumors. J Neurosci Res 81:447–455
Sonabend AM, Rolle CE, Lesniak MS (2008) The role of regulatory T cells in malignant glioma. Anticancer Res 28:1143–1150
Kamran N, Chandran M, Lowenstein PR, Castro MG (2016) Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy. Clin Immunol. pii:S1521-6616(16)30518-6
Chang AL, Miska J, Wainwright DA et al (2016) CCL2 produced by the Glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res 76:5671–5682
Hwang JS, Jung EH, Kwon MY, Han IO (2016) Glioma-secreted soluble factors stimulate microglial activation: the role of interleukin-1β and tumor necrosis factor-α. J Neuroimmunol 298:165–171
Barnum SR (1999) Inhibition of complement as a therapeutic approach in inflammatory central nervous system (CNS) disease. Mol Med 5:569–582
Morioka T, Baba T, Black KL, Streit WJ (1992) Immunophenotypic analysis of infiltrating leukocytes and microglia in an experimental rat glioma. Acta Neuropathol 83:590–597
Pong WW, Higer SB, Gianino SM, Emnett RJ, Gutmann DH (2013) Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation. Ann Neurol 73:303–308
Daginakatte GC, Gutmann DH (2007) Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth. Hum Mol Genet 16:1098–1112
Morimura T, Neuchrist C, Kitz K et al (1990) Monocyte subpopulations in human gliomas: expression of fc and complement receptors and correlation with tumor proliferation. Acta Neuropathol 80:287–294
Sutter A, Hekmat A, Luckenbach GA (1991) Antibody-mediated tumor cytotoxicity of microglia. Pathobiology 59:254–258
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 216:15–24
Zhang H, Zhang W, Sun X et al (2016) Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization. Oncotarget 7:50099–50116
Wu A, Wei J, Kong LY et al (2010) Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-Oncology 12:1113–1125
Ye XZ, Xu SL, Xin YH et al (2012) Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol 189:444–453
Yi L, Xiao H, Xu M et al (2011) Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J Neuroimmunol 232:75–82
Noorani I, Petty G, Grundy PL et al (2015) Novel association between microglia and stem cells in human gliomas: a contributor to tumour proliferation? J Pathol Clin Res 1:67–75
Zhou W, Ke SQ, Huang Z et al (2015) Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol 17:170–182
Wu T, Luo Q, Ouyang G (2015) Periostin: a potent chemotactic factor for recruiting tumor-associated macrophage. Protein Cell 6:235–237
Brandenburg S, Müller A, Turkowski K et al (2016) Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol 131:365–378
Coniglio S, Miller I, Symons M, Segall JE (2016) Coculture assays to study macrophage and microglia stimulation of glioblastoma invasion. J Vis Exp 116
Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro-Oncology 8:261–279
Parney IF, Waldron JS, Parsa AT (2009) Flow cytometry and in vitro analysis of human glioma-associated macrophages. Laboratory investigation J Neurosurg 110:572–582
Wei J, Gabrusiewicz K, Heimberger A (2013) The controversial role of microglia in malignant gliomas. Clin Dev Immunol 2013:285246
Prinz M, Tay TL, Wolf Y, Jung S (2014) Microglia: unique and common features with other tissue macrophages. Acta Neuropathol 128:319–331
Müller A, Brandenburg S, Turkowski K, Müller S, Vajkoczy P (2015) Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells. Int J Cancer 137:278–288
Zhu W, Carney KE, Pigott VM et al (2016) Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis 37:839–851
Szulzewsky F, Arora S, de Witte L et al (2016) Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples. Glia 64:1416–1436
Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553
Sielska M, Przanowski P, Wylot B et al (2013) Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. J Pathol 230:310–321
Coniglio SJ, Eugenin E, Dobrenis K et al (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
Sarkar S, Döring A, Zemp FJ et al (2014) Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells. Nat Neurosci 17:46–55
Placone AL, Quiñones-Hinojosa A, Searson PC (2016) The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. Tumour Biol 37:61–69
Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G (2013) Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One 8:e80908
Schiffer D (1991) Pathology and neuroepidemiology of the brain and nervous system. Curr Opin Oncol 3:449–458
Hochreiter-Hufford A, Ravichandran KS (2013) Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harb Perspect Biol 5:a008748
Bayerl SH, Niesner R, Cseresnyes Z et al (2016) Time lapse in vivo microscopy reveals distinct dynamics of microglia-tumor environment interactions-a new role for the tumor perivascular space as highway for trafficking microglia. Glia 64:1210–1226
Prosniak M, Harshyne LA, Andrews DW et al (2013) Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. Clin Cancer Res 19:3776–3786
Christofides A, Kosmopoulos M, Piperi C (2015) Pathophysiological mechanisms regulated by cytokines in gliomas. Cytokine 71:377–384
Michelson N, Rincon-Torroella J, Quiñones-Hinojosa A, Greenfield JP (2016) Exploring the role of inflammation in the malignant transformation of low-grade gliomas. J Neuroimmunol 297:132–140
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This work was supported by Cassa di Risparmio di Vercelli Foundation, Vercelli, Italy.
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Schiffer, D., Mellai, M., Bovio, E. et al. The neuropathological basis to the functional role of microglia/macrophages in gliomas. Neurol Sci 38, 1571–1577 (2017). https://doi.org/10.1007/s10072-017-3002-x
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DOI: https://doi.org/10.1007/s10072-017-3002-x