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Cited by 1,683Immune cells in cancerGlioma Diagnosis and TreatmentNeuroinflammation and Neurodegeneration Mechanisms

The role of microglia and macrophages in glioma maintenance and progression

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Hambardzumyan, Dolores, Gutmann, David H, Kettenmann, Helmut·2016·Nature Neuroscience
DOI 10.1038/nn.4185PMC PMC4876023
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Abstract

There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.

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Crossref · 10.1038/nn.4185

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  • This is the first study to provide direct evidence that chronic stress is sufficient to allow infiltration of circulating cytokines in the absence of local mechanical trauma or a brain tumor.

    “To our knowledge, this is the first study to provide direct evidence that chronic stress is sufficient to allow infiltration of circulating cytokines in the absence of local mechanical trauma or a brain tumor41, 42.”

    From Social stress induces neurovascular pathology promoting depression (2017) · cites this paper as [42]

    The ‘Origins of glioma associated microglia and macrophages’ section (page unavailable) discusses infiltration of blood-derived monocytes into the diseased CNS, and ‘TAM recruitment’ describes macrophages accumulating around gliomas. This supports the brain-tumor comparison, but the paper does not report infiltration of circulating cytokines or show that chronic stress is sufficient to cause it. The ‘first study’ characterization is the citing authors’ own conclusion. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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  1. [1]Gutmann DH Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma Genome Res 23 431 439 2013 23222849 PMC3589532
  2. [2]Simmons GW 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 51 62 2011 21157378 PMC3044783
  3. [3]Morantz RA Wood GW Foster M Clark M Gollahon K Macrophages in experimental and human brain tumors. Part 2: studies of the macrophage content of human brain tumors J Neurosurg 50 305 311 1979 422981
  4. [4]Rossi ML Hughes JT Esiri MM Coakham HB Brownell DB Immunohistological study of mononuclear cell infiltrate in malignant gliomas Acta Neuropathol 74 269 277 1987 3314311
  5. [6]Ling EA Wong WC The origin and nature of ramified and amoeboid microglia: a historical review and current concepts Glia 7 9 18 1993 8423067
  6. [7]Biffi A Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells J Clin Invest 113 1118 1129 2004 15085191 PMC385395
  7. [8]Simard AR Rivest S Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia FASEB J 18 998 1000 2004 15084516
  8. [9]Priller J Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment Nat Med 7 1356 1361 2001 11726978
  9. [10]Flügel A Bradl M Kreutzberg GW Graeber MB Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy J Neurosci Res 66 74 82 2001 11599003
  10. [12]Massengale M Wagers AJ Vogel H Weissman IL Hematopoietic cells maintain hematopoietic fates upon entering the brain J Exp Med 201 1579 1589 2005 15897275 PMC2212913
  11. [13]Ajami B Bennett JL Krieger C Tetzlaff W Rossi FM Local self-renewal can sustain CNS microglia maintenance and function throughout adult life Nat Neurosci 10 1538 1543 2007 18026097
  12. [14]Ajami B Bennett JL Krieger C McNagny KM Rossi FM Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool Nat Neurosci 14 1142 1149 2011 21804537
  13. [18]Shi C Pamer EG Monocyte recruitment during infection and inflammation Nat Rev Immunol 11 762 774 2011 21984070 PMC3947780
  14. [19]Geissmann F Jung S Littman DR Blood monocytes consist of two principal subsets with distinct migratory properties Immunity 19 71 82 2003 12871640
  15. [21]Badie B Schartner JM Flow cytometric characterization of tumor-associated macrophages in experimental gliomas Neurosurgery 46 957 961 discussion 961–962 2000 10764271
  16. [22]Parney IF Waldron JS Parsa AT Flow cytometry and in vitro analysis of human glioma-associated macrophages. Laboratory investigation J Neurosurg 110 572 582 2009 19199469 PMC3064468
  17. [23]Muller A Brandenburg S Turkowski K Muller S Vajkoczy P Resident microglia, and not peripheral macrophages, are the main source of brain tumor mononuclear cells Int J Cancer 137 278 288 2014 25477239
  18. [25]Feng X Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis Oncotarget 6 15077 15094 2015 25987130 PMC4558137
  19. [26]Yang I Han SJ Sughrue ME Tihan T Parsa AT Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology J Neurosurg 115 505 511 2011 21663411
  20. [27]Klein R Roggendorf W Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study Acta Neuropathol 101 245 248 2001 11307624
  21. [28]Komohara Y Ohnishi K Kuratsu J Takeya M Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas J Pathol 216 15 24 2008 18553315
  22. [29]Dorward IG Postoperative imaging surveillance in pediatric pilocytic astrocytomas J Neurosurg Pediatr 6 346 352 2010 20887107
  23. [30]Bajenaru ML Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity Cancer Res 63 8573 8577 2003 14695164
  24. [31]Listernick R Charrow J Greenwald MJ Esterly NB Optic gliomas in children with neurofibromatosis type 1 J Pediatr 114 788 792 1989 2497236
  25. [32]Kim KY Ju WK Hegedus B Gutmann DH Ellisman MH Ultrastructural characterization of the optic pathway in a mouse model of neurofibromatosis-1 optic glioma Neuroscience 170 178 188 2010 20600672 PMC2926211
  26. [33]Pong WW Higer SB Gianino SM Emnett RJ Gutmann DH Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation Ann Neurol 73 303 308 2013 23424002 PMC3608848
  27. [34]Bajenaru ML Garbow JR Perry A Hernandez MR Gutmann DH Natural history of neurofibromatosis 1-associated optic nerve glioma in mice Ann Neurol 57 119 127 2005 15622533
  28. [35]Daginakatte GC Gutmann DH Neurofibromatosis-1 (Nf1) heterozygous brain microglia elaborate paracrine factors that promote Nf1-deficient astrocyte and glioma growth Hum Mol Genet 16 1098 1112 2007 17400655
  29. [36]Daginakatte GC Gianino SM Zhao NW Parsadanian AS Gutmann DH Increased c-Jun-NH2-kinase signaling in neurofibromatosis-1 heterozygous microglia drives microglia activation and promotes optic glioma proliferation Cancer Res 68 10358 10366 2008 19074905
  30. [37]Prada CE Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition Acta Neuropathol 125 159 168 2013 23099891 PMC3547628
  31. [38]Yang FC Nf1-dependent tumors require a microenvironment containing Nf1+/– and c-kit–dependent bone marrow Cell 135 437 448 2008 18984156 PMC2788814
  32. [39]Warrington NM Spatiotemporal differences in CXCL12 expression and cyclic AMP underlie the unique pattern of optic glioma growth in neurofibromatosis type 1 Cancer Res 67 8588 8595 2007 17875698
  33. [40]Warrington NM Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1 Cancer Res 70 5717 5727 2010 20551058 PMC2905483
  34. [41]Solga AC RNA-sequencing reveals oligodendrocyte and neuronal transcripts in microglia relevant to central nervous system disease Glia 63 531 548 2014 25258010 PMC4331255
  35. [42]Solga AC RNA-sequencing of tumor-associated microglia reveals Ccl5 as a stromal chemokine critical for neurofibromatosis-1 glioma growth Neoplasia 17 777 788 2015 PMC4656811 26585233
  36. [43]Mantovani A Sozzani S Locati M Allavena P Sica A Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes Trends Immunol 23 549 555 2002 12401408
  37. [45]Kennedy BC Tumor-associated macrophages in glioma: friend or foe? J Oncol 2013 486912 2013 23737783 PMC3664503
  38. [46]Gabrusiewicz K Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas PLoS One 6 e23902 2011 21901144 PMC3162015
  39. [47]Kees T Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation Neurooncol 14 64 78 2012 PMC3245995 22015597
  40. [48]Umemura N Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1- and M2-type characteristics J Leukoc Biol 83 1136 1144 2008 18285406
  41. [49]Li W Graeber MB The molecular profile of microglia under the influence of glioma Neurooncol 14 958 978 2012 PMC3408253 22573310
  42. [50]Markovic DS Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion Proc Natl Acad Sci USA 106 12530 12535 2009 19617536 PMC2718387
  43. [51]Sica A Schioppa T Mantovani A Allavena P Tumour-associated macrophages are a distinct M2 polarized population promoting tumour progression: potential targets of anti-cancer therapy Eur J Cancer 42 717 727 2006 16520032
  44. [52]Ye XZ Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway J Immunol 189 444 453 2012 22664874
  45. [53]Szulzewsky F Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1 PLoS One 10 e0116644 2015 25658639 PMC4320099
  46. [54]Zeiner PS MIF receptor CD74 is restricted to microglia/macrophages, associated with a M1-polarized immune milieu and prolonged patient survival in gliomas Brain Pathol 25 491 504 2014 25175718 PMC8029437
  47. [55]Pong WW F11R is a novel monocyte prognostic biomarker for malignant glioma PLoS One 8 e77571 2013 24147027 PMC3795683
  48. [57]Lisi L Laudati E Navarra P Dello Russo C The mTOR kinase inhibitors polarize glioma-activated microglia to express a M1 phenotype J Neuroinflammation 11 125 2014 25051975 PMC4128534
  49. [58]Qin T Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma Toxicol Appl Pharmacol 286 112 123 2015 25818600
  50. [59]Xu S Effect of miR-142-3p on the M2 macrophage and therapeutic efficacy against murine glioblastoma J Natl Cancer Inst 106 dju162 2014 24974128 PMC4271080
  51. [60]Platten M Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas Ann Neurol 54 388 392 2003 12953273
  52. [61]Okada M Tumor-associated macrophage/microglia infiltration in human gliomas is correlated with MCP-3, but not MCP-1 Int J Oncol 34 1621 1627 2009 19424580
  53. [62]Badie B Schartner J Klaver J Vorpahl J In vitro modulation of microglia motility by glioma cells is mediated by hepatocyte growth factor/scatter factor Neurosurgery 44 1077 1082 discussion 1082–1083 1999 10232541
  54. [63]Wang SC Hong JH Hsueh C Chiang CS Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model Lab Invest 92 151 162 2012 21894147
  55. [64]Paolicelli RC Bisht K Tremblay ME Fractalkine regulation of microglial physiology and consequences on the brain and behavior Front Cell Neurosci 8 129 2014 24860431 PMC4026677
  56. [65]Liu C Luo D Streit WJ Harrison JK 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 98 105 2008 18508133 PMC2561213
  57. [66]Rodero M Polymorphism in the microglial cell-mobilizing CX3CR1 gene is associated with survival in patients with glioblastoma J Clin Oncol 26 5957 5964 2008 19001328
  58. [67]Ku MC GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis Acta Neuropathol 125 609 620 2013 23344256
  59. [68]Coniglio SJ 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 2012 22294205 PMC3356419
  60. [69]Sielska M Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response J Pathol 230 310 321 2013 23520016
  61. [70]Bettinger I Thanos S Paulus W Microglia promote glioma migration Acta Neuropathol 103 351 355 2002 11904754
  62. [71]Markovic DS Glass R Synowitz M Rooijen Nv Kettenmann H Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2 J Neuropathol Exp Neurol 64 754 762 2005 16141784
  63. [72]Carvalho da Fonseca AC Increased expression of stress inducible protein 1 in glioma-associated microglia/macrophages J Neuroimmunol 274 71 77 2014 25042352 PMC4152559
  64. [73]Zhang J A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis Carcinogenesis 33 312 319 2012 22159219
  65. [75]Mizutani M The fractalkine receptor but not CCR2 is present on microglia from embryonic development throughout adulthood J Immunol 188 29 36 2012 22079990 PMC3244524
  66. [76]Wick W Platten M Weller M Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta J Neurooncol 53 177 185 2001 11716069
  67. [77]Wesolowska A 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 27 918 930 2008 17684491
  68. [78]Lehnardt S Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor–mediated neuronal injury Glia 58 253 263 2010 19705460
  69. [79]Vinnakota K Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion Neurooncol 15 1457 1468 2013 PMC3813418 24014382
  70. [80]Hu F Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling Neurooncol 17 200 210 2015 PMC4288527 25452390
  71. [81]Hu F Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline Int J Cancer 135 2569 2578 2014 24752463 PMC4519695
  72. [82]Chen X RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma Cancer Res 74 7285 7297 2014 25326491 PMC4268204
  73. [83]Bao S Glioma stem cells promote radioresistance by preferential activation of the DNA damage response Nature 444 756 760 2006 17051156
  74. [84]Hambardzumyan D Squatrito M Holland EC Radiation resistance and stem-like cells in brain tumors Cancer Cell 10 454 456 2006 17157785
  75. [85]Bleau AM PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells Cell Stem Cell 4 226 235 2009 19265662 PMC3688060
  76. [86]Yi L Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma J Neuroimmunol 232 75 82 2011 21056915
  77. [87]Sarkar S Therapeutic activation of macrophages and microglia to suppress brain tumor-initiating cells Nat Neurosci 17 46 55 2014 24316889
  78. [88]Wu A Glioma cancer stem cells induce immunosuppressive macrophages/microglia Neurooncol 12 1113 1125 2010 PMC3098021 20667896
  79. [89]Hoelzinger DB Demuth T Berens ME Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment J Natl Cancer Inst 99 1583 1593 2007 17971532
  80. [90]Kioi M Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice J Clin Invest 120 694 705 2010 20179352 PMC2827954
  81. [91]Wang SC Yu CF Hong JH Tsai CS Chiang CS Radiation therapy-induced tumor invasiveness is associated with SDF-1-regulated macrophage mobilization and vasculogenesis PLoS One 8 e69182 2013 23940516 PMC3734136
  82. [92]Lu-Emerson C Increase in tumor-associated macrophages after antiangiogenic therapy is associated with poor survival among patients with recurrent glioblastoma Neurooncol 15 1079 1087 2013 PMC3714160 23828240
  83. [93]Piao Y Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype Neurooncol 14 1379 1392 2012 PMC3480262 22965162
  84. [94]Zhang L Stat3 inhibition activates tumor macrophages and abrogates glioma growth in mice Glia 57 1458 1467 2009 19306372
  85. [95]Frazier JL Local delivery of minocycline and systemic BCNU have synergistic activity in the treatment of intracranial glioma J Neurooncol 64 203 209 2003 14558595
  86. [96]Poli A Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival Oncotarget 4 1527 1546 2013 24127551 PMC3824525

Cited by

Sorted by citations

Authors
Hambardzumyan, D., Gutmann, D. H., & Kettenmann, H.
Affiliations
  • Cleveland Clinic (US)
  • Washington University in St. Louis (US)
  • Max Delbrück Center (DE)
Corresponding author
Kettenmann, Helmut
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2015-12-29
Volume
19
Issue
1
Pages
20-27
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.4185
PMC
PMC4876023
OpenAlex
W2220215167
Cited by
1,683
References
9
Citations by year
2026: 185 · 2025: 158 · 2024: 200 · 2023: 190 · 2022: 218 · 2021: 206 · 2020: 179 · 2019: 131 · 2018: 96 · 2017: 84 · 2016: 31 · 2015: 2
FWCI
6.79
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Defense (W81XWH, W81XWH-13)
  • James S. McDonnell Foundation
  • Cleveland Clinic
  • National Cancer Institute (U01CA160882)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
glioma, tumor-associated macrophages, microglia, tumor microenvironment, tumor stroma, glioma progression, tumor cell migration, cytokines, growth factors, therapeutic targeting
MeSH terms
Animals, Glioma, Humans, Macrophages, Central Nervous System Neoplasms, Microglia, Disease Progression

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