Cellular and Molecular Neurobiology

, Volume 38, Issue 6, pp 1179–1195 | Cite as

Glioma Cell and Astrocyte Co-cultures As a Model to Study Tumor–Tissue Interactions: A Review of Methods

  • Ivan V. ChekhoninEmail author
  • Dimitry A. Chistiakov
  • Nadezhda F. Grinenko
  • Olga I. Gurina
Review Paper


Astrocytes are a dominant cell type that envelopes the glioma bed. Typically, that is followed by formation of contacts between astrocytes and glioma cells and accompanied by change in astrocyte phenotype, a phenomenon known as a ‘reactive astrogliosis.’ Generally considered glioma-promoting, astrocytes have many controversial peculiarities in communication with tumor cells, which need thorough examination in vitro. This review is devoted to in vitro co-culture studies of glioma cells and astrocytes. Firstly, we list several fundamental works which allow understanding the modalities of co-culturing. Cell-to-cell interactions between astrocytes and glioma cells, the roles of astrocytes in tumor metabolism, and glioma-related angiogenesis are reviewed. In the review, we also discuss communications between glioma stem cells and astrocytes. Co-cultures of glioma cells and astrocytes are used for studying anti-glioma treatment approaches. We also enumerate surgical, chemotherapeutic, and radiotherapeutic methods assessed in co-culture experiments. In conclusion, we underline collisions in the field and point out the role of the co-cultures for neurobiological studies.


Astrocytes Glioma Co-culture Periglioma zone Tumorigenesis 





Ataxia-telangiectasia mutated


Dimethyl sulfoxide


Excitatory amino acid transporter 2


Epidermal growth factor


Fibroblast growth factor


Glutamate and aspartate transporter






Glutamate transporter


Glioma stem-like cell


Glial fibrillary acidic protein


Connexin 43


Growth-related oncogene


Janus kinase




Monocyte chemoattractant protein


Matrix metalloproteinase


Matrix RNA

miRNA, miR



Mesenchymal stem cells


Neuropilin 2


Polymerase chain reaction


Propidium iodide


Small interfering RNA


Secreted protein acidic and rich and cysteine


Signal transducer and activator


Transforming growth factor


Tissue inhibitor of metalloproteinase


Tumor necrosis factor-related apoptosis-inducing ligand


Vascular endothelial growth factor



The work was carried out within the Grant Number 17-00-00161 issued by the Russian Foundation For Basic Research.

Author Contributions

IVC: source selection, analytical discussion, manuscript composing; OIG: analytical discussion; DAC and NFG: scientific editing.

Compliance with Ethical Standards

Conflict of interest

I.V. Chekhonin declares that he has financial relationship with the funding organization. O.I. Gurina declares that she has financial relationship with the funding organization. D.A. Chistiakov declares that he has no potential conflict of interest. N.F. Grinenko declares that she has no potential conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. Amara SG, Fontana AC (2002) Excitatory amino acid transporters: keeping up with glutamate. Neurochem Int 41:313–318PubMedCrossRefGoogle Scholar
  2. Aubert M, Badoual M, Christov C, Grammaticos B (2008) A model for glioma cell migration on collagen and astrocytes. J R Soc Interface 5:75–83. PubMedCrossRefGoogle Scholar
  3. Biasoli D, Sobrinho MF, da Fonseca AC, de Matos DG, Romao L, de Moraes Maciel R, Rehen SK, Moura-Neto V, Borges HL, Lima FR (2014) Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy. Oncogenesis 3:e123. PubMedPubMedCentralCrossRefGoogle Scholar
  4. Blank AE, Baumgarten P, Zeiner P, Zachskorn C, Loffler C, Schittenhelm J, Czupalla CJ, Capper D, Plate KH, Harter PN, Mittelbronn M (2015) Tumour necrosis factor receptor superfamily member 9 (TNFRSF9) is up-regulated in reactive astrocytes in human gliomas. Neuropathol Appl Neurobiol 41:e56-67. PubMedCrossRefGoogle Scholar
  5. Burdak-Rothkamm S, Short SC, Folkard M, Rothkamm K, Prise KM (2007) ATR-dependent radiation-induced gamma H2AX foci in bystander primary human astrocytes and glioma cells. Oncogene 26:993–1002. PubMedCrossRefGoogle Scholar
  6. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2012) The brain tumor microenvironment. Glia 60:502–514PubMedCrossRefGoogle Scholar
  7. Chekhonin VP, Baklaushev VP, Yusubalieva GM, Belorusova AE, Gulyaev MV, Tsitrin EB, Grinenko NF, Gurina OI, Pirogov YA (2012) Targeted delivery of liposomal nanocontainers to the peritumoral zone of glioma by means of monoclonal antibodies against GFAP and the extracellular loop of Cx43. Nanomedicine 8:63–70. PubMedCrossRefGoogle Scholar
  8. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, Parada LF (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526. PubMedPubMedCentralCrossRefGoogle Scholar
  9. Chen X, Zhang L, Zhang IY, Liang J, Wang H, Ouyang M, Wu S, da Fonseca ACC, Weng L, Yamamoto Y, Yamamoto H, Natarajan R, Badie B (2014) RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res 74:7285–7297. PubMedPubMedCentralCrossRefGoogle Scholar
  10. Chen W, Wang D, Du X, He Y, Chen S, Shao Q, Ma C, Huang B, Chen A, Zhao P, Qu X, Li X (2015) Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol 32:43. PubMedCrossRefGoogle Scholar
  11. Chen W, Xia T, Wang D, Huang B, Zhao P, Wang J, Qu X, Li X (2016) Human astrocytes secrete IL-6 to promote glioma migration and invasion through upregulation of cytomembrane MMP14. Oncotarget 7:62425–62438. PubMedPubMedCentralCrossRefGoogle Scholar
  12. Chen J, Mao S, Li H, Zheng M, Yi L, Lin JM, Lin ZX (2017) The pathological structure of the perivascular niche in different microvascular patterns of glioblastoma. PLoS ONE 12:e0182183. PubMedPubMedCentralCrossRefGoogle Scholar
  13. Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, Fang X, Sloan AE, Mao Y, Lathia JD, Min W, McLendon RE, Rich JN, Bao S (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153:139–152. PubMedPubMedCentralCrossRefGoogle Scholar
  14. Cottin S, Ghani K, de Campos-Lima PO, Caruso M (2010) Gemcitabine intercellular diffusion mediated by gap junctions: new implications for cancer therapy. Mol Cancer 9:141. PubMedPubMedCentralCrossRefGoogle Scholar
  15. de Bouard S, Christov C, Guillamo JS, Kassar-Duchossoy L, Palfi S, Leguerinel C, Masset M, Cohen-Hagenauer O, Peschanski M, Lefrancois T (2002) Invasion of human glioma biopsy specimens in cultures of rodent brain slices: a quantitative analysis. J Neurosurg 97:169–176. PubMedCrossRefGoogle Scholar
  16. de Groot JF, Liu TJ, Fuller G, Yung WK (2005) The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Res 65:1934–1940. PubMedCrossRefGoogle Scholar
  17. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci USA 104:19345–19350. PubMedCrossRefGoogle Scholar
  18. Doucette T, Rao G, Yang Y, Gumin J, Shinojima N, Bekele BN, Qiao W, Zhang W, Lang FF (2011) Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model. Neoplasia (New York NY) 13:716–725CrossRefGoogle Scholar
  19. Faria J, Romao L, Martins S, Alves T, Mendes FA, de Faria GP, Hollanda R, Takiya C, Chimelli L, Morandi V, de Souza JM, Abreu JG, Moura Neto V (2006) Interactive properties of human glioblastoma cells with brain neurons in culture and neuronal modulation of glial laminin organization. Differentiation 74:562–572. PubMedCrossRefGoogle Scholar
  20. Fidoamore A, Cristiano L, Antonosante A, d’Angelo M, Di Giacomo E, Astarita C, Giordano A, Ippoliti R, Benedetti E, Cimini A (2016) Glioblastoma stem cells microenvironment: The paracrine roles of the niche in drug and radioresistance. Stem Cells Int 2016:6809105. PubMedPubMedCentralCrossRefGoogle Scholar
  21. Flach EH, Rebecca VW, Herlyn M, Smalley KS, Anderson AR (2011) Fibroblasts contribute to melanoma tumor growth and drug resistance. Mol Pharm 8:2039–2049. PubMedPubMedCentralCrossRefGoogle Scholar
  22. Foreman PM, Friedman GK, Cassady KA, Markert JM (2017) Oncolytic virotherapy for the treatment of malignant glioma. Neurotherapeutics 14:333–344. PubMedPubMedCentralCrossRefGoogle Scholar
  23. Gabashvili AN, Baklaushev VP, Grinenko NF, Mel’nikov PA, Cherepanov SA, Levinsky AB, Chehonin VP (2016) Antitumor activity of rat mesenchymal stem cells during direct or indirect co-culturing with C6 glioma cells. Bull Experim Biol Med 160:519–524. CrossRefGoogle Scholar
  24. Gagliano N, Costa F, Cossetti C, Pettinari L, Bassi R, Chiriva-Internati M, Cobos E, Gioia M, Pluchino S (2009) Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model. Oncol Rep 22:1349–1356PubMedCrossRefGoogle Scholar
  25. Galavotti S, Bartesaghi S, Faccenda D, Shaked-Rabi M, Sanzone S, McEvoy A, Dinsdale D, Condorelli F, Brandner S, Campanella M, Grose R, Jones C, Salomoni P (2013) The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene 32:699–712. PubMedCrossRefGoogle Scholar
  26. Germano IM, Uzzaman M, Benveniste RJ, Zaurova M, Keller G (2006) Apoptosis in human glioblastoma cells produced using embryonic stem cell-derived astrocytes expressing tumor necrosis factor-related apoptosis-inducing ligand. J Neurosurg 105:88–95. PubMedCrossRefGoogle Scholar
  27. Gieryng A, Pszczolkowska D, Walentynowicz KA, Rajan WD, Kaminska B (2017) Immune microenvironment of gliomas. Lab Invest 97:498–518. PubMedCrossRefGoogle Scholar
  28. Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, Chong WY, Hummersone M, Rigoreau L, Menear KA, O’Connor MJ, Povirk LF, van Meter T, Valerie K (2009) Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther 8:2894–2902. PubMedPubMedCentralCrossRefGoogle Scholar
  29. Golding SE, Rosenberg E, Adams BR, Wignarajah S, Beckta JM, O’Connor MJ, Valerie K (2012) Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth control. Cell Cycle 11:1167–1173. PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gonzalez-Sanchez A, Jaraiz-Rodriguez M, Dominguez-Prieto M, Herrero-Gonzalez S, Medina JM, Tabernero A (2016) Connexin43 recruits PTEN and Csk to inhibit c-Src activity in glioma cells and astrocytes. Oncotarget 7:49819–49833. PubMedPubMedCentralCrossRefGoogle Scholar
  31. Grau SJ, Trillsch F, Tonn JC, Goldbrunner RH, Noessner E, Nelson PJ, von Luettichau I (2015) Podoplanin increases migration and angiogenesis in malignant glioma. Int J Clin Exp Pathol 8:8663–8670PubMedPubMedCentralGoogle Scholar
  32. Gritsenko PG, Ilina O, Friedl P (2012) Interstitial guidance of cancer invasion. J Pathol 226:185–199. PubMedCrossRefGoogle Scholar
  33. Gritsenko P, Leenders W, Friedl P (2017) Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma. Histochem Cell Biol. PubMedPubMedCentralCrossRefGoogle Scholar
  34. Grodecki J, Short AR, Winter JO, Rao SS, Winter JO, Otero JJ, Lannutti JJ, Sarkar A (2015) Glioma-astrocyte interactions on white matter tract-mimetic aligned electrospun nanofibers. Biotechnol Prog 31:1406–1415. PubMedCrossRefGoogle Scholar
  35. Guo J, Niu R, Huang W, Zhou M, Shi J, Zhang L, Liao H (2012) Growth factors from tumor microenvironment possibly promote the proliferation of glioblastoma-derived stem-like cells in vitro. Pathol Oncol Res 18:1047–1057. PubMedCrossRefGoogle Scholar
  36. Haghikia A, Ladage K, Hinkerohe D, Vollmar P, Heupel K, Dermietzel R, Faustmann PM (2008) Implications of antiinflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. J Neurosci Res 86:1781–1788. PubMedCrossRefGoogle Scholar
  37. Hinkerohe D, Wolfkuhler D, Haghikia A, Meier C, Faustmann PM, Schlegel U (2011) Dexamethasone differentially regulates functional membrane properties in glioma cell lines and primary astrocytes in vitro. J Neurooncol 103:479–489. PubMedCrossRefGoogle Scholar
  38. Ho IA, Toh HC, Ng WH, Teo YL, Guo CM, Hui KM, Lam PY (2013) Human bone marrow-derived mesenchymal stem cells suppress human glioma growth through inhibition of angiogenesis. Stem Cells (Dayton Ohio) 31:146–155. CrossRefGoogle Scholar
  39. Hong X, Sin WC, Harris AL, Naus CC (2015) Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget 6:15566–15577. PubMedPubMedCentralCrossRefGoogle Scholar
  40. Iwadate Y, Fukuda K, Matsutani T, Saeki N (2016) Intrinsic protective mechanisms of the neuron-glia network against glioma invasion. J Clin Neurosci 26:19–25. PubMedCrossRefGoogle Scholar
  41. Jacobs VL, De Leo JA (2013) Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model. J Neurooncol 114:33–42. PubMedPubMedCentralCrossRefGoogle Scholar
  42. Jacobs VL, Landry RP, Liu Y, Romero-Sandoval EA, De Leo JA (2012) Propentofylline decreases tumor growth in a rodent model of glioblastoma multiforme by a direct mechanism on microglia. Neuro-oncology 14:119–131. PubMedCrossRefGoogle Scholar
  43. Jamal M, Rath BH, Tsang PS, Camphausen K, Tofilon PJ (2012) The brain microenvironment preferentially enhances the radioresistance of CD133(+) glioblastoma stem-like cells. Neoplasia (New York NY) 14:150–158CrossRefGoogle Scholar
  44. Jaraiz-Rodriguez M, Tabernero MD, Gonzalez-Tablas M, Otero A, Orfao A, Medina JM, Tabernero A (2017) A short region of Connexin43 reduces human glioma stem cell migration, invasion, and survival through Src, PTEN, and FAK. Stem Cell Rep 9:451–463. CrossRefGoogle Scholar
  45. Jehs T, Faber C, Juel HB, Nissen MH (2011) Astrocytoma cells upregulate expression of pro-inflammatory cytokines after co-culture with activated peripheral blood mononuclear cells. APMIS 119:551–561. PubMedCrossRefGoogle Scholar
  46. Jhaveri N, Chen TC, Hofman FM (2016) Tumor vasculature and glioma stem cells: contributions to glioma progression. Cancer Lett 380:545–551. PubMedCrossRefGoogle Scholar
  47. Jones EV, Bouvier DS (2014) Astrocyte-secreted matricellular proteins in CNS remodelling during development and disease. Neural Plast 2014:321209. PubMedPubMedCentralCrossRefGoogle Scholar
  48. Katakowski M, Buller B, Wang X, Rogers T, Chopp M (2010) Functional microRNA is transferred between glioma cells. Cancer Res 70:8259–8263. PubMedPubMedCentralCrossRefGoogle Scholar
  49. Kees T, Lohr J, Noack J, Mora R, Gdynia G, Todt G, Ernst A, Radlwimmer B, Falk CS, Herold-Mende C, Regnier-Vigouroux A (2012) Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation. Neuro-oncology 14:64–78. PubMedCrossRefGoogle Scholar
  50. Kim JK, Jin X, Sohn YW, Jin X, Jeon HY, Kim EJ, Ham SW, Jeon HM, Chang SY, Oh SY, Yin J, Kim SH, Park JB, Nakano I, Kim H (2014) Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling. Cancer Lett 353:194–200. PubMedCrossRefGoogle Scholar
  51. Kim Y, Jeon H, Othmer H (2017) The role of the tumor microenvironment in glioblastoma: a mathematical model. IEEE Trans Biomed Eng 64:519–527. PubMedCrossRefGoogle Scholar
  52. Kober C, Rohn S, Weibel S, Geissinger U, Chen NG, Szalay AA (2015) Microglia and astrocytes attenuate the replication of the oncolytic vaccinia virus LIVP 1.1.1 in murine GL261 gliomas by acting as vaccinia virus traps. J Transl Med 13:216. PubMedPubMedCentralCrossRefGoogle Scholar
  53. Kolar K, Freitas-Andrade M, Bechberger JF, Krishnan H, Goldberg GS, Naus CC, Sin WC (2015) Podoplanin: a marker for reactive gliosis in gliomas and brain injury. J Neuropathol Exp Neurol 74:64–74. PubMedCrossRefGoogle Scholar
  54. Koto M, Cho H, Riesterer O, Giri U, Story MD, Ha CS, Raju U (2011) Human lymphoma cells develop resistance to radiation in the presence of astrocytes in vitro. Anticancer Res 31:33–38PubMedGoogle Scholar
  55. Lal PG, Ghirnikar RS, Eng LF (1996) Astrocyte-astrocytoma cell line interactions in culture. J Neurosci Res 44:216–222PubMedCrossRefGoogle Scholar
  56. Le DM, Besson A, Fogg DK, Choi KS, Waisman DM, Goodyer CG, Rewcastle B, Yong VW (2003) Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J Neurosci 23:4034–4043PubMedCrossRefGoogle Scholar
  57. Lee J, Borboa AK, Baird A, Eliceiri BP (2011a) Non-invasive quantification of brain tumor-induced astrogliosis. BMC Neurosci 12:9. PubMedPubMedCentralCrossRefGoogle Scholar
  58. Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, Emdad L, Howlett EL, Jeon HY, Su ZZ, Yoo BK, Sarkar D, Kim SH, Kang DC, Fisher PB (2011b) Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res 71:6514–6523. PubMedPubMedCentralCrossRefGoogle Scholar
  59. Lee HK, Finniss S, Cazacu S, Bucris E, Ziv-Av A, Xiang C, Bobbitt K, Rempel SA, Hasselbach L, Mikkelsen T, Slavin S, Brodie C (2013) Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget 4:346–361. PubMedPubMedCentralCrossRefGoogle Scholar
  60. Lin Q, Liu Z, Ling F, Xu G (2016) Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication. Mol Med Rep 13:1329–1335. PubMedCrossRefGoogle Scholar
  61. Liu K, Ji K, Guo L, Wu W, Lu H, Shan P, Yan C (2014) Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res 92:10–18. PubMedCrossRefGoogle Scholar
  62. Lu P, Wang Y, Liu X, Wang H, Zhang X, Wang K, Wang Q, Hu R (2016) Malignant gliomas induce and exploit astrocytic mesenchymal-like transition by activating canonical Wnt/beta-catenin signaling. Med Oncol 33:66. PubMedCrossRefGoogle Scholar
  63. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H (2007) Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67:9463–9471. PubMedPubMedCentralCrossRefGoogle Scholar
  64. McCord AM, Jamal M, Williams ES, Camphausen K, Tofilon PJ (2009) CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin Cancer Res 15:5145–5153. PubMedCrossRefGoogle Scholar
  65. Mehta G, Hsiao AY, Ingram M, Luker GD, Takayama S (2012) Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy. J Control Release 164:192–204. PubMedPubMedCentralCrossRefGoogle Scholar
  66. Moinfar Z, Dambach H, Faustmann PM (2014) Influence of drugs on gap junctions in glioma cell lines and primary astrocytes in vitro. Front Physiol 5:186. PubMedPubMedCentralCrossRefGoogle Scholar
  67. Nakamura JL, Haas-Kogan DA, Pieper RO (2007) Glioma invasiveness responds variably to irradiation in a co-culture model. Int J Radiat Oncol Biol Phys 69:880–886. PubMedCrossRefGoogle Scholar
  68. Okolie O, Bago JR, Schmid RS, Irvin DM, Bash RE, Miller CR, Hingtgen SD (2016) Reactive astrocytes potentiate tumor aggressiveness in a murine glioma resection and recurrence model. Neuro-oncology 18:1622–1633. PubMedPubMedCentralCrossRefGoogle Scholar
  69. Oliveira R, Christov C, Guillamo JS, de Bouard S, Palfi S, Venance L, Tardy M, Peschanski M (2005) Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas. BMC Cell Biol 6:7. PubMedPubMedCentralCrossRefGoogle Scholar
  70. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro-oncology 16:896–913. PubMedPubMedCentralCrossRefGoogle Scholar
  71. Piao Y, Lu L, de Groot J (2009) AMPA receptors promote perivascular glioma invasion via β1 integrin-dependent adhesion to the extracellular matrix. Neuro-oncology 11:260–273. PubMedPubMedCentralCrossRefGoogle Scholar
  72. Placone AL, Quinones-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. PubMedCrossRefGoogle Scholar
  73. Poon CC, Sarkar S, Yong VW, Kelly JJP (2017) Glioblastoma-associated microglia and macrophages: targets for therapies to improve prognosis. Brain 140:1548–1560. PubMedCrossRefGoogle Scholar
  74. Rape A, Ananthanarayanan B, Kumar S (2014) Engineering strategies to mimic the glioblastoma microenvironment. Adv Drug Deliv Rev 79–80:172–183. PubMedCrossRefGoogle Scholar
  75. Rath BH, Fair JM, Jamal M, Camphausen K, Tofilon PJ (2013) Astrocytes enhance the invasion potential of glioblastoma stem-like cells. PLoS ONE 8:e54752. PubMedPubMedCentralCrossRefGoogle Scholar
  76. Rath BH, Wahba A, Camphausen K, Tofilon PJ (2015) Coculture with astrocytes reduces the radiosensitivity of glioblastoma stem-like cells and identifies additional targets for radiosensitization. Cancer Med 4:1705–1716. PubMedPubMedCentralCrossRefGoogle Scholar
  77. Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T, Maira G, Parati EA, Stassi G, Larocca LM, De Maria R (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468:824–828. PubMedCrossRefGoogle Scholar
  78. Rivera-Zengotita M, Yachnis AT (2012) Gliosis versus glioma?: don’t grade until you know. Adv Anat Pathol 19:239–249. PubMedCrossRefGoogle Scholar
  79. Robe PA, Nguyen-Khac M, Jolois O, Rogister B, Merville MP, Bours V (2005) Dexamethasone inhibits the HSV-tk/ganciclovir bystander effect in malignant glioma cells. BMC Cancer 5:32. PubMedPubMedCentralCrossRefGoogle Scholar
  80. 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-oncology 12:351–365. PubMedCrossRefGoogle Scholar
  81. Roos A, Ding Z, Loftus JC, Tran NL (2017) Molecular and microenvironmental determinants of glioma stem-like cell survival and invasion. Front Oncol 7:120. PubMedPubMedCentralCrossRefGoogle Scholar
  82. Rupp T, Langlois B, Koczorowska MM, Radwanska A, Sun Z, Hussenet T, Lefebvre O, Murdamoothoo D, Arnold C, Klein A, Biniossek ML, Hyenne V, Naudin E, Velazquez-Quesada I, Schilling O, Van Obberghen-Schilling E, Orend G (2016) Tenascin-C orchestrates glioblastoma angiogenesis by modulation of pro- and anti-angiogenic signaling. Cell Rep 17:2607–2619. PubMedCrossRefGoogle Scholar
  83. Schichor C, Kerkau S, Visted T, Martini R, Bjerkvig R, Tonn JC, Goldbrunner R (2005) The brain slice chamber, a novel variation of the Boyden Chamber Assay, allows time-dependent quantification of glioma invasion into mammalian brain in vitro. J Neurooncol 73:9–18. PubMedCrossRefGoogle Scholar
  84. Seftor RE, Hess AR, Seftor EA, Kirschmann DA, Hardy KM, Margaryan NV, Hendrix MJ (2012) Tumor cell vasculogenic mimicry: from controversy to therapeutic promise. Am J Pathol 181:1115–1125. PubMedPubMedCentralCrossRefGoogle Scholar
  85. Shabtay-Orbach A, Amit M, Binenbaum Y, Na’ara S, Gil Z (2015) Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial-derived neurotrophic factor. Int J Cancer 137:1012–1020. PubMedCrossRefGoogle Scholar
  86. Sharma A, Shiras A (2016) Cancer stem cell-vascular endothelial cell interactions in glioblastoma. Biochem Biophys Res Commun 473:688–692. PubMedCrossRefGoogle Scholar
  87. Sin WC, Aftab Q, Bechberger JF, Leung JH, Chen H, Naus CC (2016) Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene 35:1504–1516. PubMedCrossRefGoogle Scholar
  88. Singh SK, Clarke ID, Hide T, Dirks PB (2004a) Cancer stem cells in nervous system tumors. Oncogene 23:7267–7273. PubMedCrossRefGoogle Scholar
  89. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004b) Identification of human brain tumour initiating cells. Nature 432:396–401. PubMedCrossRefGoogle Scholar
  90. Souza GR, Molina JR, Raphael RM, Ozawa MG, Stark DJ, Levin CS, Bronk LF, Ananta JS, Mandelin J, Georgescu MM, Bankson JA, Gelovani JG, Killian TC, Arap W, Pasqualini R (2010) Three-dimensional tissue culture based on magnetic cell levitation. Nat Nanotechnol 5:291–296. PubMedPubMedCentralCrossRefGoogle Scholar
  91. Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M (2001) Glutamate release promotes growth of malignant gliomas. Nat Med 7:1010–1015. PubMedCrossRefGoogle Scholar
  92. Tamura R, Tanaka T, Miyake K, Yoshida K, Sasaki H (2017) Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 34:62–77. PubMedCrossRefGoogle Scholar
  93. Tardito S, Oudin A, Ahmed SU, Fack F, Keunen O, Zheng L, Miletic H, Sakariassen PO, Weinstock A, Wagner A, Lindsay SL, Hock AK, Barnett SC, Ruppin E, Morkve SH, Lund-Johansen M, Chalmers AJ, Bjerkvig R, Niclou SP, Gottlieb E (2015) Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol 17:1556–1568. PubMedPubMedCentralCrossRefGoogle Scholar
  94. Ulasov I, Yi R, Guo D, Sarvaiya P, Cobbs C (2014) The emerging role of MMP14 in brain tumorigenesis and future therapeutics. Biochimica et biophysica acta 1846:113–120. PubMedCrossRefGoogle Scholar
  95. van Lith SA, Navis AC, Verrijp K, Niclou SP, Bjerkvig R, Wesseling P, Tops B, Molenaar R, van Noorden CJ, Leenders WP (2014) Glutamate as chemotactic fuel for diffuse glioma cells: are they glutamate suckers? Biochimica et biophysica acta 1846:66–74. PubMedCrossRefGoogle Scholar
  96. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, Wilson KF, Ambrosio AL, Dias SM, Dang CV, Cerione RA (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell 18:207–219. PubMedPubMedCentralCrossRefGoogle Scholar
  97. Wang N, Jain RK, Batchelor TT (2017) New directions in anti-angiogenic therapy for glioblastoma. Neurotherapeutics 14:321–332. PubMedPubMedCentralCrossRefGoogle Scholar
  98. Xiao W, Sohrabi A, Seidlits SK (2017) Integrating the glioblastoma microenvironment into engineered experimental models. Futur Sci OA 3:Fso189. CrossRefGoogle Scholar
  99. Yamada KM, Cukierman E (2007) Modeling tissue morphogenesis and cancer in 3D. Cell 130:601–610. PubMedCrossRefGoogle Scholar
  100. Yang N, Yan T, Zhu H, Liang X, Leiss L, Sakariassen PO, Skaftnesmo KO, Huang B, Costea DE, Enger PO, Li X, Wang J (2014) A co-culture model with brain tumor-specific bioluminescence demonstrates astrocyte-induced drug resistance in glioblastoma. J Transl Med 12:278. PubMedPubMedCentralCrossRefGoogle Scholar
  101. Yao PS, Kang DZ, Lin RY, Ye B, Wang W, Ye ZC (2014) Glutamate/glutamine metabolism coupling between astrocytes and glioma cells: neuroprotection and inhibition of glioma growth. Biochem Biophys Res Commun 450:295–299. PubMedCrossRefGoogle Scholar
  102. Yusubalieva GM, Baklaushev VP, Gurina OI, Zorkina YA, Gubskii IL, Kobyakov GL, Golanov AV, Goryainov SA, Gorlachev GE, Konovalov AN, Potapov AA, Chekhonin VP (2014) Treatment of poorly differentiated glioma using a combination of monoclonal antibodies to extracellular connexin-43 fragment, temozolomide, and radiotherapy. Bull Experim Biol Med 157:510–515. CrossRefGoogle Scholar
  103. Zarrabi K, Dufour A, Li J, Kuscu C, Pulkoski-Gross A, Zhi J, Hu Y, Sampson NS, Zucker S, Cao J (2011) Inhibition of matrix metalloproteinase 14 (MMP-14)-mediated cancer cell migration. J Biol Chem 286:33167–33177. PubMedPubMedCentralCrossRefGoogle Scholar
  104. Zhang L, Zhang Y (2015) Tunneling nanotubes between rat primary astrocytes and C6 glioma cells alter proliferation potential of glioma cells. Neurosci Bull 31:371–378. PubMedPubMedCentralCrossRefGoogle Scholar
  105. Zhang W, Nwagwu C, Le DM, Yong VW, Song H, Couldwell WT (2003) Increased invasive capacity of connexin43-overexpressing malignant glioma cells. J Neurosurg 99:1039–1046. PubMedCrossRefGoogle Scholar
  106. Zhang C, Chen W, Zhang X, Huang B, Chen A, He Y, Wang J, Li X (2016) Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes. Sci Rep 6:23056. PubMedPubMedCentralCrossRefGoogle Scholar
  107. Zhang L, Xu Y, Sun J, Chen W, Zhao L, Ma C, Wang Q, Sun J, Huang B, Zhang Y, Li X, Qu X (2017) M2-like tumor-associated macrophages drive vasculogenic mimicry through amplification of IL-6 expression in glioma cells. Oncotarget 8:819–832. PubMedCrossRefGoogle Scholar
  108. Zhao X, Chen R, Liu M, Feng J, Chen J, Hu K (2017) Remodeling the blood-brain barrier microenvironment by natural products for brain tumor therapy. Acta Pharm Sin B 7:541–553. PubMedPubMedCentralCrossRefGoogle Scholar
  109. Zheng X, Chopp M, Lu Y, Buller B, Jiang F (2013) MiR-15b and miR-152 reduce glioma cell invasion and angiogenesis via NRP-2 and MMP-3. Cancer Lett 329:146–154. PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Fundamental and Applied NeurobiologyV. Serbsky National Medical Research Centre for Psychiatry and NarcologyMoscowRussian Federation

Personalised recommendations