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MIKROGLIJA: PASIVNI POSMATRAČ ILI AKTIVNI SAUČESNIK U GLIOBLASTOMU? /

MICROGLIA: PASSIVE OBSERVER OR ACTIVE ACCOMPLICE IN GLIOBLASTOMA?

Authors

 

Natali Rakočević1, Nikola Aleksić1, Jovana Drljača1, Bojana Andrejić Višnjić1, Nada Vučković2, Ivan Čapo1

1Katedra za histologiju i embriologiju, Medicinski fakultet, Univerzitet u Novom Sadu
2Katedra za patologiju, Medicinski fakultet, Univerzitet u Novom Sadu.

 

UDK: 616.831-006


The paper was received / Rad primljen: 12.10.2020.

Accepted / Rad prihvaćen: 30.11.2020.

 


Correspondence to:


Natali Rakočević
Medicinski fakultet Univerziteta u Novom Sadu,
Hajduk Veljkova 3, 21000 Novi Sad, Republika Srbija.
e-mail: 1441d20@mf.uns.ac.rs

 

 

Sažetak


Glioblastom je najagresivniji primarni tumor centralnog nervnog sistema, i uprkos radikalnoj multimodalnoj terapiji, prosečno preživljavanje je veoma kratko. Jedna od histoloških karakteristika je prisustvo većeg broja GAM ćelija – glioblastom asocirane mikroglije/makrofaga. Usled hemoatraktanata koje sekretuje glioblastom, prvobitno dolazi do migracije rezidentne mikrogije okolnog moždanog parenhima, a kasnije i do infiltracije cirkulišućim monocitima. Ipak, ove ćelije urođenog imuniteta ne usporavaju dalju progresiju tumora. Uočena je sposobnost glioblastoma da menja fenotip GAM ćelija iz pro- u antiinflamatorni. Osim što ne napadaju tumorske ćelije, ove reprogramirane ćelije aktivno suprimiraju odgovor celularnog imuniteta. Ovaj imunološki beg dopušta glioblastomu dalju progresiju. Međutim, međusobni odnos mikroglije i tumorskih ćelija je znatno kompleksniji. Brojni radovi uspeli su da dokažu ulogu mikroglije u potenciranju proliferativnog, invazivnog i neoangiogenetskog potencijala glioblastoma. Posebno interesantni su rezultati koji identifikuju mikrogliju kao važan faktor u rezistenciji glioblastoma na radioterapiju i različite hemioterapeutike, što ukazuje na njen značaj u lošoj prognozi i preživljavanju pacijenata. Istovremeno međutim, modulacija funkcije mikroglije kao supstrata novih terapijskih modaliteta, mogla bi povećati senzitivnost glioblastoma na terapiju, a sledstveno i poboljšati stopu preživljavanja.


Ključne reči:

glioblastom; mikroglija; makrofagi; urođeni imunitet; mikrosredina tumora;

 

Abstract


Glioblastoma is the most aggressive primary central nervous system malignancy, and despite radical multimodal treatment, the average survival period is very short. One of the histological characteristics is the high number of GAM cells – glioblastoma associated microglia/macrophages. Through chemoattractants that glioblastoma secretes, initially, the resident microglia of surrounding brain tissue accumulates in the tumour. Later, the tumour is infiltrated by circulating monocytes. However, these innate immune cells are not able to slow down the tumour progression. It has been observed that glioblastoma can change the phenotype of GAM cells from pro- to anti-inflammatory. In addition to not attacking the tumour cells, these reprogrammed GAM cells strongly suppress the cellular immune response. This immune escape enables the further progression of glioblastoma. Relationship between microglia and tumour cells is much more complex, though. Numerous studies have shown the significant potentiating role of microglia in tumour proliferation, invasion and neoangiogenesis. Of particular interest are results that identified microglia as an essential factor for glioblastoma resistance to radiotherapy and chemotherapeutic agents, underlining its significance for bad prognosis and survival rate. On the other hand, modulating the microglia function as a new treatment target could potentially increase tumour sensitivity and therefore, the survival rate.


Keywords:

glioblastoma; microglia; macrophages; innate immunity; tumour microenvironment;

 

 

References:

  1. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014;23(10):1985-96.
  2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.
  3. Sarkaria JN, Kitange GJ, James CD, Plummer R, Calvert H, Weller M, et al. Mechanisms of chemoresistance to alkylating agents in malignant glioma. Clin Cancer Res. 2008;14:2900-08.
  4. Ellison D, Love S et al. Neuropathology: A Reference Text of CNS Pathology. 3rd ed. St. Louis: Mosby; 2012.
  5. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia. 2012;60:502-14.
  6. Graeber MB, Scheithauer BW, Kreutzberg GW. Microglia in brain tumors. Glia. 2002;40:252-9.
  7. von Bernhardi R, Heredia F, Salgado N, Muñoz P. Microglia function in the normal brain. In: von Bernhardi R, editor. Glial Cells in Health and Disease of the CNS. Advances in Experimental Medicine and Biology. Cham: Springer; 2016. P. 67-92.
  8. Matias D, Balça-Silva J, da Graça GC, Wanjiru CM, Macharia LW, Nascimento CP, et al. Microglia/Astrocytes-Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors. Front Cell Neurosci. 2018;12:235.
  9. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15(5):300-12.
  10. Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013;14:986-95.
  11. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S,et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841-45.
  12. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10(11):1387-94.
  13. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314-18.
  14. Kierdorf K, Prinz M. Factors regulating microglia activation. Front Cell Neurosci. 2013;7:44.
  15. Kettenmann H, Hanisch UK, Noda M, Verkhratsky A. Physiology of microglia. Physiol. Rev. 2011;91:461-553.
  16. Prat E, Baron P, Meda L, Scarpini E, Galimberti D, Ardolino G, et al. The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with beta-amyloid protein. Neurosci Lett. 2000;283:177-80.
  17. Alterman RL, Stanley E. Colony stimulating factor-1 expression in human glioma. Mol Chem Neuropathol. 1994;21(2-3):177-88.
  18. 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. 1999;44:1077-82.
  19. 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. 2015; 137:278–88.
  20. Gabrusiewicz K, Ellert-Miklaszewska A, Lipko M, Sielska M, Frankowska M, Kaminska B. Characteristics of the alternative phenotype of microglia/macrophages and its modulation in experimental gliomas. PLoS One. 2011;6(8):e23902.
  21. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, et al. Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci. 2007;10(12):1544-53.
  22. Orihuela, R, McPherson, CA, Harry GJ. Microglial M1/M2 polarization and metabolic states.Br J Pharmacol. 2016;173:649-65.
  23. Locarno CV, Simonelli M, Carenza C, Capucetti A, Stanzani E, Lorenzi E, et al. Role of myeloid cells in the immunosuppressive microenvironment in gliomas. Immunobiology. 2019; 225:151853.
  24. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006; 66:3294-302.
  25. Schneider J, Hofman FM, Apuzzo ML, Hinton DR. Cytokines and immunoregulatory molecules in malignant glial neoplasms. J Neurosurg 1992;77:265-73.
  26. Matias D, Predes D, Niemeyer Filho P, Lopes MC, Abreu JG, Lima FRS, et al. Microglia-glioblastoma interactions: New role for Wnt signaling. Biochim Biophys Acta Rev Cancer. 2017;1868(1):333-40.
  27. Hussain SF, Yang D, Suki D, Grimm E, Heimberger AB. Innate immune functions of microglia isolated from human glioma patients. J. Transl. Med. 2006;4:15.
  28. Taniguchi Y, Ono K, Yoshida S, Tanaka R. Antigen-presenting capability of glial cells under glioma-harboring conditions and the effect of glioma-derived factors on antigen presentation. J Neuroimmunol. 2000;111:177-85. 
  29. Flugel A, Labeur MS, Grasbon-Frodl EM, Kreutzberg GW, Graeber MB. Microglia only weakly present glioma antigen to cytotoxic T cells. Int J Dev Neurosci 1999;17:547-56.
  30. Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol. 2010;12:351-65.
  31. Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the m2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol. 2008;216:15-24.
  32. Prosniak M, Harshyne LA, Andrews DW, Kenyon LC, Bedelbaeva K, Apanasovich TV, et al. Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. Clin Cancer Res. 2013;19(14):3776-86.
  33. Sorensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW. Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol. 2018;44(2):185-206.
  34. Poon CC, Gordon PMK, Liu K, Yang R,Sarkar S, Mirzaei R, et al. Differential microglia and macrophage profiles in human IDH-mutant and -wild type glioblastoma. Oncotarget 2019;10:3129-43.
  35. Roggendorf W, Strupp S, Paulus W. Distribution and characterization of microglia/macrophages in human brain tumors. Acta Neuropathol 1996;92:288-93.
  36. Morris CS, Esiri MM. Immunocytochemical study of macrophages and microglial cells and extracellular matrix components in human CNS disease. 1. Gliomas. J Neurol Sci. 1991;101(1):47-58.
  37. Yi L, Xiao H, Xu M, Ye X, Hu J, Li F, et al. Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J Neuroimmunol 2011;232:75-82.
  38. Klein R, Roggendorf, W. Increased microglia proliferation separates pilocytic astrocytomas from diffuse astrocytomas: a double labeling study. Acta Neuropathol. 2001;101:245-48.
  39. Badie B, Schartner J, Prabakaran S, Paul J, Vorpahl J. Expression of Fas ligand by microglia: possible role in glioma immune evasion. J Neuroimmunol. 2001;120:19-24.
  40. Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 2006; 66:3294-302.
  41. Zhai H, Heppner FL, Tsirka SE. Microglia/macrophages promote glioma progression. Glia. 2011;59:472-85.
  42. Brandenburg S, Muller A, Turkowski K, Radev YT, Rot S, Schmidt C, et al. Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors. Acta Neuropathol. 2016;131:365-78.
  43. Fonseca AC, Romao L, Amaral RF, Assad Kahn S, Lobo D, Martins S, et al. Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neuroscience. 2012;200:130-41.
  44. Morimura T, Neuchrist C, Kitz K, Budka H, Scheiner O, Kraft D, et al. Monocyte subpopulations in human gliomas: expression of Fc and complement receptors and correlation with tumour proliferation. Acta Neuropathol (Berl). 1990;80:287-94.
  45. Bettinger I,Thanos S,Paulus W. Microglia promote glioma migration. Acta Neuropathol 2002;103:351-55.
  46. Markovic DS, Glass R, Synowitz M, Rooijen N, Kettenmann H. Microglia stimulate the invasiveness of glioma cells by increasing the activity of metalloprotease-2. J Neuropathol Exp Neurol. 2005;64(9):754-62.
  47. Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, et al. Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA. 2009;106(30):12530-5.
  48. Coniglio SJ, Segall JE. Review: Molecular mechanism of microglia stimulated glioblastoma invasion. Matrix Biol. 2013;32:372-80.
  49. Brem S, Cotran R, Folkman J. Tumor angiogenesis: A quantitative method for histologic grading. J Natl Cancer Inst. 1972;48:347-56.
  50. Soda Y, Myskiw C, Rommel A, Verma IM. Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme. J Mol Med (Berl). 2013;91(4):439-48.
  51. Hardee ME, Zagzag D. Mechanisms of glioma-associated neovascularization. Am J Pathol. 2012;181:1126-41.
  52. Shao R, Taylor SL, Oh DS, Schwartz LM. Vascular heterogeneity and targeting: the role of YKL-40 in glioblastoma vascularization. Oncotarget. 2015;6(38):40507-18.
  53. Nijaguna MB, Patil V, Urbach S, Shwetha SD, Sravani K, Hegde AS, et al. Glioblastoma-derived Macrophage Colony-stimulating Factor (MCSF) Induces Microglial Release of Insulin-like Growth Factor-binding Protein 1 (IGFBP1) to Promote Angiogenesis. J Biol Chem. 2015;290(38):23401-15.
  54. Chen X, Zhang L, Zhang IY, Liang J, Wang H, Ouyang M, et al.RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res 2014; 74:7285-97.
  55. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39:151-70.
  56. Bayerl SH, Niesner R, Cseresnyes Z, Radbruch H, Pohlan J, Brandenburg S et al.  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 2016; 64:1210-26.
  57. Kvisten M, Mikkelsen VE, Stensjøen AL, Solheim O, Van Der Want J, Torp SH. Microglia and macrophages in human glioblastomas: A morphological and immunohistochemical study. Mol Clin Oncol. 2019;11(1):31-6.
  58. Lima FR, Kahn SA, Soletti RC, Biasoli D, Alves T, da Fonseca AC, et al. Glioblastoma: therapeutic challenges, what lies ahead. Biochim Biophys Acta. 2012;1826(2):338-49.
  59. Julow J, Szeifert GT, Bálint K, Nyáry I, Nemes Z. The role of microglia/macrophage system in the tissue response to I-125 interstitial brachytherapy of cerebral gliomas. Neurol Res. 2007;29(3):233-8.
  60. Wang Q, Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. Cancer Cell. 2017;32(1):42-56.e6.
  61. Meng Y, Beckett MA, Liang H, Mauceri HJ, van Rooijen N, Cohen KS, et al. Blockade of tumor necrosis factor alpha signaling in tumor-associated macrophages as a radiosensitizing strategy. Cancer Res. 2010;70(4):1534-43.
  62. Leite DM, Baskovic BZ, Civita P, Neto C, Gumbleton M, Pilkington GJ. A human co-culture cell model incorporating microglia supports glioblastoma growth and migration, and confers resistance to cytotoxics. FASEB J. 2020;34:1710-27.

PDF 06-Vol 12 No4 Rakočević

 

 

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