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A neurocentric perspective on glioma invasion

Key Points

  • All malignant gliomas share an important feature: aggressive invasiveness. This invasion is largely contained within the cranium, typically without metastasis to other organs.

  • Glioma cells secrete brevican and tenascins into the extracellular space, promoting migration. They also release proteases, including membrane type matrix metalloproteinase 1 (MMP1), MMP2 and MMP9, to degrade the dense extracellular matrix, which provides a path for migration.

  • Bradykinin is produced in vascular endothelial cells and promotes the association of human glioma cells with blood vessels. Inhibition of bradykinin receptors on glioma cells with icatibant, a US Food and Drug Administration (FDA)-approved drug, significantly reduces glioma cell migration and association with blood vessels.

  • Glioma cells undergo hydrodynamic shape and volume changes, changing volume by up to 33% to fit through the narrow extracellular spaces of the brain. Cell volume changes are accomplished by the efflux of salt though K+ and Cl channels, leading to subsequent osmotic release of cytoplasmic water.

  • The close association of glioma cells with the vasculature disrupts the interaction between astrocytic endfeet and endothelial cells. This in turn leads to a breakdown of the blood–brain barrier and abolishes the neurovascular unit where astrocytes locally regulate blood flow.

  • Glutamate is released from glioma cells through system xc. This glutamate acts in an autocrine and paracrine manner to promote glioma migration and proliferation, kills peritumoural neurons through excitotoxicity and increases neuronal excitability, leading to seizures. Sulfasalazine, an FDA-approved drug, inhibits glioma-induced seizures by blocking glutamate released through system xc.

  • Glioma cells use the same extracellular routes for migration as immature neurons, repurpose ion channels to undergo volume changes during migration and release excessive amounts of glutamate, culminating in seizures and neuronal death. Understanding this unique biology of gliomas through a neurocentric perspective reveals brain-specific therapeutic targets that have thus far not been exploited.

Abstract

Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood–brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease.

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Figure 1: Glioma cells associate with blood vessels in the brain.
Figure 2: A hydrodynamic model of glioma cell migration.
Figure 3: Glioma cells break down the blood–brain barrier.
Figure 4: Glioma cells displace astrocytic endfeet from blood vessels.

References

  1. Central Brain Tumor Registry of the United States. CBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004–2006. CBTRUS [online], (2010).

  2. Dandy, W. E. Removal of right cerebral hemisphere for certain tumors with hemiplegia: preliminary report. JAMA 90, 823–825 (1928).

    Article  Google Scholar 

  3. Hou, L. C., Veeravagu, A., Hsu, A. R. & Tse, V. C. Recurrent glioblastoma multiforme: a review of natural history and management options. Neurosurg. Focus 20, E5 (2006).

    Article  PubMed  Google Scholar 

  4. Verhaak, R. G. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010). This paper shows that gliomas can be molecularly classified into four subtypes (pro-neural, neural, classical and mesenchymal) that respond differently to therapeutic intervention.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Huse, J. T. & Holland, E. C. Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma. Nature Rev. Cancer 10, 319–331 (2010).

    Article  CAS  Google Scholar 

  6. Chen, J., McKay, R. M. & Parada, L. F. Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149, 36–47 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanai, N., Alvarez-Buylla, A. & Berger, M. S. Neural stem cells and the origin of gliomas. N. Engl. J. Med. 353, 811–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Stiles, C. D. & Rowitch, D. H. Glioma stem cells: a midterm exam. Neuron. 58, 832–846 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Zong, H., Verhaak, R. G. & Canoll, P. The cellular origin for malignant glioma and prospects for clinical advancements. Expert. Rev. Mol. Diagn. 12, 383–394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sanai, N. et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sugiarto, S. et al. Asymmetry-defective oligodendrocyte progenitors are glioma precursors. Cancer Cell 20, 328–340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu, C. et al. Mosaic analysis with double markers reveals tumor cell of origin in glioma. Cell 146, 209–221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Friedmann-Morvinski, D. et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 338, 1080–1084 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Beauchesne, P. Extra-neural metastases of malignant gliomas: myth or reality? Cancers 3, 461–477 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hamilton, J. D. et al. Glioblastoma multiforme metastasis outside the CNS: three case reports and possible mechanisms of escape. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2013.48.7546 (2014).

  16. Lun, M., Lok, E., Gautam, S., Wu, E. & Wong, E. T. The natural history of extracranial metastasis from glioblastoma multiforme. J. Neurooncol. 105, 261–273 (2011).

    Article  PubMed  Google Scholar 

  17. Bernstein, J. J. & Woodard, C. A. Glioblastoma cells do not intravasate into blood vessels. Neurosurgery 36, 124–132 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Slowik, F. & Balogh, I. Extracranial spreading of glioblastoma multiforme. Zentralbl. Neurochir. 41, 57–68 (1980).

    CAS  PubMed  Google Scholar 

  19. Gritsenko, P. G., Ilina, O. & Friedl, P. Interstitial guidance of cancer invasion. J. Pathol. 226, 185–199 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Zimmermann, D. R. & Dours-Zimmermann, M. T. Extracellular matrix of the central nervous system: from neglect to challenge. Histochem. Cell Biol. 130, 635–653 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Mentlein, R., Hattermann, K. & Held-Feindt, J. Lost in disruption: role of proteases in glioma invasion and progression. Biochim. Biophys. Acta 1825, 178–185 (2012).

    CAS  PubMed  Google Scholar 

  22. Zhang, H., Kelly, G., Zerillo, C., Jaworski, D. M. & Hockfield, S. Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion in vivo. J. Neurosci. 18, 2370–2376 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brosicke, N., van Landeghem, F. K., Scheffler, B. & Faissner, A. Tenascin-C is expressed by human glioma in vivo and shows a strong association with tumor blood vessels. Cell Tissue Res. 354, 409–430 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Joester, A. & Faissner, A. The structure and function of tenascins in the nervous system. Matrix Biol. 20, 13–22 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Martina, E. et al. Tenascin-W is a specific marker of glioma-associated blood vessels and stimulates angiogenesis in vitro. FASEB J. 24, 778–787 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alves, T. R. et al. Tenascin-C in the extracellular matrix promotes the selection of highly proliferative and tubulogenesis-defective endothelial cells. Exp. Cell Res. 317, 2073–2085 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Sixt, M. et al. Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J. Cell Biol. 153, 933–946 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Reese, T. S. & Karnovsky, M. J. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J. Cell Biol. 34, 207–217 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kalluri, R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev. Cancer 3, 422–433 (2003).

    Article  CAS  Google Scholar 

  30. Fukushima, Y., Tamura, M., Nakagawa, H. & Itoh, K. Induction of glioma cell migration by vitronectin in human serum and cerebrospinal fluid. J. Neurosurg. 107, 578–585 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Ohnishi, T. et al. Fibronectin-mediated cell migration promotes glioma cell invasion through chemokinetic activity. Clin. Exp. Metastasis 15, 538–546 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Persidsky, Y., Ramirez, S. H., Haorah, J. & Kanmogne, G. D. Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J. Neuroimmune Pharmacol. 1, 223–236 (2006).

    Article  PubMed  Google Scholar 

  33. Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Beadle, C. et al. The role of myosin II in glioma invasion of the brain. Mol. Biol. Cell 19, 3357–3368 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wolfenson, H., Lavelin, I. & Geiger, B. Dynamic regulation of the structure and functions of integrin adhesions. Dev. Cell 24, 447–458 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Demuth, T. & Berens, M. E. Molecular mechanisms of glioma cell migration and invasion. J. Neurooncol. 70, 217–228 (2004).

    Article  PubMed  Google Scholar 

  37. Kwiatkowska, A. & Symons, M. Signaling determinants of glioma cell invasion. Adv. Exp. Med. Biol. 986, 121–141 (2013).

    Article  CAS  PubMed  Google Scholar 

  38. Lucio-Eterovic, A. K., Piao, Y. & de Groot, J. F. Mediators of glioblastoma resistance and invasion during antivascular endothelial growth factor therapy. Clin. Cancer Res. 15, 4589–4599 (2009).

    Article  CAS  PubMed  Google Scholar 

  39. Scaringi, C., Minniti, G., Caporello, P. & Enrici, R. M. Integrin inhibitor cilengitide for the treatment of glioblastoma: a brief overview of current clinical results. Anticancer Res. 32, 4213–4223 (2012).

    CAS  PubMed  Google Scholar 

  40. Reardon, D. A. et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J. Clin. Oncol. 26, 5610–5617 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Montana, V. & Sontheimer, H. Bradykinin promotes the chemotactic invasion of primary brain tumors. J. Neurosci. 31, 4858–4867 (2011). In this paper, bradykinin is shown to bind to the B2R on glioma cells, attracting the majority of glioma cells to blood vessels and increasing migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kang, S. S. et al. Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival. Cancer Res. 70, 1173–1183 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Iliff, J. J. et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci. Transl. Med. 4, 147ra111 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thorne, R. G. & Nicholson, C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc. Natl Acad. Sci. USA 103, 5567–5572 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Farin, A. et al. Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia 53, 799–808 (2006).

    Article  PubMed  Google Scholar 

  46. Watkins, S. & Sontheimer, H. Hydrodynamic cellular volume changes enable glioma cell invasion. J. Neurosci. 31, 17250–17259 (2011). This study shows that the cellular volume of human glioma cells migrating through cerebral parenchyma oscillates by 33%, enabling these cells to fit through narrow spaces in the brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. McCoy, E. & Sontheimer, H. Expression and function of water channels (Aquaporins) in migrating malignant astrocytes. Glia 55, 1034–1043 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ding, T. et al. Role of aquaporin-4 in the regulation of migration and invasion of human glioma cells. Int. J. Oncol. 38, 1521–1531 (2011).

    CAS  PubMed  Google Scholar 

  49. McCoy, E. S., Haas, B. R. & Sontheimer, H. Water permeability through aquaporin-4 is regulated by protein kinase C and becomes rate-limiting for glioma invasion. Neuroscience 168, 971–981 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Cuddapah, V. A., Turner, K. L., Seifert, S. & Sontheimer, H. Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. J. Neurosci. 33, 1427–1440 (2013). A study showing that bradykinin promotes migration by activating ion channels that are involved in volume regulation in glioma cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Habela, C. W., Ernest, N. J., Swindall, A. F. & Sontheimer, H. Chloride accumulation drives volume dynamics underlying cell proliferation and migration. J. Neurophysiol. 101, 750–757 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Garzon-Muvdi, T. et al. Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol. 10, e1001320 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Haas, B. R. et al. With-No-Lysine Kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume. Am. J. Physiol. Cell Physiol. 301, C1150–C1160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Haas, B. R. & Sontheimer, H. Inhibition of the sodium-potassium-chloride cotransporter isoform-1 reduces glioma invasion. Cancer Res. 70, 5597–5606 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cuddapah, V. A. & Sontheimer, H. Molecular interaction and functional regulation of ClC-3 by Ca2+/calmodulin-dependent protein kinase II (CaMKII) in human malignant glioma. J. Biol. Chem. 285, 11188–11196 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Soroceanu, L., Manning, T. J. Jr & Sontheimer, H. Modulation of glioma cell migration and invasion using Cl and K+ ion channel blockers. J. Neurosci. 19, 5942–5954 (1999). This study introduces a hydrodynamic model of cell invasion and shows that K+ and Cl channels promote glioma cell invasion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lui, V. C., Lung, S. S., Pu, J. K., Hung, K. N. & Leung, G. K. Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer Res. 30, 4515–4524 (2010).

    CAS  PubMed  Google Scholar 

  58. Soroceanu, L., Gillespie, Y., Khazaeli, M. B. & Sontheimer, H. Use of chlorotoxin for targeting of primary brain tumors. Cancer Res. 58, 4871–4879 (1998).

    CAS  PubMed  Google Scholar 

  59. Mamelak, A. N. et al. Phase I single-dose study of intracavitary-administered iodine-131-TM-601 in adults with recurrent high-grade glioma. J. Clin. Oncol. 24, 3644–3650 (2006). This Phase I trial is the first to demonstrate that a Cl channel inhibitor (chlorotoxin) specifically binds to gliomas in patients.

    Article  CAS  PubMed  Google Scholar 

  60. Hockaday, D. C. et al. Imaging glioma extent with 131I-TM-601. J. Nucl. Med. 46, 580–586 (2005).

    CAS  PubMed  Google Scholar 

  61. Veiseh, M. et al. Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. Cancer Res. 67, 6882–6888 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Weaver, A. K., Bomben, V. C. & Sontheimer, H. Expression and function of calcium-activated potassium channels in human glioma cells. Glia. 54, 223–233 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  63. McFerrin, M. B., Turner, K. L., Cuddapah, V. A. & Sontheimer, H. Differential role of IK and BK potassium channels as mediators of intrinsic and extrinsic apoptotic cell death. Am. J. Physiol. Cell Physiol. 303, C1070–C1078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. D'Alessandro, G. et al. KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death Dis. 4, e773 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Sciaccaluga, M. et al. CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am. J. Physiol. Cell Physiol. 299, C175–C184 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Ransom, C. B. & Sontheimer, H. B. K. Channels in human glioma cells. J. Neurophysiol. 85, 790–803 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Ransom, C. B., Liu, X. & Sontheimer, H. BK channels in human glioma cells have enhanced calcium sensitivity. Glia 38, 281–291 (2002).

    Article  PubMed  Google Scholar 

  68. Liu, X., Chang, Y., Reinhart, P. H., Sontheimer, H. & Chang, Y. Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. J. Neurosci. 22, 1840–1849 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Manning, T. J. Jr, Parker, J. C. & Sontheimer, H. Role of lysophosphatidic acid and Rho in glioma cell motility. Cell. Motil. Cytoskeleton 45, 185–199 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Wen, P. Y. & Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 359, 492–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Bomben, V. C., Turner, K. L., Barclay, T. T. & Sontheimer, H. Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas. J. Cell. Physiol. 226, 1879–1888 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. Cuddapah, V. A., Turner, K. L. & Sontheimer, H. Calcium entry via TRPC1 channels activates chloride currents in human glioma cells. Cell Calcium 53, 187–194 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Caric, D. et al. EGFRs mediate chemotactic migration in the developing telencephalon. Development 128, 4203–4216 (2001).

    CAS  PubMed  Google Scholar 

  74. Lindberg, O. R., Persson, A., Brederlau, A., Shabro, A. & Kuhn, H. G. EGF-induced expansion of migratory cells in the rostral migratory stream. PLoS ONE 7, e46380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Iadecola, C. & Nedergaard, M. Glial regulation of the cerebral microvasculature. Nature Neurosci. 10, 1369–1376 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Mathiisen, T. M., Lehre, K. P., Danbolt, N. C. & Ottersen, O. P. The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction. Glia 58, 1094–1103 (2010).

    Article  PubMed  Google Scholar 

  77. Yousif, L. F., Di Russo, J. & Sorokin, L. Laminin isoforms in endothelial and perivascular basement membranes. Cell Adh. Migr. 7, 101–110 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wolburg, H., Noell, S., Mack, A., Wolburg-Buchholz, K. & Fallier-Becker, P. Brain endothelial cells and the glio-vascular complex. Cell Tissue Res. 335, 75–96 (2009).

    Article  PubMed  Google Scholar 

  79. Wolburg, H., Noell, S., Wolburg-Buchholz, K., Mack, A. & Fallier-Becker, P. Agrin, aquaporin-4, and astrocyte polarity as an important feature of the blood-brain barrier. Neuroscientist 15, 180–193 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Nagelhus, E. A. et al. Immunogold evidence suggests that coupling of K+ siphoning and water transport in rat retinal Muller cells is mediated by a coenrichment of Kir4.1 and AQP4 in specific membrane domains. Glia 26, 47–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Magistretti, P. J., Pellerin, L., Rothman, D. L. & Shulman, R. G. Energy on demand. Science 283, 496–497 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Watkins, S. et al. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nature Commun. (in the press). This recent study demonstrates that invading glioma cells disrupt physiological interactions between astrocytes and blood vessels, hijack control of vascular tone and break down the BBB.

  83. Zagzag, D. et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab. Invest. 80, 837–849 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Nagano, N., Sasaki, H., Aoyagi, M. & Hirakawa, K. Invasion of experimental rat brain tumor: early morphological changes following microinjection of C6 glioma cells. Acta Neuropathol. 86, 117–125 (1993).

    Article  CAS  PubMed  Google Scholar 

  85. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. de Groot, J. & Sontheimer, H. Glutamate and the biology of gliomas. Glia 59, 1181–1189 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Ye, Z. C. & Sontheimer, H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res. 59, 4383–4391 (1999). This study is the first to show that inhibition of glutamate release from glioma cells (and thus of the resulting glutamate excitotoxicity) decreases neurotoxicity.

    CAS  PubMed  Google Scholar 

  88. Lyons, S. A., Chung, W. J., Weaver, A. K., Ogunrinu, T. & Sontheimer, H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 67, 9463–9471 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ishiuchi, S. et al. Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nature Med. 8, 971–978 (2002). This study shows that glutamate acts at Ca2+-permeable AMPA receptors in glioma cells to promote migration.

    Article  CAS  PubMed  Google Scholar 

  90. Marcus, H. J., Carpenter, K. L., Price, S. J. & Hutchinson, P. J. In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J. Neurooncol. 97, 11–23 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. Takeuchi, S. et al. Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery 72, 33–41 (2013).

    Article  PubMed  Google Scholar 

  92. Chung, W. J. et al. Inhibition of cystine uptake disrupts the growth of primary brain tumors. J. Neurosci. 25, 7101–7110 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Buckingham, S. C. et al. Glutamate release by primary brain tumors induces epileptic activity. Nature Med. 17, 1269–1274 (2011). A study showing that gliomas release glutamate through system x c. This leads to epileptic activity, which can be inhibited by sulfasalazine, an FDA-approved drug.

    Article  CAS  PubMed  Google Scholar 

  94. Campbell, S. L., Buckingham, S. C. & Sontheimer, H. Human glioma cells induce hyperexcitability in cortical networks. Epilepsia 53, 1360–1370 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ishiuchi, S. et al. Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J. Neurosci. 27, 7987–8001 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chung, W. J. & Sontheimer, H. Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-κB. J. Neurochem. 110, 182–193 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Robe, P. A. et al. Early termination of ISRCTN45828668, a phase 1/2 prospective, randomized study of sulfasalazine for the treatment of progressing malignant gliomas in adults. BMC Cancer 9, 372 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Scherer, H. J. Structural development in gliomas. Am. J. Cancer 34, 333–351 (1938). This visionary description by Scherer demonstrates the most common sites for glioma invasion, now known as Scherer's structures.

    Google Scholar 

  99. Bozoyan, L., Khlghatyan, J. & Saghatelyan, A. Astrocytes control the development of the migration-promoting vasculature scaffold in the postnatal brain via VEGF signaling. J. Neurosci. 32, 1687–1704 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Saghatelyan, A. Role of blood vessels in the neuronal migration. Semin. Cell Dev. Biol. 20, 744–750 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Bardehle, S. et al. Live imaging of astrocyte responses to acute injury reveals selective juxtavascular proliferation. Nature Neurosci. 16, 580–586 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Hughes, E. G., Kang, S. H., Fukaya, M. & Bergles, D. E. Oligodendrocyte progenitors balance growth with self-repulsion to achieve homeostasis in the adult brain. Nature Neurosci. 16, 668–676 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Jablonska, B. et al. Chordin-induced lineage plasticity of adult SVZ neuroblasts after demyelination. Nature Neurosci. 13, 541–550 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. Cayre, M., Canoll, P. & Goldman, J. E. Cell migration in the normal and pathological postnatal mammalian brain. Prog. Neurobiol. 88, 41–63 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Komuro, H. & Rakic, P. Intracellular Ca2+ fluctuations modulate the rate of neuronal migration. Neuron 17, 275–285 (1996).

    Article  CAS  PubMed  Google Scholar 

  106. Turner, K. L. & Sontheimer, H. KCa3.1 modulates neuroblast migration along the rostral migratory stream (RMS) in vivo. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bht090 (2013).

  107. Scherer, H. J. A critical review: the pathology of cerebral gliomas. J. Neurol. Psychiatry 3, 147–177 (1940).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Meighan, S. E. et al. Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J.Neurochem. 96, 1227–1241 (2006).

    Article  CAS  PubMed  Google Scholar 

  109. Bovetti, S., Bovolin, P., Perroteau, I. & Puche, A. C. Subventricular zone-derived neuroblast migration to the olfactory bulb is modulated by matrix remodelling. Eur. J. Neurosci. 25, 2021–2033 (2007).

    Article  PubMed  Google Scholar 

  110. Clegg, D. O., Wingerd, K. L., Hikita, S. T. & Tolhurst, E. C. Integrins in the development, function and dysfunction of the nervous system. Front. Biosci. 8, d723–d750 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Venero, J. L., Vizuete, M. L., Machado, A. & Cano, J. Aquaporins in the central nervous system. Prog. Neurobiol. 63, 321–336 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Farmer, L. M., Le, B. N. & Nelson, D. J. CLC-3 chloride channels moderate long-term potentiation at Schaffer collateral-CA1 synapses. J. Physiol. 591, 1001–1015 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Riazanski, V. et al. Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus. Nature Neurosci. 14, 487–494 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Du, W. et al. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nature Genet. 37, 733–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Brenner, R. et al. BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures. Nature Neurosci. 8, 1752–1759 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Yamada, J. et al. Cl uptake promoting depolarizing GABA actions in immature rat neocortical neurones is mediated by NKCC1. J. Physiol. 557, 829–841 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. MacVicar, B. A., Feighan, D., Brown, A. & Ransom, B. Intrinsic optical signals in the rat optic nerve: role for K+ uptake via NKCC1 and swelling of astrocytes. Glia 37, 114–123 (2002).

    Article  PubMed  Google Scholar 

  118. McBean, G. J. Cerebral cystine uptake: a tale of two transporters. Trends Pharmacol. Sci. 23, 299–302 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) research grants 2RO1-NS036692, 5RO1NS031234, 1RO1-NS082851 and 5RO1-NS052634 to H.S., V.A.C. (F31NS073181) and S.W. (F31NS074597) were supported by Ruth L. Kirschstein National Research Service Awards. S.R. received funding from the German Research Foundation (DFG), the Epilepsy Foundation and the American Brain Tumor Association (ABTA).

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Cuddapah, V., Robel, S., Watkins, S. et al. A neurocentric perspective on glioma invasion. Nat Rev Neurosci 15, 455–465 (2014). https://doi.org/10.1038/nrn3765

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