Characterization of the blood-brain barrier of metastatic and primary malignant neoplasms

Laboratory investigation

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  • 1 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland;
  • 2 Department of Neurological Surgery, Emory University, Atlanta, Georgia; and
  • 3 Department of Neurological Surgery, The Ohio State University, Columbus, Ohio
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Object

The astrocytic contribution to the blood-brain barrier (BBB) in metastatic and primary malignant brain tumors is not well understood. To better understand the vascular properties associated with metastatic and primary malignant brain tumors, the authors systematically analyzed the astrocytic component of the BBB in brain neoplasms.

Methods

Twelve patients who underwent resection of metastatic or primary brain neoplasms (4 metastatic lesions, 2 low-grade astrocytomas, 2 anaplastic astrocytomas, and 4 glioblastoma multiforme) were included. Clinical, MRI, operative, histopathological and immunohistochemical (glial fibrillary acidic protein [GFAP], CD31, and aquaporin 4 [AQ4]) findings were analyzed.

Results

Intratumoral regions of MRI enhancement corresponded with breakdown of the normal astrocyte–endothelial cell relationship in the BBB in metastatic deposits and malignant gliomas. Metastases demonstrated lack of perivascular GFAP and AQ4 on CD31-positive intratumoral vessels. At the metastasis-brain interface, normalization of GFAP and AQ4 staining associated with intraparenchymal vessels was observed. Intratumoral vasculature in enhancing regions of high-grade gliomas revealed gaps in GFAP and AQ4 staining consistent with disintegration of the normal astrocyte–endothelial cell association in the BBB. Intratumoral vasculature in low-grade and nonenhancing regions of high-grade gliomas maintained the normal astrocyte–endothelial cell relationship seen in an intact BBB, with GFAP- and AQ4-positive glial processes that were uniformly associated with the CD31-positive vasculature.

Conclusions

Regions of MRI enhancement in metastatic and primary malignancies correspond to areas of breakdown of the physiological astrocyte–endothelial cell relationship of the BBB, including loss of normal perivascular astrocytic architecture on GFAP and AQ4 immunohistochemistry. Nonenhancing areas are associated with preservation of the normal astrocyte–endothelial cell relationship of the intact BBB.

Abbreviations used in this paper:AQ4 = aquaporin 4; BBB = blood-brain barrier; GFAP = glial fibrillary acidic protein.

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Contributor Notes

Address correspondence to: Russell R. Lonser, M.D., Department of Neurological Surgery, The Ohio State University Wexner Medical Center, 410 West 10th Avenue, N1047 Doan Hall, Columbus, Ohio 43210. email: russell.lonser@osumc.edu.

Please include this information when citing this paper: published online April 26, 2013; DOI: 10.3171/2013.3.JNS122226.

  • 1

    Abbott NJ, , Rönnbäck L, & Hansson E: Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:4153, 2006

  • 2

    Albelda SM, , Muller WA, , Buck CA, & Newman PJ: Molecular and cellular properties of PECAM-1 (endoCAM/CD31): a novel vascular cell-cell adhesion molecule. J Cell Biol 114:10591068, 1991

    • Search Google Scholar
    • Export Citation
  • 3

    Antonetti DA, , Barber AJ, , Hollinger LA, , Wolpert EB, & Gardner TW: Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Biol Chem 274:2346323467, 1999

    • Search Google Scholar
    • Export Citation
  • 4

    Antonetti DA, , Barber AJ, , Khin S, , Lieth E, , Tarbell JM, & Gardner TW: Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes 47:19531959, 1998

    • Search Google Scholar
    • Export Citation
  • 5

    Caraglia M, , De Rosa G, , Salzano G, , Santini D, , Lamberti M, & Sperlongano P, : Nanotech revolution for the anti-cancer drug delivery through blood-brain barrier. Curr Cancer Drug Targets 12:186196, 2012

    • Search Google Scholar
    • Export Citation
  • 6

    Cardoso FL, , Brites D, & Brito MA: Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Brain Res Rev 64:328363, 2010

    • Search Google Scholar
    • Export Citation
  • 7

    Claes A, , Idema AJ, & Wesseling P: Diffuse glioma growth: a guerilla war. Acta Neuropathol 114:443458, 2007

  • 8

    Ellemann K, , Christensen L, , Gjerris F, , Briand P, & Kruse-Larsen C: Glucocorticoid receptors in glioblastoma multiforme: a new approach to antineoplastic glucocorticoid therapy. Acta Neurochir (Wien) 93:69, 1988

    • Search Google Scholar
    • Export Citation
  • 9

    Ezan P, , André P, , Cisternino S, , Saubaméa B, , Boulay AC, & Doutremer S, : Deletion of astroglial connexins weakens the blood-brain barrier. J Cereb Blood Flow Metab 32:14571467, 2012

    • Search Google Scholar
    • Export Citation
  • 10

    Fazakas C, , Wilhelm I, , Nagyoszi P, , Farkas AE, , Haskó J, & Molnár J, : Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE 6:e20758, 2011

    • Search Google Scholar
    • Export Citation
  • 11

    Fidler IJ, , Yano S, , Zhang RD, , Fujimaki T, & Bucana CD: The seed and soil hypothesis: vascularisation and brain metastases. Lancet Oncol 3:5357, 2002

    • Search Google Scholar
    • Export Citation
  • 12

    Förster C, , Waschke J, , Burek M, , Leers J, & Drenckhahn D: Glucocorticoid effects on mouse microvascular endothelial barrier permeability are brain specific. J Physiol 573:413425, 2006

    • Search Google Scholar
    • Export Citation
  • 13

    Fortin D: The blood-brain barrier: its influence in the treatment of brain tumors metastases. Curr Cancer Drug Targets 12:247259, 2012

    • Search Google Scholar
    • Export Citation
  • 14

    Habgood MD, , Begley DJ, & Abbott NJ: Determinants of passive drug entry into the central nervous system. Cell Mol Neurobiol 20:231253, 2000

    • Search Google Scholar
    • Export Citation
  • 15

    Hawkins BT, & Davis TP: The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173185, 2005

  • 16

    Heiss JD, , Papavassiliou E, , Merrill MJ, , Nieman L, , Knightly JJ, & Walbridge S, : Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. J Clin Invest 98:14001408, 1996

    • Search Google Scholar
    • Export Citation
  • 17

    Kienast Y, , von Baumgarten L, , Fuhrmann M, , Klinkert WE, , Goldbrunner R, & Herms J, : Real-time imaging reveals the single steps of brain metastasis formation. Nat Med 16:116122, 2010

    • Search Google Scholar
    • Export Citation
  • 18

    Kotsarini C, , Griffiths PD, , Wilkinson ID, & Hoggard N: A systematic review of the literature on the effects of dexamethasone on the brain from in vivo human-based studies: implications for physiological brain imaging of patients with intracranial tumors. Neurosurgery 67:17991815, 2010

    • Search Google Scholar
    • Export Citation
  • 19

    Liebner S, , Fischmann A, , Rascher G, , Duffner F, , Grote EH, & Kalbacher H, : Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100:323331, 2000

    • Search Google Scholar
    • Export Citation
  • 20

    Lohle PN, , Wurzer HA, , Seelen PJ, , Kingma LM, & Go KG: Analysis of fluid in cysts accompanying various primary and metastatic brain tumours: proteins, lactate and pH. Acta Neurochir (Wien) 140:1419, 1998

    • Search Google Scholar
    • Export Citation
  • 21

    Lohle PN, , Wurzer HA, , Seelen PJ, , Kingma LM, & Go KG: The pathogenesis of cysts accompanying intra-axial primary and metastatic tumors of the central nervous system. J Neurooncol 40:277285, 1998

    • Search Google Scholar
    • Export Citation
  • 22

    Lonser RR, , Vortmeyer AO, , Butman JA, , Glasker S, , Finn MA, & Ammerman JM, : Edema is a precursor to central nervous system peritumoral cyst formation. Ann Neurol 58:392399, 2005

    • Search Google Scholar
    • Export Citation
  • 23

    Mehta AI, , Brufsky AM, & Sampson JH: Therapeutic approaches for HER2-positive brain metastases: circumventing the blood-brain barrier. Cancer Treat Rev 39:261269, 2013

    • Search Google Scholar
    • Export Citation
  • 24

    Mitic LL, & Anderson JM: Molecular architecture of tight junctions. Annu Rev Physiol 60:121142, 1998

  • 25

    Muldoon LL, , Alvarez JI, , Begley DJ, , Boado RJ, , Del Zoppo GJ, & Doolittle ND, : Immunologic privilege in the central nervous system and the blood-brain barrier. J Cereb Blood Flow Metab 33:1321, 2013

    • Search Google Scholar
    • Export Citation
  • 26

    Persidsky Y, , Ramirez SH, , Haorah J, & Kanmogne GD: Bloodbrain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1:223236, 2006

    • Search Google Scholar
    • Export Citation
  • 27

    Petty MA, & Lo EH: Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 68:311323, 2002

    • Search Google Scholar
    • Export Citation
  • 28

    Raff MC, , Fields KL, , Hakomori SI, , Mirsky R, , Pruss RM, & Winter J: Cell-type-specific markers for distinguishing and studying neurons and the major classes of glial cells in culture. Brain Res 174:283308, 1979

    • Search Google Scholar
    • Export Citation
  • 29

    Romero IA, , Radewicz K, , Jubin E, , Michel CC, , Greenwood J, & Couraud PO, : Changes in cytoskeletal and tight junctional proteins correlate with decreased permeability induced by dexamethasone in cultured rat brain endothelial cells. Neurosci Lett 344:112116, 2003

    • Search Google Scholar
    • Export Citation
  • 30

    Rössler K, , Neuchrist C, , Kitz K, , Scheiner O, , Kraft D, & Lassmann H: Expression of leucocyte adhesion molecules at the human blood-brain barrier (BBB). J Neurosci Res 31:365374, 1992

    • Search Google Scholar
    • Export Citation
  • 31

    Seelbach M, , Chen L, , Powell A, , Choi YJ, , Zhang B, & Hennig B, : Polychlorinated biphenyls disrupt blood-brain barrier integrity and promote brain metastasis formation. Environ Health Perspect 118:479484, 2010

    • Search Google Scholar
    • Export Citation
  • 32

    Spiegl-Kreinecker S, , Buchroithner J, , Elbling L, , Steiner E, , Wurm G, & Bodenteich A, : Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. J Neurooncol 57:2736, 2002

    • Search Google Scholar
    • Export Citation
  • 33

    Underwood JL, , Murphy CG, , Chen J, , Franse-Carman L, , Wood I, & Epstein DL, : Glucocorticoids regulate transendothelial fluid flow resistance and formation of intercellular junctions. Am J Physiol 277:C330C342, 1999

    • Search Google Scholar
    • Export Citation
  • 34

    Warth A, , Kröger S, & Wolburg H: Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol 107:311318, 2004

    • Search Google Scholar
    • Export Citation
  • 35

    Willis CL, , Leach L, , Clarke GJ, , Nolan CC, & Ray DE: Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia 48:113, 2004

    • Search Google Scholar
    • Export Citation
  • 36

    Willis CL, , Nolan CC, , Reith SN, , Lister T, , Prior MJ, & Guerin CJ, : Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 45:325337, 2004

    • Search Google Scholar
    • Export Citation
  • 37

    Wolburg H, , Wolburg-Buchholz K, , Kraus J, , Rascher-Eggstein G, , Liebner S, & Hamm S, : Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105:586592, 2003

    • Search Google Scholar
    • Export Citation

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