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Glioblastoma cells release factors that disrupt blood-brain barrier features

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Abstract

The blood-brain barrier (BBB), mediated by endothelial tight junctions, is defective in malignant gliomas such as glioblastoma, resulting in cerebral edema and contrast enhancement upon neuroradiological examination. The mechanisms underlying BBB breakdown are essentially unknown. Since non-neoplastic astrocytes are required to induce BBB features of cerebral endothelial cells, it is conceivable that malignant astrocytes have lost this ability due to dedifferentiation. Alternatively, glioma cells might actively degrade previously intact BBB tight junctions. To examine the latter hypothesis, we have employed a transepithelial electrical resistance breakdown assay using monolayers of the C7 subclone of Madin-Darby canine kidney (MDCK-C7) cells forming tight junctions similar to those of BBB endothelial cells. We found that glioblastoma primary cells co-cultured with the MDCK-C7 monolayer (without direct contact of the two cell types) resulted in marked breakdown of electrical resistance, whereas primary cultures derived from low-grade gliomas (fibrillary astrocytoma, oligoastrocytoma) showed delayed or no effects. These results suggest that malignant gliomas have acquired the ability to actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue.

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References

  1. Abbott NJ (2002) Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat 200:629–638

    Article  CAS  PubMed  Google Scholar 

  2. Bertossi M, Virgintino D, Maiorano E, Occhiogrosso M, Roncali L (1997) Ultrastructural and morphometric investigation of human brain capillaries in normal and peritumoral tissues. Ultrastruct Pathol 21:41–49

    CAS  PubMed  Google Scholar 

  3. Binder DK, Berger MS (2000) Proteases and the biology of glioma invasion. J Neurooncol 56:149–158

    Article  Google Scholar 

  4. Descamps L, Coisne C, Dehouck B, Cecchelli R, Torpier G (2003) Protective effect of glial cells against lipopolysaccharide-mediated blood-brain barrier injury. Glia 42:46–58

    Article  PubMed  Google Scholar 

  5. Dinda AK, Sarkar C, Roy S, Kharbanda K, Mathur M, Khosla AK, Banerji AK (1993) A transmission and scanning electron microscopic study of tumoral and peritumoral microblood vessels in human gliomas. J Neurooncol 16:149–158

    CAS  PubMed  Google Scholar 

  6. Engelhard HH, Groothuis DG (1999) The blood-brain barrier: structure, function, and response to neoplasia. In: Berger MD, Wilson CB (eds) Gliomas. Saunders, Philadelphia, pp 115–121

  7. Furuse M, Furuse K, Sasaki H, Tsukita S (2001) Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney cells. J Cell Biol 153:263–272

    Article  CAS  PubMed  Google Scholar 

  8. Janzer RC, Raff MC (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325:253–257

    CAS  PubMed  Google Scholar 

  9. Jiang WG, Martin TA, Matsumoto K, Nakamura T, Mansel RE (1999) Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol 181:319–329

    Article  PubMed  Google Scholar 

  10. Kleihues P, Cavenee WK (2000) World Health Organization classification of tumours. Pathology and genetics. Tumours of the nervous system. WHO, Lyon

  11. Kniesel U, Wolburg H (2000) Tight junctions of the blood-brain barrier. Cell Mol Neurobiol 20:57–76

    Article  CAS  PubMed  Google Scholar 

  12. Lamszus K, Laterra J, Westphal M, Rosen EM (1999) Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas. Int J Dev Neurosci 17:517–530

    Article  PubMed  Google Scholar 

  13. Lee SW, Kim WJ, Choi YK, Song HS, Son MJ, Gelman IH, Kim YJ, Kim KW (2003) SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat Med 9:900–906

    Article  PubMed  Google Scholar 

  14. Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100:323–331

    CAS  PubMed  Google Scholar 

  15. Lo EH, Wang X, Cuzner ML (2002) Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J Neurosci Res 69:1–9

    Article  CAS  PubMed  Google Scholar 

  16. Ludwig T, Ossig R, Graessel S, Wilhelmi M, Oberleithner H, Schneider SW (2002) The electrical resistance breakdown assay determines the role of proteinases in tumor cell invasion. Am J Physiol Renal Physiol 283:F319–F327

    PubMed  Google Scholar 

  17. Machein MR, Plate KH (2000) VEGF in brain tumors. J Neurooncol 50:109–120

    Article  PubMed  Google Scholar 

  18. Machein MR, Kullmer J, Fiebich BL, Plate KH, Warnke PC (1999) Vascular endothelial growth factor expression, vascular volume, and capillary permeability in human brain tumors. Neurosurgery 44:732–740

    PubMed  Google Scholar 

  19. Mun-Bryce S, Rosenberg GA (1998) Gelatinase B modulates selective opening of the blood-brain barrier during inflammation. Am J Physiol 274: R1203–R1211

    PubMed  Google Scholar 

  20. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S (2003) Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161:653–660

    Article  PubMed  Google Scholar 

  21. Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR (2003) Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res 1:333–345

    PubMed  Google Scholar 

  22. Papadopoulos MC, Saadoun S, Davies DC, Bell BA (2001) Emerging molecular mechanisms of brain tumour oedema. Br J Neurosurg 15:101–108

    Article  CAS  PubMed  Google Scholar 

  23. Papadopoulos MC, Saadoun S, Woodrow CJ, Davies DC, Costa-Martins P, Moss RF, Krishna S, Bell BA (2001) Occludin expression in microvessels of neoplastic and non-neoplastic human brain. Neuropathol Appl Neurobiol 27:384–395

    Article  PubMed  Google Scholar 

  24. Pietsch T, Valter MM, Wolf HK, Deimling A von, Huang HJ, Cavenee WK, Wiestler OD (1997) Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol 93:109–117

    Article  PubMed  Google Scholar 

  25. Roberts HC, Roberts TP, Brasch RC, Dillon WP (2000) Quantitative measurement of microvascular permeability in human brain tumors achieved using dynamic contrast-enhanced MR imaging: correlation with histologic grade. Am J Neuroradiol 21:891–899

    PubMed  Google Scholar 

  26. Rubin LL, Staddon JM (1999) The cell biology of the blood-brain barrier. Annu Rev Neurosci 22:11–28

    CAS  PubMed  Google Scholar 

  27. Sameshima T, Nabeshima K, Toole BP, Yokogami K, Okada Y, Goya T, Koono M, Wakisaka S (2000) Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas. Int J Cancer 88:21–27

    Article  CAS  PubMed  Google Scholar 

  28. Sawada T, Kato Y, Kobayashi M, Takekekawa Y (2000) Immunohistochemical study of tight junction-related protein in neovasculature in astrocytic tumor. Brain Tumor Pathol 17:1–6

    Article  PubMed  Google Scholar 

  29. Seitz RJ, Wechsler W (1987) Immunohistochemical demonstration of serum proteins in human cerebral gliomas. Acta Neuropathol 73:145–152

    Google Scholar 

  30. Veronesi B (1996) Characterization of the MDCK cell line for screening neurotoxicants. Neurotoxicology 17:433–443

    PubMed  Google Scholar 

  31. Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier: development, composition, and regulation. Vascul Pharmacol 38:323–337

    Article  PubMed  Google Scholar 

  32. Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B (2003) 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 105:586–592

    CAS  PubMed  Google Scholar 

  33. Wunsch S, Gekle M, Kersting U, Schuricht B, Oberleithner H (1995) Phenotypically and karyotypically distinct Madin-Darby canine kidney cell clones respond differently to alkaline stress. J Cell Physiol 164:164–171

    PubMed  Google Scholar 

  34. Zak J, Schneider SW, Eue I, Ludwig T, Oberleithner H (2000) High-resistance MDCK-C7 monolayers used for measuring invasive potency of tumour cells. Pflugers Arch 440:179–183

    Article  PubMed  Google Scholar 

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Acknowledgement

This study was supported by grant Pa 328/5 from Deutsche Forschungsgemeinschaft.

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Correspondence to Werner Paulus.

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Schneider, S.W., Ludwig, T., Tatenhorst, L. et al. Glioblastoma cells release factors that disrupt blood-brain barrier features. Acta Neuropathol 107, 272–276 (2004). https://doi.org/10.1007/s00401-003-0810-2

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  • DOI: https://doi.org/10.1007/s00401-003-0810-2

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