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Novel concept of the border niche: glioblastoma cells use oligodendrocytes progenitor cells (GAOs) and microglia to acquire stem cell-like features

  • Takuichiro HideEmail author
  • Ichiyo Shibahara
  • Toshihiro Kumabe
Review Article
  • 84 Downloads

Abstract

Glioblastoma (GBM) is a major malignant brain tumor developing in adult brain white matter, characterized by rapid growth and invasion. GBM cells spread into the contralateral hemisphere, even during early tumor development. However, after complete resection of tumor mass, GBM commonly recurs around the tumor removal cavity, suggesting that a microenvironment at the tumor border provides chemo-radioresistance to GBM cells. Thus, clarification of the tumor border microenvironment is critical for improving prognosis in GBM patients. MicroRNA (miRNA) expression in samples from the tumor, tumor border, and peripheral region far from tumor mass was compared, and five miRNAs showing characteristically higher expression in the tumor border were identified, with the top three related to oligodendrocyte differentiation. Pathologically, oligodendrocyte lineage cells increased in the border, but were rare in tumors. Macrophages/microglia also colocalized in the border area. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, suggesting that OPCs and macrophages/microglia constitute a special microenvironment for GBM cells at the tumor border. The supportive function of OPCs for GBM cells has not been discussed previously. OPCs are indispensable for GBM cells to establish special niches for chemo-radioresistance outside the tumor mass.

Keywords

Oligodendrocyte progenitor cell Microglia Border niche Microenvironment Glioblastoma 

Notes

References

  1. 1.
    Stupp R, Hegi ME, Mason WP et al (2009) 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 10:459–466CrossRefGoogle Scholar
  2. 2.
    Ostrom QT, Gittleman H, Liao P et al (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16(Suppl 4):iv1-63CrossRefGoogle Scholar
  3. 3.
    Wilson CB (1992) Glioblastoma: the past, the present, and the future. Clin Neurosurg 38:32–48Google Scholar
  4. 4.
    Brandes AA, Tosoni A, Franceschi E et al (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol 27:1275–1279CrossRefGoogle Scholar
  5. 5.
    Schaub C, Kebir S, Junold N et al (2018) Tumor growth patterns of MGMT-non-methylated glioblastoma in the randomized GLARIUS trial. J Cancer Res Clin Oncol 144:1581–1589CrossRefGoogle Scholar
  6. 6.
    Hide T, Komohara Y, Miyasato Y et al (2018) Oligodendrocyte progenitor cells and macrophages/microglia produce glioma stem cell niches at the tumor border. EBioMedicine 30:94–104CrossRefGoogle Scholar
  7. 7.
    Singh SK, Hawkins C, Clarke ID et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401CrossRefGoogle Scholar
  8. 8.
    Hide T, Makino K, Nakamura H et al (2013) New treatment strategies to eradicate cancer stem cells and niches in glioblastoma. Neurol Med Chir (Tokyo) 53:764–772CrossRefGoogle Scholar
  9. 9.
    Charles NA, Holland EC, Gilbertson R et al (2011) The brain tumor microenvironment. Glia 59:1169–1180CrossRefGoogle Scholar
  10. 10.
    Fidoamore A, Cristiano L, Antonosante A et al (2016) Glioblastoma stem cells microenvironment: the paracrine roles of the niche in drug and radioresistance. Stem Cells Int 2016:6809105CrossRefGoogle Scholar
  11. 11.
    Ishii A, Kimura T, Sadahiro H et al (2016) Histological characterization of the tumorigenic “Peri-Necrotic Niche” harboring quiescent stem-like tumor cells in glioblastoma. PLoS One 11:e0147366CrossRefGoogle Scholar
  12. 12.
    Quail DF, Joyce JA (2017) The microenvironmental landscape of brain tumors. Cancer Cell 31:326–341CrossRefGoogle Scholar
  13. 13.
    Schiffer D, Annovazzi L, Casalone C et al (2018) Glioblastoma: microenvironment and niche concept. Cancers (Basel) 11(1):5CrossRefGoogle Scholar
  14. 14.
    Schiffer D, Mellai M, Bovio E et al (2018) Glioblastoma niches: from the concept to the phenotypical reality. Neurol Sci 39:1161–1168CrossRefGoogle Scholar
  15. 15.
    Lathia JD, Heddleston JM, Venere M et al (2011) Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell 8:482–485CrossRefGoogle Scholar
  16. 16.
    Silver DJ, Lathia JD (2018) Revealing the glioma cancer stem cell interactome, one niche at a time. J Pathol 244:260–264CrossRefGoogle Scholar
  17. 17.
    Leblond MM, Peres EA, Helaine C et al (2017) M2 macrophages are more resistant than M1 macrophages following radiation therapy in the context of glioblastoma. Oncotarget 8:72597–72612CrossRefGoogle Scholar
  18. 18.
    Arcuri C, Fioretti B, Bianchi R et al (2017) Microglia-glioma cross-talk: a two way approach to new strategies against glioma. Front Biosci (Landmark Ed) 22:268–309CrossRefGoogle Scholar
  19. 19.
    Roesch S, Rapp C, Dettling S et al (2018) When immune cells turn bad-tumor-associated microglia/macrophages in glioma. Int J Mol Sci 19:436CrossRefGoogle Scholar
  20. 20.
    Kros JM, Mustafa DM, Dekker LJ et al (2015) Circulating glioma biomarkers. Neuro Oncol 17:343–360CrossRefGoogle Scholar
  21. 21.
    Li C, Sun J, Xiang Q et al (2016) Prognostic role of microRNA-21 expression in gliomas: a meta-analysis. J Neurooncol 130:11–17CrossRefGoogle Scholar
  22. 22.
    Kohlhapp FJ, Mitra AK, Lengyel E et al (2015) MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene 34:5857CrossRefGoogle Scholar
  23. 23.
    Rooj AK, Mineo M, Godlewski J (2016) MicroRNA and extracellular vesicles in glioblastoma: small but powerful. Brain Tumor Pathol 33:77–88CrossRefGoogle Scholar
  24. 24.
    Barca-Mayo O, Lu QR (2012) Fine-tuning oligodendrocyte development by microRNAs. Front Neurosci 6:13CrossRefGoogle Scholar
  25. 25.
    Dugas JC, Cuellar TL, Scholze A et al (2010) Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron 65:597–611CrossRefGoogle Scholar
  26. 26.
    Zhao X, He X, Han X et al (2010) MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65:612–626CrossRefGoogle Scholar
  27. 27.
    Nazari B, Soleimani M, Ebrahimi-Barough S et al (2018) Overexpression of miR-219 promotes differentiation of human induced pluripotent stem cells into pre-oligodendrocyte. J Chem Neuroanat 91:8–16CrossRefGoogle Scholar
  28. 28.
    Wegener A, Deboux C, Bachelin C et al (2015) Gain of Olig2 function in oligodendrocyte progenitors promotes remyelination. Brain 138:120–135CrossRefGoogle Scholar
  29. 29.
    Birey F, Kokkosis AG, Aguirre A (2017) Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders. Curr Opin Neurobiol 47:93–103CrossRefGoogle Scholar
  30. 30.
    Lou W, Zhang X, Hu XY et al (2016) MicroRNA-219-5p inhibits morphine-induced apoptosis by targeting key cell cycle regulator WEE1. Med Sci Monit 22:1872–1879CrossRefGoogle Scholar
  31. 31.
    Kuratsu J, Leonard EJ, Yoshimura T (1989) Production and characterization of human glioma cell-derived monocyte chemotactic factor. J Natl Cancer Inst 81:347–351CrossRefGoogle Scholar
  32. 32.
    Komohara Y, Horlad H, Ohnishi K et al (2012) Importance of direct macrophage-tumor cell interaction on progression of human glioma. Cancer Sci 103:2165–2172CrossRefGoogle Scholar
  33. 33.
    Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20–27CrossRefGoogle Scholar
  34. 34.
    Pyonteck SM, Akkari L, Schuhmacher AJ et al (2013) CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19:1264–1272CrossRefGoogle Scholar
  35. 35.
    Wei J, Gabrusiewicz K, Heimberger A (2013) The controversial role of microglia in malignant gliomas. Clin Dev Immunol 2013:285246CrossRefGoogle Scholar
  36. 36.
    Komohara Y, Jinushi M, Takeya M (2014) Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci 105:1–8CrossRefGoogle Scholar
  37. 37.
    Jahani-Asl A, Yin H, Soleimani VD et al (2016) Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci 19:798–806CrossRefGoogle Scholar
  38. 38.
    Kaneko S, Nakatani Y, Takezaki T et al (2015) Ceacam1L modulates STAT3 signaling to control the proliferation of glioblastoma-initiating cells. Cancer Res 75:4224–4234CrossRefGoogle Scholar
  39. 39.
    Diksin M, Smith SJ, Rahman R (2017) The molecular and phenotypic basis of the glioma invasive perivascular niche. Int J Mol Sci 18(11):2342CrossRefGoogle Scholar
  40. 40.
    Calabrese C, Poppleton H, Kocak M et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82CrossRefGoogle Scholar
  41. 41.
    Ho IAW, Shim WSN (2017) Contribution of the microenvironmental Niche to glioblastoma heterogeneity. Biomed Res Int 2017:9634172Google Scholar
  42. 42.
    Bercury KK, Macklin WB (2015) Dynamics and mechanisms of CNS myelination. Dev Cell 32:447–458CrossRefGoogle Scholar
  43. 43.
    Kaller MS, Lazari A, Blanco-Duque C et al (2017) Myelin plasticity and behaviour-connecting the dots. Curr Opin Neurobiol 47:86–92CrossRefGoogle Scholar
  44. 44.
    Yeung MS, Zdunek S, Bergmann O et al (2014) Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 159:766–774CrossRefGoogle Scholar
  45. 45.
    Liu C, Sage JC, Miller MR et al (2011) Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146:209–221CrossRefGoogle Scholar
  46. 46.
    Hide T, Takezaki T, Nakatani Y et al (2011) Combination of a ptgs2 inhibitor and an epidermal growth factor receptor-signaling inhibitor prevents tumorigenesis of oligodendrocyte lineage-derived glioma-initiating cells. Stem Cells 29:590–599CrossRefGoogle Scholar
  47. 47.
    Sugiarto S, Persson AI, Munoz EG et al (2011) Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20:328–340CrossRefGoogle Scholar
  48. 48.
    Galvao RP, Kasina A, McNeill RS et al (2014) Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process. Proc Natl Acad Sci USA 111:E4214–E4223CrossRefGoogle Scholar
  49. 49.
    Hughes EG, Kang SH, Fukaya M et al (2013) Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nat Neurosci 16:668–676CrossRefGoogle Scholar
  50. 50.
    Dimou L, Gallo V (2015) NG2-glia and their functions in the central nervous system. Glia 63:1429–1451CrossRefGoogle Scholar
  51. 51.
    Fernandez-Castaneda A, Gaultier A (2016) Adult oligodendrocyte progenitor cells—multifaceted regulators of the CNS in health and disease. Brain Behav Immun 57:1–7CrossRefGoogle Scholar
  52. 52.
    McKenzie IA, Ohayon D, Li H et al (2014) Motor skill learning requires active central myelination. Science 346:318–322CrossRefGoogle Scholar
  53. 53.
    Young KM, Psachoulia K, Tripathi RB et al (2013) Oligodendrocyte dynamics in the healthy adult CNS: evidence for myelin remodeling. Neuron 77:873–885CrossRefGoogle Scholar
  54. 54.
    Marques S, Zeisel A, Codeluppi S et al (2016) Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system. Science 352:1326–1329CrossRefGoogle Scholar
  55. 55.
    Hosono J, Morikawa S, Ezaki T et al (2017) Pericytes promote abnormal tumor angiogenesis in a rat RG2 glioma model. Brain Tumor Pathol 34:120–129CrossRefGoogle Scholar
  56. 56.
    Butovsky O, Ziv Y, Schwartz A et al (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31:149–160CrossRefGoogle Scholar
  57. 57.
    Shigemoto-Mogami Y, Hoshikawa K, Goldman JE et al (2014) Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. J Neurosci 34:2231–2243CrossRefGoogle Scholar
  58. 58.
    Miron VE (2017) Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J Leukoc Biol 101:1103–1108CrossRefGoogle Scholar
  59. 59.
    Chen Z, Feng X, Herting CJ et al (2017) Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res 77:2266–2278CrossRefGoogle Scholar
  60. 60.
    Chen Z, Hambardzumyan D (2018) Immune microenvironment in glioblastoma subtypes. Front Immunol 9:1004CrossRefGoogle Scholar
  61. 61.
    Guan X, Hasan MN, Maniar S et al (2018) Reactive astrocytes in glioblastoma multiforme. Mol Neurobiol 55:6927–6938CrossRefGoogle Scholar
  62. 62.
    Brandao M, Simon T, Critchley G et al (2019) Astrocytes, the rising stars of the glioblastoma microenvironment. Glia 67:779–790CrossRefGoogle Scholar
  63. 63.
    Katz AM, Amankulor NM, Pitter K et al (2012) Astrocyte-specific expression patterns associated with the PDGF-induced glioma microenvironment. PLoS One 7:e32453CrossRefGoogle Scholar
  64. 64.
    Barcia C Jr, Gomez A, Gallego-Sanchez JM et al (2009) Infiltrating CTLs in human glioblastoma establish immunological synapses with tumorigenic cells. Am J Pathol 175:786–798CrossRefGoogle Scholar
  65. 65.
    Lundgaard I, Osorio MJ, Kress BT et al (2014) White matter astrocytes in health and disease. Neuroscience 276:161–173CrossRefGoogle Scholar
  66. 66.
    Moore CS, Abdullah SL, Brown A et al (2011) How factors secreted from astrocytes impact myelin repair. J Neurosci Res 89:13–21CrossRefGoogle Scholar
  67. 67.
    Bardehle S, Kruger M, Buggenthin F et al (2013) Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nat Neurosci 16:580–586CrossRefGoogle Scholar
  68. 68.
    Gibson EM, Purger D, Mount CW et al (2014) Neuronal activity promotes oligodendrogenesis and adaptive myelination in the mammalian brain. Science 344:1252304CrossRefGoogle Scholar
  69. 69.
    Mitew S, Gobius I, Fenlon LR et al (2018) Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner. Nat Commun 9:306CrossRefGoogle Scholar
  70. 70.
    Venkatesh HS, Johung TB, Caretti V et al (2015) Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161:803–816CrossRefGoogle Scholar
  71. 71.
    Venkatesh HS, Tam LT, Woo PJ et al (2017) Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549:533–537CrossRefGoogle Scholar
  72. 72.
    Massague J, Obenauf AC (2016) Metastatic colonization by circulating tumour cells. Nature 529:298–306CrossRefGoogle Scholar
  73. 73.
    Plaks V, Koopman CD, Werb Z (2013) Cancer. Circulating tumor cells. Science 341:1186–1188CrossRefGoogle Scholar
  74. 74.
    Muller C, Holtschmidt J, Auer M et al (2014) Hematogenous dissemination of glioblastoma multiforme. Sci Transl Med 6:247ra101CrossRefGoogle Scholar
  75. 75.
    Macarthur KM, Kao GD, Chandrasekaran S et al (2014) Detection of brain tumor cells in the peripheral blood by a telomerase promoter-based assay. Cancer Res 74:2152–2159CrossRefGoogle Scholar
  76. 76.
    Liu T, Xu H, Huang M et al (2018) Circulating glioma cells exhibit stem cell-like properties. Cancer Res 78:6632–6642Google Scholar
  77. 77.
    Muragaki Y, Akimoto J, Maruyama T et al (2013) Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors. J Neurosurg 119:845–852CrossRefGoogle Scholar
  78. 78.
    Nitta M, Muragaki Y, Maruyama T et al (2018) Role of photodynamic therapy using talaporfin sodium and a semiconductor laser in patients with newly diagnosed glioblastoma. J Neurosurg 1:1–8CrossRefGoogle Scholar
  79. 79.
    Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5:79–88CrossRefGoogle Scholar
  80. 80.
    Shibahara I, Hanihara M, Watanabe T et al (2018) Tumor microenvironment after biodegradable BCNU wafer implantation: special consideration of immune system. J Neurooncol 137:417–427CrossRefGoogle Scholar
  81. 81.
    Asano K, Kurose A, Kamataki A et al (2018) Importance and accuracy of intraoperative frozen section diagnosis of the resection margin for effective carmustine wafer implantation. Brain Tumor Pathol 35:131–140CrossRefGoogle Scholar
  82. 82.
    Iuchi T, Hatano K, Kodama T et al (2014) Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 88:793–800CrossRefGoogle Scholar
  83. 83.
    Zschaeck S, Wust P, Graf R et al (2018) Locally dose-escalated radiotherapy may improve intracranial local control and overall survival among patients with glioblastoma. Radiat Oncol 13:251CrossRefGoogle Scholar

Copyright information

© The Japan Society of Brain Tumor Pathology 2019

Authors and Affiliations

  • Takuichiro Hide
    • 1
    Email author
  • Ichiyo Shibahara
    • 1
  • Toshihiro Kumabe
    • 1
  1. 1.Department of NeurosurgeryKitasato University School of MedicineSagamiharaJapan

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