Skip to main content

Advertisement

SpringerLink
Log in

Reactive Astrocytes in Glioblastoma Multiforme

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Despite the multidisciplinary integration in the therapeutic management of glioblastoma multiforme (GBM), the prognosis of GBM patients is poor. There is growing recognition that the cells in the tumor microenvironment play a vital role in regulating the progression of glioma. Astrocytes are an important component of the blood-brain barrier (BBB) as well as the tripartite synapse neural network to promote bidirectional communication with neurons under physiological conditions. Emerging evidence shows that tumor-associated reactive astrocytes interact with glioma cells and facilitate the progression, aggression, and survival of tumors by releasing different cytokines. Communication between reactive astrocytes and glioma cells is further promoted through ion channels and ion transporters, which augment the migratory capacity and invasiveness of tumor cells by modifying H+ and Ca2+ concentrations and stimulating volume changes in the cell. This in part contributes to the loss of epithelial polarization, initiating epithelial-mesenchymal transition. Therefore, this review will summarize the recent findings on the role of reactive astrocytes in the progression of GBM and in the development of treatment-resistant glioma. In addition, the involvement of ion channels and transporters in bridging the interactions between tumor cells and astrocytes and their potential as new therapeutic anti-tumor targets will be discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  2. Gallego O (2015) Nonsurgical treatment of recurrent glioblastoma. Curr Oncol 22(4):e273–e281. https://doi.org/10.3747/co.22.2436

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Franceschi E, Minichillo S, Brandes AA (2017) Pharmacotherapy of glioblastoma: established treatments and emerging concepts. CNS Drugs 31(8):675–684. https://doi.org/10.1007/s40263-017-0454-8

    Article  PubMed  CAS  Google Scholar 

  4. Szulzewsky F, Arora S, de Witte L, Ulas T, Markovic D, Schultze JL, Holland EC, Synowitz M et al (2016) Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples. Glia 64(8):1416–1436. https://doi.org/10.1002/glia.23014

    Article  PubMed  Google Scholar 

  5. Wang J, Su HK, Zhao HF, Chen ZP, To SS (2015) Progress in the application of molecular biomarkers in gliomas. Biochem Biophys Res Commun 465(1):1–4. https://doi.org/10.1016/j.bbrc.2015.07.148

    Article  PubMed  CAS  Google Scholar 

  6. Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H (2012) The brain tumor microenvironment. Glia 60(3):502–514. https://doi.org/10.1002/glia.21264

    Article  PubMed  Google Scholar 

  7. Fidoamore A, Cristiano L, Antonosante A, d'Angelo M, Di Giacomo E, Astarita C, Giordano A, Ippoliti R et al (2016) Glioblastoma stem cells microenvironment: the paracrine roles of the niche in drug and radioresistance. Stem Cells Int 2016:6809105–6809117. https://doi.org/10.1155/2016/6809105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Liebelt BD, Shingu T, Zhou X, Ren J, Shin SA, Hu J (2016) Glioma stem cells: signaling, microenvironment, and therapy. Stem Cells Int 2016:7849890. doi:https://doi.org/10.1155/2016/7849890, 1, 10

  9. Miller IS, Didier S, Murray DW, Turner TH, Issaivanan M, Ruggieri R, Al-Abed Y, Symons M (2014) Semapimod sensitizes glioblastoma tumors to ionizing radiation by targeting microglia. PLoS One 9(5):e95885. https://doi.org/10.1371/journal.pone.0095885

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Hambardzumyan D, Gutmann DH, Kettenmann H (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19(1):20–27. https://doi.org/10.1038/nn.4185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma. Neuro-Oncology 14(8):958–978. https://doi.org/10.1093/neuonc/nos116

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 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: J Int Soc Oncodevelopmental Biol Med 37(1):61–69. https://doi.org/10.1007/s13277-015-4242-0

    Article  CAS  Google Scholar 

  13. Alptekin M, Eroglu S, Tutar E, Sencan S, Geyik MA, Ulasli M, Demiryurek AT, Camci C (2015) Gene expressions of TRP channels in glioblastoma multiforme and relation with survival. Tumour Biol: J Int Soc Oncodevelopmental Biol Med 36(12):9209–9213. https://doi.org/10.1007/s13277-015-3577-x

    Article  CAS  Google Scholar 

  14. Bury M, Girault A, Megalizzi V, Spiegl-Kreinecker S, Mathieu V, Berger W, Evidente A, Kornienko A et al (2013) Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity. Cell Death Dis 4(3):e561. https://doi.org/10.1038/cddis.2013.85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Herculano-Houzel S (2014) The glia/neuron ratio: how it varies uniformly across brain structures and species and what that means for brain physiology and evolution. Glia 62(9):1377–1391. https://doi.org/10.1002/glia.22683

    Article  PubMed  Google Scholar 

  16. Butt AM, Fern RF, Matute C (2014) Neurotransmitter signaling in white matter. Glia 62(11):1762–1779. https://doi.org/10.1002/glia.22674

    Article  PubMed  Google Scholar 

  17. Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G (2014) Myelination, oligodendrocytes, and serious mental illness. Glia 62(11):1856–1877. https://doi.org/10.1002/glia.22716

    Article  PubMed  CAS  Google Scholar 

  18. Clarke LE, Barres BA (2013) Emerging roles of astrocytes in neural circuit development. Nat Rev Neurosci 14(5):311–321. https://doi.org/10.1038/nrn3484

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Pekny M, Pekna M (2014) Astrocyte reactivity and reactive astrogliosis: costs and benefits. Physiol Rev 94(4):1077–1098. https://doi.org/10.1152/physrev.00041.2013

    Article  PubMed  Google Scholar 

  20. Barres BA, Stevens B, Khakh BS, Sofroniew MV (2015) Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci 18(7):942–952. https://doi.org/10.1038/nn.4043

    Article  CAS  Google Scholar 

  21. Choudhury GR, Ding S (2016) Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol Dis 85:234–244. https://doi.org/10.1016/j.nbd.2015.05.003

    Article  PubMed  Google Scholar 

  22. Bazargani N, Attwell D (2016) Astrocyte calcium signaling: the third wave. Nat Neurosci 19(2):182–189. https://doi.org/10.1038/nn.4201

    Article  PubMed  CAS  Google Scholar 

  23. Boccazzi M, Ceruti S (2016) Where do you come from and what are you going to become, reactive astrocyte? Stem Cell Investig 3:15. https://doi.org/10.21037/sci.2016.05.02

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275(Pt 3):305–315. https://doi.org/10.1016/j.expneurol.2015.03.020

    Article  PubMed  CAS  Google Scholar 

  25. Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, Jacobs AH, Wyss-Coray T et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14(4):388–405. https://doi.org/10.1016/s1474-4422(15)70016-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Gagliano N, Costa F, Cossetti C, Pettinari L, Bassi R, Chiriva-Internati M, Cobos E, Gioia M et al (2009) Glioma-astrocyte interaction modifies the astrocyte phenotype in a co-culture experimental model. Oncol Rep 22(6):1349–1356

    Article  PubMed  CAS  Google Scholar 

  27. Barbero S, Bajetto A, Bonavia R, Porcile C, Piccioli P, Pirani P, Ravetti JL, Zona G et al (2002) Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro. Ann N Y Acad Sci 973(1):60–69. https://doi.org/10.1111/j.1749-6632.2002.tb04607.x

    Article  PubMed  CAS  Google Scholar 

  28. Biasoli D, Sobrinho MF, da Fonseca AC, de Matos DG, Romao L, de Moraes Maciel R, Rehen SK, Moura-Neto V et al (2014) Glioblastoma cells inhibit astrocytic p53-expression favoring cancer malignancy. Oncogene 3(10):e123. https://doi.org/10.1038/oncsis.2014.36

    Article  CAS  Google Scholar 

  29. Lin ST, Wang Y, Xue Y, Feng DC, Xu Y, Xu LY (2008) Tetrandrine suppresses LPS-induced astrocyte activation via modulating IKKs-IkappaBalpha-NF-kappaB signaling pathway. Mol Cell Biochem 315(1–2):41–49. https://doi.org/10.1007/s11010-008-9787-4

    Article  PubMed  CAS  Google Scholar 

  30. Kim JK, Jin X, Sohn YW, Jin X, Jeon HY, Kim EJ, Ham SW, Jeon HM et al (2014) Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling. Cancer Lett 353(2):194–200. https://doi.org/10.1016/j.canlet.2014.07.034

    Article  PubMed  CAS  Google Scholar 

  31. Cancer Genome Atlas Research N (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068. https://doi.org/10.1038/nature07385

    Article  CAS  Google Scholar 

  32. Rangel LP, Costa DC, Vieira TC, Silva JL (2014) The aggregation of mutant p53 produces prion-like properties in cancer. Prion 8(1):75–84. https://doi.org/10.4161/pri.27776

    Article  PubMed  CAS  Google Scholar 

  33. Theodoric N, Bechberger JF, Naus CC, Sin WC (2012) Role of gap junction protein connexin43 in astrogliosis induced by brain injury. PLoS One 7(10):e47311. https://doi.org/10.1371/journal.pone.0047311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Zhang L, Zhang Y (2015) Tunneling nanotubes between rat primary astrocytes and C6 glioma cells alter proliferation potential of glioma cells. Neurosci Bull 31(3):371–378. https://doi.org/10.1007/s12264-014-1522-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 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(38):62425–62438. https://doi.org/10.18632/oncotarget.11515

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gielen PR, Aftab Q, Ma N, Chen VC, Hong X, Lozinsky S, Naus CC, Sin WC (2013) Connexin43 confers temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75:539–548. https://doi.org/10.1016/j.neuropharm.2013.05.002

    Article  PubMed  CAS  Google Scholar 

  37. 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(12):1504–1516. https://doi.org/10.1038/onc.2015.210

    Article  PubMed  CAS  Google Scholar 

  38. Hong X, Sin WC, Harris AL, Naus CC (2015) Gap junctions modulate glioma invasion by direct transfer of microRNA. Oncotarget 6(17):15566–15577. https://doi.org/10.18632/oncotarget.3904

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tardito S, Oudin A, Ahmed SU, Fack F, Keunen O, Zheng L, Miletic H, Sakariassen PO et al (2015) Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma. Nat Cell Biol 17(12):1556–1568. https://doi.org/10.1038/ncb3272

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Bharti R, Dey G, Mandal M (2016) Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: a snapshot of IL-6 mediated involvement. Cancer Lett 375(1):51–61. https://doi.org/10.1016/j.canlet.2016.02.048

    Article  PubMed  CAS  Google Scholar 

  41. Li (2010) IL-6 augments the invasiveness of U87MG human glioblastoma multiforme cells via up-regulation of MMP-2 and fascin-1. Oncol Rep 23(6). https://doi.org/10.3892/or_00000795

  42. 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 : Off J Soc Neurosci 23(10):4034–4043

    Article  Google Scholar 

  43. 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(5):1012–1020. https://doi.org/10.1002/ijc.29380

    Article  PubMed  CAS  Google Scholar 

  44. Hu B, Emdad L, Bacolod MD, Kegelman TP, Shen XN, Alzubi MA, Das SK, Sarkar D et al (2014) Astrocyte elevated gene-1 interacts with Akt isoform 2 to control glioma growth, survival, and pathogenesis. Cancer Res 74(24):7321–7332. https://doi.org/10.1158/0008-5472.can-13-2978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Emdad L, Sarkar D, Su ZZ, Randolph A, Boukerche H, Valerie K, Fisher PB (2006) Activation of the nuclear factor kappaB pathway by astrocyte elevated gene-1: implications for tumor progression and metastasis. Cancer Res 66(3):1509–1516. https://doi.org/10.1158/0008-5472.can-05-3029

    Article  PubMed  CAS  Google Scholar 

  46. Sarkar D, Park ES, Emdad L, Lee SG, Su ZZ, Fisher PB (2008) Molecular basis of nuclear factor-kappaB activation by astrocyte elevated gene-1. Cancer Res 68(5):1478–1484. https://doi.org/10.1158/0008-5472.can-07-6164

    Article  PubMed  CAS  Google Scholar 

  47. Zou M, Duan Y, Wang P, Gao R, Chen X, Ou Y, Liang M, Wang Z et al (2016) DYT-40, a novel synthetic 2-styryl-5-nitroimidazole derivative, blocks malignant glioblastoma growth and invasion by inhibiting AEG-1 and NF-kappaB signaling pathways. Sci Rep 6(1):27331. https://doi.org/10.1038/srep27331

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C et al (2016) CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 375(2):263–273. https://doi.org/10.1016/j.canlet.2016.01.024

    Article  PubMed  CAS  Google Scholar 

  49. Hingtgen S, Figueiredo JL, Farrar C, Duebgen M, Martinez-Quintanilla J, Bhere D, Shah K (2013) Real-time multi-modality imaging of glioblastoma tumor resection and recurrence. J Neuro-Oncol 111(2):153–161. https://doi.org/10.1007/s11060-012-1008-z

    Article  Google Scholar 

  50. 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(12):1622–1633. https://doi.org/10.1093/neuonc/now117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Agarwala SS, Kirkwood JM (2000) Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist 5(2):144–151. https://doi.org/10.1634/theoncologist.5-2-144

    Article  PubMed  CAS  Google Scholar 

  52. Villano JL, Seery TE, Bressler LR (2009) Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 64(4):647–655. https://doi.org/10.1007/s00280-009-1050-5

    Article  PubMed  CAS  Google Scholar 

  53. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG (2000) Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 343(19):1350–1354. https://doi.org/10.1056/NEJM200011093431901

    Article  PubMed  CAS  Google Scholar 

  54. 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(2):1329–1335. https://doi.org/10.3892/mmr.2015.4680

    Article  PubMed  CAS  Google Scholar 

  55. Munoz JL, Rodriguez-Cruz V, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P (2014) Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43. Cell Death Dis 5(3):e1145. https://doi.org/10.1038/cddis.2014.111

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Chen W, Wang D, Du X, He Y, Chen S, Shao Q, Ma C, Huang B et al (2015) Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol (Northwood, London, England) 32(3):43. https://doi.org/10.1007/s12032-015-0487-0

    Article  CAS  Google Scholar 

  57. 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(11):1705–1716. https://doi.org/10.1002/cam4.510

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Nelson M, Yang M, Millican-Slater R, Brackenbury WJ (2015) Nav1.5 regulates breast tumor growth and metastatic dissemination in vivo. Oncotarget 6(32):32914–32929. https://doi.org/10.18632/oncotarget.5441

    Article  PubMed  PubMed Central  Google Scholar 

  59. House CD, Wang BD, Ceniccola K, Williams R, Simaan M, Olender J, Patel V, Baptista-Hon DT et al (2015) Voltage-gated Na+ channel activity increases colon cancer transcriptional activity and invasion via persistent MAPK signaling. Sci Rep 5(1):11541. https://doi.org/10.1038/srep11541

    Article  PubMed  PubMed Central  Google Scholar 

  60. Li F, Abuarab N, Sivaprasadarao A (2016) Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels. J Cell Sci 129(10):2016–2029. https://doi.org/10.1242/jcs.179796

    Article  PubMed  CAS  Google Scholar 

  61. Olsen ML, Khakh BS, Skatchkov SN, Zhou M, Lee CJ, Rouach N (2015) New insights on astrocyte ion channels: critical for homeostasis and neuron-glia signaling. J Neurosci: Off J Soc Neurosci 35(41):13827–13835. https://doi.org/10.1523/JNEUROSCI.2603-15.2015

    Article  CAS  Google Scholar 

  62. Molenaar RJ (2011) Ion channels in glioblastoma. ISRN Neurology 2011:590249. doi:https://doi.org/10.5402/2011/590249, 1, 7

  63. Sforna L, Cenciarini M, Belia S, D'Adamo MC, Pessia M, Franciolini F, Catacuzzeno L (2014) The role of ion channels in the hypoxia-induced aggressiveness of glioblastoma. Front Cell Neurosci 8:467. https://doi.org/10.3389/fncel.2014.00467

    Article  PubMed  Google Scholar 

  64. Boscia F, Begum G, Pignataro G, Sirabella R, Cuomo O, Casamassa A, Sun D, Annunziato L (2016) Glial Na(+)-dependent ion transporters in pathophysiological conditions. Glia 64(10):1677–1697. https://doi.org/10.1002/glia.23030

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kang SS, Han KS, BM K, Lee YK, Hong J, Shin HY, Almonte AG, Woo DH et al (2010) Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Res 70(3):1173–1183. https://doi.org/10.1158/0008-5472.can-09-2886

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Potier M, Trebak M (2008) New developments in the signaling mechanisms of the store-operated calcium entry pathway. Pflugers Archiv : Eur J Physiol 457(2):405–415. https://doi.org/10.1007/s00424-008-0533-2

    Article  CAS  Google Scholar 

  67. Motiani RK, Hyzinski-Garcia MC, Zhang X, Henkel MM, Abdullaev IF, Kuo YH, Matrougui K, Mongin AA et al (2013) STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Archiv : Eur J Physiol 465(9):1249–1260. https://doi.org/10.1007/s00424-013-1254-8

    Article  CAS  Google Scholar 

  68. Liu H, Hughes JD, Rollins S, Chen B, Perkins E (2011) Calcium entry via ORAI1 regulates glioblastoma cell proliferation and apoptosis. Exp Mol Pathol 91(3):753–760. https://doi.org/10.1016/j.yexmp.2011.09.005

    Article  PubMed  CAS  Google Scholar 

  69. Morrone FB, Gehring MP, Nicoletti NF (2016) Calcium channels and associated receptors in malignant brain tumor therapy. Mol Pharmacol 90(3):403–409. https://doi.org/10.1124/mol.116.103770

    Article  PubMed  CAS  Google Scholar 

  70. Zhang Y, Zhang J, Jiang D, Zhang D, Qian Z, Liu C, Tao J (2012) Inhibition of T-type Ca(2)(+) channels by endostatin attenuates human glioblastoma cell proliferation and migration. Br J Pharmacol 166(4):1247–1260. https://doi.org/10.1111/j.1476-5381.2012.01852.x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Zhang Y, Wang H, Qian Z, Feng B, Zhao X, Jiang X, Tao J (2014) Low-voltage-activated T-type Ca2+ channel inhibitors as new tools in the treatment of glioblastoma: the role of endostatin. Pflugers Archiv : Eur J Physiol 466(4):811–818. https://doi.org/10.1007/s00424-013-1427-5

    Article  CAS  Google Scholar 

  72. Valerie NC, Dziegielewska B, Hosing AS, Augustin E, Gray LS, Brautigan DL, Larner JM, Dziegielewski J (2013) Inhibition of T-type calcium channels disrupts Akt signaling and promotes apoptosis in glioblastoma cells. Biochem Pharmacol 85(7):888–897. https://doi.org/10.1016/j.bcp.2012.12.017

    Article  PubMed  CAS  Google Scholar 

  73. Nilius B, Owsianik G (2011) The transient receptor potential family of ion channels. Genome Biol 12(3):218. https://doi.org/10.1186/gb-2011-12-3-218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Bomben VC, Sontheimer H (2010) Disruption of transient receptor potential canonical channel 1 causes incomplete cytokinesis and slows the growth of human malignant gliomas. Glia 58(10):1145–1156. https://doi.org/10.1002/glia.20994

    Article  PubMed  PubMed Central  Google Scholar 

  75. Leng TD, Li MH, Shen JF, Liu ML, Li XB, Sun HW, Branigan D, Zeng Z et al (2015) Suppression of TRPM7 inhibits proliferation, migration, and invasion of malignant human glioma cells. CNS Neurosci Ther 21(3):252–261. https://doi.org/10.1111/cns.12354

    Article  PubMed  CAS  Google Scholar 

  76. Stock K, Kumar J, Synowitz M, Petrosino S, Imperatore R, Smith ES, Wend P, Purfurst B et al (2012) Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med 18(8):1232–1238. https://doi.org/10.1038/nm.2827

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wondergem R, Ecay TW, Mahieu F, Owsianik G, Nilius B (2008) HGF/SF and menthol increase human glioblastoma cell calcium and migration. Biochem Biophys Res Commun 372(1):210–215. https://doi.org/10.1016/j.bbrc.2008.05.032

    Article  PubMed  CAS  Google Scholar 

  78. Chen WL, Barszczyk A, Turlova E, Deurloo M, Liu B, Yang BB, Rutka JT, Feng ZP et al (2015) Inhibition of TRPM7 by carvacrol suppresses glioblastoma cell proliferation, migration and invasion. Oncotarget 6(18):16321–16340. https://doi.org/10.18632/oncotarget.3872

    Article  PubMed  PubMed Central  Google Scholar 

  79. Liu M, Inoue K, Leng T, Guo S, Xiong ZG (2014) TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways. Cell Signal 26(12):2773–2781. https://doi.org/10.1016/j.cellsig.2014.08.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Bomben VC, Turner KL, Barclay TT, Sontheimer H (2011) Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas. J Cell Physiol 226(7):1879–1888. https://doi.org/10.1002/jcp.22518

    Article  PubMed  CAS  Google Scholar 

  81. Chigurupati S, Venkataraman R, Barrera D, Naganathan A, Madan M, Paul L, Pattisapu JV, Kyriazis GA et al (2010) Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. Cancer Res 70(1):418–427. https://doi.org/10.1158/0008-5472.can-09-2654

    Article  PubMed  CAS  Google Scholar 

  82. Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, Giangaspero F, Santoni G (2007) Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem 102(3):977–990. https://doi.org/10.1111/j.1471-4159.2007.04582.x

    Article  PubMed  CAS  Google Scholar 

  83. Medina-Ceja L, Pardo-Pena K, Morales-Villagran A, Ortega-Ibarra J, Lopez-Perez S (2015) Increase in the extracellular glutamate level during seizures and electrical stimulation determined using a high temporal resolution technique. BMC Neurosci 16(1):11. https://doi.org/10.1186/s12868-015-0147-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Masi A, Becchetti A, Restano-Cassulini R, Polvani S, Hofmann G, Buccoliero AM, Paglierani M, Pollo B et al (2005) hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines. Br J Cancer 93(7):781–792. https://doi.org/10.1038/sj.bjc.6602775

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Patt S, Preussat K, Beetz C, Kraft R, Schrey M, Kalff R, Schonherr K, Heinemann SH (2004) Expression of ether a go-go potassium channels in human gliomas. Neurosci Lett 368(3):249–253. https://doi.org/10.1016/j.neulet.2004.07.001

    Article  PubMed  CAS  Google Scholar 

  86. Staudacher I, Jehle J, Staudacher K, Pledl HW, Lemke D, Schweizer PA, Becker R, Katus HA et al (2014) HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells. PLoS One 9(2):e88164. https://doi.org/10.1371/journal.pone.0088164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Wang J, Li Y, Jiang C (2015) MiR-133b contributes to arsenic-induced apoptosis in U251 glioma cells by targeting the hERG channel. J Mol Neurosci : MN 55(4):985–994. https://doi.org/10.1007/s12031-014-0455-8

    Article  PubMed  CAS  Google Scholar 

  88. Bai Y, Liao H, Liu T, Zeng X, Xiao F, Luo L, Guo H, Guo L (2013) MiR-296-3p regulates cell growth and multi-drug resistance of human glioblastoma by targeting ether-a-go-go (EAG1). Eur J Cancer (Oxford, England : 1990) 49(3):710–724. https://doi.org/10.1016/j.ejca.2012.08.020

    Article  CAS  Google Scholar 

  89. Arvind S, Arivazhagan A, Santosh V, Chandramouli BA (2012) Differential expression of a novel voltage gated potassium channel—Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma. Br J Neurosurg 26(1):16–20. https://doi.org/10.3109/02688697.2011.583365

    Article  PubMed  CAS  Google Scholar 

  90. Martinez R, Stuhmer W, Martin S, Schell J, Reichmann A, Rohde V, Pardo L (2015) Analysis of the expression of Kv10.1 potassium channel in patients with brain metastases and glioblastoma multiforme: impact on survival. BMC Cancer 15(1):839. https://doi.org/10.1186/s12885-015-1848-y

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Turner KL, Honasoge A, Robert SM, McFerrin MM, Sontheimer H (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62(6):971–981. https://doi.org/10.1002/glia.22655

    Article  PubMed  PubMed Central  Google Scholar 

  92. Catacuzzeno L, Aiello F, Fioretti B, Sforna L, Castigli E, Ruggieri P, Tata AM, Calogero A et al (2011) Serum-activated K and Cl currents underlay U87-MG glioblastoma cell migration. J Cell Physiol 226(7):1926–1933. https://doi.org/10.1002/jcp.22523

    Article  PubMed  CAS  Google Scholar 

  93. Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M, Catalano M, D'Alessandro G et al (2010) CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am J Physiol Cell Physiol 299(1):C175–C184. https://doi.org/10.1152/ajpcell.00344.2009

    Article  PubMed  CAS  Google Scholar 

  94. So EC, Huang YM, Hsing CH, Liao YK, Wu SN (2015) Arecoline inhibits intermediate-conductance calcium-activated potassium channels in human glioblastoma cell lines. Eur J Pharmacol 758:177–187. https://doi.org/10.1016/j.ejphar.2015.03.065

    Article  PubMed  CAS  Google Scholar 

  95. Fioretti B, Castigli E, Micheli MR, Bova R, Sciaccaluga M, Harper A, Franciolini F, Catacuzzeno L (2006) Expression and modulation of the intermediate- conductance Ca2+-activated K+ channel in glioblastoma GL-15 cells. Cell Physiol Biochem : Int J Exp Cell Physiol, Biochem Pharmacol 18(1–3):47–56. https://doi.org/10.1159/000095135

    Article  CAS  Google Scholar 

  96. Stegen B, Butz L, Klumpp L, Zips D, Dittmann K, Ruth P, Huber SM (2015) Ca2+-activated IK K+ channel blockade radiosensitizes glioblastoma cells. Mol Cancer Res : MCR 13(9):1283–1295. https://doi.org/10.1158/1541-7786.mcr-15-0075

    Article  PubMed  CAS  Google Scholar 

  97. Wondergem R, Bartley JW (2009) Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. J Biomed Sci 16(1):90. https://doi.org/10.1186/1423-0127-16-90

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hoa NT, Ge L, Martini F, Chau V, Ahluwalia A, Kruse CA, Jadus MR (2016) Temozolomide induces the expression of the glioma big potassium (gBK) ion channel, while inhibiting fascin-1 expression: possible targets for glioma therapy. Expert Opin Ther Targets 20(10):1155–1167. https://doi.org/10.1080/14728222.2016.1208172

    Article  PubMed  CAS  Google Scholar 

  99. Joshi AD, Parsons DW, Velculescu VE, Riggins GJ (2011) Sodium ion channel mutations in glioblastoma patients correlate with shorter survival. Mol Cancer 10(1):17. https://doi.org/10.1186/1476-4598-10-17

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Hanukoglu I, Hanukoglu A (2016) Epithelial sodium channel (ENaC) family: phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene 579(2):95–132. https://doi.org/10.1016/j.gene.2015.12.061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Vila-Carriles WH, Kovacs GG, Jovov B, Zhou ZH, Pahwa AK, Colby G, Esimai O, Gillespie GY et al (2006) Surface expression of ASIC2 inhibits the amiloride-sensitive current and migration of glioma cells. J Biol Chem 281(28):19220–19232. https://doi.org/10.1074/jbc.M603100200

    Article  PubMed  CAS  Google Scholar 

  102. Kapoor N, Bartoszewski R, Qadri YJ, Bebok Z, Bubien JK, Fuller CM, Benos DJ (2009) Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J Biol Chem 284(36):24526–24541. https://doi.org/10.1074/jbc.M109.037390

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Rooj AK, McNicholas CM, Bartoszewski R, Bebok Z, Benos DJ, Fuller CM (2012) Glioma-specific cation conductance regulates migration and cell cycle progression. J Biol Chem 287(6):4053–4065. https://doi.org/10.1074/jbc.M111.311688

    Article  PubMed  CAS  Google Scholar 

  104. Kapoor N, Lee W, Clark E, Bartoszewski R, McNicholas CM, Latham CB, Bebok Z, Parpura V et al (2011) Interaction of ASIC1 and ENaC subunits in human glioma cells and rat astrocytes. Am J Physiol-Cell Physiol 300(6):C1246–C1259. https://doi.org/10.1152/ajpcell.00199.2010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Sun X, Zhao D, Li YL, Sun Y, Lei XH, Zhang JN, MM W, Li RY et al (2013) Regulation of ASIC1 by Ca2+/calmodulin-dependent protein kinase II in human glioblastoma multiforme. Oncol Rep 30(6):2852–2858. https://doi.org/10.3892/or.2013.2777

    Article  PubMed  CAS  Google Scholar 

  106. Peretti M, Angelini M, Savalli N, Florio T, Yuspa SH, Mazzanti M (2015) Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochimica et biophysica acta 1848 (10 Pt B):2523-2531. doi:https://doi.org/10.1016/j.bbamem.2014.12.012

  107. Olsen ML, Schade S, Lyons SA, Amaral MD, Sontheimer H (2003) Expression of voltage-gated chloride channels in human glioma cells. J Neurosci : Off J Soc Neurosci 23(13):5572–5582

    Article  CAS  Google Scholar 

  108. Gritti M, Wurth R, Angelini M, Barbieri F, Peretti M, Pizzi E, Pattarozzi A, Carra E et al (2014) Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current. Oncotarget 5(22):11252–11268. https://doi.org/10.18632/oncotarget.2617

    Article  PubMed  PubMed Central  Google Scholar 

  109. Setti M, Osti D, Richichi C, Ortensi B, Del Bene M, Fornasari L, Beznoussenko G, Mironov A et al (2015) Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth. Oncotarget 6(31):31413–31427. https://doi.org/10.18632/oncotarget.5105

    Article  PubMed  PubMed Central  Google Scholar 

  110. Setti M, Savalli N, Osti D, Richichi C, Angelini M, Brescia P, Fornasari L, Carro MS et al (2013) Functional role of CLIC1 ion channel in glioblastoma-derived stem/progenitor cells. J Natl Cancer Inst 105(21):1644–1655. https://doi.org/10.1093/jnci/djt278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Lui VC, Lung SS, JK P, Hung KN, Leung GK (2010) Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer Res 30(11):4515–4524

    PubMed  CAS  Google Scholar 

  112. Sahlender DA, Savtchouk I, Volterra A (2014) What do we know about gliotransmitter release from astrocytes? Philos Trans R Soc Lond Ser B Biol Sci 369(1654):20130592. https://doi.org/10.1098/rstb.2013.0592

    Article  CAS  Google Scholar 

  113. Skog J, Wurdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, Curry WT, Jr., Carter BS, Krichevsky AM, Breakefield XO (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10 (12):1470–1476. doi:https://doi.org/10.1038/ncb1800

  114. Bortner CD, Cidlowski JA (2007) Cell shrinkage and monovalent cation fluxes: role in apoptosis. Arch Biochem Biophys 462(2):176–188. https://doi.org/10.1016/j.abb.2007.01.020

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Strange K (2004) Cellular volume homeostasis. Adv Physiol Educ 28(1–4):155–159. https://doi.org/10.1152/advan.00034.2004

    Article  PubMed  Google Scholar 

  116. Algharabil J, Kintner DB, Wang Q, Begum G, Clark PA, Yang SS, Lin SH, Kahle KT et al (2012) Inhibition of Na(+)-K(+)-2Cl(−) cotransporter isoform 1 accelerates temozolomide-mediated apoptosis in glioblastoma cancer cells. Cell Physiol Biochem : Int J Exp Cell Physiol Biochem Pharmacol 30(1):33–48. https://doi.org/10.1159/000339047

    Article  CAS  Google Scholar 

  117. Cong D, Zhu W, Shi Y, Pointer KB, Clark PA, Shen H, Kuo JS, Hu S et al (2014) Upregulation of NHE1 protein expression enables glioblastoma cells to escape TMZ-mediated toxicity via increased H(+) extrusion, cell migration and survival. Carcinogenesis 35(9):2014–2024. https://doi.org/10.1093/carcin/bgu089

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Beskina O, Miller A, Mazzocco-Spezzia A, Pulina MV, Golovina VA (2007) Mechanisms of interleukin-1beta-induced Ca2+ signals in mouse cortical astrocytes: roles of store- and receptor-operated Ca2+ entry. Am J Physiol Cell Physiol 293(3):C1103–C1111. https://doi.org/10.1152/ajpcell.00249.2007

    Article  PubMed  CAS  Google Scholar 

  119. Zhu W, Carney KE, Pigott VM, Falgoust LM, Clark PA, Kuo JS, Sun D (2016) Glioma-mediated microglial activation promotes glioma proliferation and migration: roles of Na+/H+ exchanger isoform 1. Carcinogenesis 37(9):839–851. https://doi.org/10.1093/carcin/bgw068

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Ostrow LW, Suchyna TM, Sachs F (2011) Stretch induced endothelin-1 secretion by adult rat astrocytes involves calcium influx via stretch-activated ion channels (SACs). Biochem Biophys Res Commun 410(1):81–86. https://doi.org/10.1016/j.bbrc.2011.05.109

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Li JH, Zhao ST, Wu CY, Cao X, Peng MR, Li SJ, Liu XA, Gao TM (2013) Store-operated Ca2+ channels blockers inhibit lipopolysaccharide induced astrocyte activation. Neurochem Res 38(10):2216–2226. https://doi.org/10.1007/s11064-013-1130-0

    Article  PubMed  CAS  Google Scholar 

  122. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang WC, Li P, Li M et al (2015) Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527(7576):100–104. https://doi.org/10.1038/nature15376

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work was supported in part by NIH grant R01NS75995 (DS).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, No.6 Tiantan Xili, Dongcheng District, Beijing, 100050, China

    Xiudong Guan & Wang Jia

  2. Department of Neurology, University of Pittsburgh, S-598 South Biomedical Science Tower, 3500 Terrace St., Pittsburgh, PA, 15213, USA

    Xiudong Guan, Md Nabiul Hasan & Dandan Sun

  3. Chinese National Clinical Research Center for Neurological Diseases, Beijing, China

    Xiudong Guan & Wang Jia

  4. Lake Erie College of Osteopathic Medicine—Seton Hill, Greensburg, PA, USA

    Shelly Maniar

  5. Beijing Neurosurgical Institute, Beijing, China

    Wang Jia

  6. Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA, USA

    Dandan Sun

Authors
  1. Xiudong Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Md Nabiul Hasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shelly Maniar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wang Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dandan Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wang Jia or Dandan Sun.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guan, X., Hasan, M.N., Maniar, S. et al. Reactive Astrocytes in Glioblastoma Multiforme. Mol Neurobiol 55, 6927–6938 (2018). https://doi.org/10.1007/s12035-018-0880-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-018-0880-8

Keywords

Search

Navigation