Vascular Permeability Within Brain Metastases

  • Chris E. Adkins
  • Rajendar K. Mittapalli
  • Kaci A. Bohn
  • Amit Bansal
  • Vinay K. Venishetty
  • Paul R. LockmanEmail author
Part of the Cancer Metastasis - Biology and Treatment book series (CMBT, volume 18)


The vasculature within the normal brain is structurally unique compared to blood vessels found throughout the rest of the body. This unique structure highly regulates which molecules and or drugs can enter into brain tissue. However, when a brain metastasis is formed, the vasculature becomes compromised, and as a result is much more permissive in allowing molecules and or drugs to move from the blood into the brain metastasis. Quantifying these changes allow significant insight into the ability of chemotherapeutics to penetrate into a brain metastasis. Herein, we discuss the vascular structural changes that are present within a brain metastasis, clinical and preclinical differences between observed permeability in a primary tumor and a metastasis, and lastly the most common methods to determine permeability changes within a central lesion.


Brain Metastasis Vascular Permeability Metastatic Lesion Glioblastoma Multiforme Tight Junction Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Neuwelt EA (2004) Mechanisms of disease: the blood–brain barrier. Neurosurgery 54(1):131–140, discussion 41–2PubMedCrossRefGoogle Scholar
  2. 2.
    Smith QR (2003) A review of blood–brain barrier transport techniques. Methods Mol Med 89:193–208PubMedGoogle Scholar
  3. 3.
    Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16(1):1–13PubMedCrossRefGoogle Scholar
  4. 4.
    Nitta T et al (2003) Size-selective loosening of the blood–brain barrier in claudin-5-deficient mice. J Cell Biol 161(3):653–660PubMedCrossRefGoogle Scholar
  5. 5.
    Butt AM, Jones HC, Abbott NJ (1990) Electrical resistance across the blood–brain barrier in anaesthetized rats: a developmental study. J Physiol 429:47–62PubMedGoogle Scholar
  6. 6.
    Smith QR (1996) Brain perfusion systems for studies of drug uptake and metabolism in the central nervous system. Pharm Biotechnol 8:285–307PubMedGoogle Scholar
  7. 7.
    Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier. Trends Neurosci 24(12):719–725PubMedCrossRefGoogle Scholar
  8. 8.
    Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7(1):41–53PubMedCrossRefGoogle Scholar
  9. 9.
    Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and ­disease. Pharmacol Rev 57(2):173–185PubMedCrossRefGoogle Scholar
  10. 10.
    Begley DJ (2004) ABC transporters and the blood–brain barrier. Curr Pharm Des 10(12):1295–1312PubMedCrossRefGoogle Scholar
  11. 11.
    Deeken JF, Loscher W (2007) The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13(6):1663–1674PubMedCrossRefGoogle Scholar
  12. 12.
    Shen S, Zhang W (2010) ABC transporters and drug efflux at the blood–brain barrier. Rev Neurosci 21(1):29–53PubMedGoogle Scholar
  13. 13.
    Loscher W, Potschka H (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Prog Neurobiol 76(1):22–76PubMedCrossRefGoogle Scholar
  14. 14.
    Thomas FC et al (2009) Uptake of ANG1005, a novel paclitaxel derivative, through the blood–brain barrier into brain and experimental brain metastases of breast cancer. Pharm Res 26(11):2486–2494PubMedCrossRefGoogle Scholar
  15. 15.
    Minn A et al (1991) Drug metabolizing enzymes in the brain and cerebral microvessels. Brain Res Brain Res Rev 16(1):65–82PubMedCrossRefGoogle Scholar
  16. 16.
    Witt KA et al (2001) Peptide drug modifications to enhance bioavailability and blood–brain barrier permeability. Peptides 22(12):2329–2343PubMedCrossRefGoogle Scholar
  17. 17.
    Brownlees J, Williams CH (1993) Peptidases, peptides, and the mammalian blood–brain ­barrier. J Neurochem 60(3):793–803PubMedCrossRefGoogle Scholar
  18. 18.
    Pardridge WM (2003) Blood–brain barrier drug targeting: the future of brain drug development. Mol Interv 3(2):90–105, 51PubMedCrossRefGoogle Scholar
  19. 19.
    Laron Z (2009) Insulin and the brain. Arch Physiol Biochem 115(2):112–116PubMedCrossRefGoogle Scholar
  20. 20.
    Boado RJ et al (2009) Engineering and expression of a chimeric transferrin receptor monoclonal antibody for blood–brain barrier delivery in the mouse. Biotechnol Bioeng 102(4):1251–1258PubMedCrossRefGoogle Scholar
  21. 21.
    Abbott NJ et al (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37(1):13–25PubMedCrossRefGoogle Scholar
  22. 22.
    Bronger H et al (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res 65(24):11419–11428PubMedCrossRefGoogle Scholar
  23. 23.
    Gerstner ER, Fine RL (2007) Increased permeability of the blood–brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol 25(16):2306–2312PubMedCrossRefGoogle Scholar
  24. 24.
    Hiesiger EM et al (1986) Opening the blood–brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann Neurol 19(1):50–59PubMedCrossRefGoogle Scholar
  25. 25.
    Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86(3):353–364PubMedCrossRefGoogle Scholar
  26. 26.
    Blasberg RG, Fenstermacher JD, Patlak CS (1983) Transport of alpha-aminoisobutyric acid across brain capillary and cellular membranes. J Cereb Blood Flow Metab 3(1):8–32PubMedCrossRefGoogle Scholar
  27. 27.
    Inamura T, Black KL (1994) Bradykinin selectively opens blood-tumor barrier in experimental brain tumors. J Cereb Blood Flow Metab 14(5):862–870PubMedCrossRefGoogle Scholar
  28. 28.
    Inamura T et al (1994) Intracarotid infusion of RMP-7, a bradykinin analog: a method for selective drug delivery to brain tumors. J Neurosurg 81(5):752–758PubMedCrossRefGoogle Scholar
  29. 29.
    Levin VA et al (1972) Uptake and distribution of 3 H-methotrexate by the murine ependymoblastoma. J Natl Cancer Inst 48(4):875–883PubMedGoogle Scholar
  30. 30.
    Levin VA, Freeman-Dove M, Landahl HD (1975) Permeability characteristics of brain ­adjacent to tumors in rats. Arch Neurol 32(12):785–791PubMedCrossRefGoogle Scholar
  31. 31.
    Nakagawa H et al (1987) Dexamethasone effects on [125I]albumin distribution in experimental RG-2 gliomas and adjacent brain. J Cereb Blood Flow Metab 7(6):687–701PubMedCrossRefGoogle Scholar
  32. 32.
    Robinson PJ, Rapoport SI (1990) Model for drug uptake by brain tumors: effects of osmotic treatment and of diffusion in brain. J Cereb Blood Flow Metab 10(2):153–161PubMedCrossRefGoogle Scholar
  33. 33.
    Lockman PR et al (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in mouse brain metastases of breast cancer. Clin Cancer Res 16(23):5664–5678PubMedCrossRefGoogle Scholar
  34. 34.
    Percy DB et al (2011) In vivo characterization of changing blood-tumor barrier permeability in a mouse model of breast cancer metastasis: a complementary magnetic resonance imaging approach. Invest Radiol 46(11):718–725PubMedGoogle Scholar
  35. 35.
    Mitic LL, Anderson JM (1998) Molecular architecture of tight junctions. Annu Rev Physiol 60:121–142PubMedCrossRefGoogle Scholar
  36. 36.
    Sawada T et al (2000) Immunohistochemical study of tight junction-related protein in neovasculature in astrocytic tumor. Brain Tumor Pathol 17(1):1–6PubMedCrossRefGoogle Scholar
  37. 37.
    Liu LB et al (2008) Bradykinin increases blood-tumor barrier permeability by down-regulating the expression levels of ZO-1, occludin, and claudin-5 and rearranging actin cytoskeleton. J Neurosci Res 86(5):1153–1168PubMedCrossRefGoogle Scholar
  38. 38.
    Gardner TW et al (1996) Histamine reduces ZO-1 tight-junction protein expression in cultured retinal microvascular endothelial cells. Biochem J 320(3):717–721PubMedGoogle Scholar
  39. 39.
    Hobson B, Denekamp J (1984) Endothelial proliferation in tumours and normal tissues: ­continuous labelling studies. Br J Cancer 49(4):405–413PubMedCrossRefGoogle Scholar
  40. 40.
    Hull C et al (2002) Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase. J Immunol 169(5):2611–2618PubMedGoogle Scholar
  41. 41.
    Karsan A, Yee E, Harlan JM (1996) Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1. J Biol Chem 271(44):27201–27204PubMedCrossRefGoogle Scholar
  42. 42.
    Karsan A et al (1997) Fibroblast growth factor-2 inhibits endothelial cell apoptosis by Bcl-2-dependent and independent mechanisms. Am J Pathol 151(6):1775–1784PubMedGoogle Scholar
  43. 43.
    Marti HH, Risau W (1998) Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. Proc Natl Acad Sci U S A 95(26):15809–15814PubMedCrossRefGoogle Scholar
  44. 44.
    Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186PubMedCrossRefGoogle Scholar
  45. 45.
    Jain RK et al (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8(8):610–622PubMedCrossRefGoogle Scholar
  46. 46.
    Idoate MA et al (2011) Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence. Neuropathology 31(6):575–582PubMedCrossRefGoogle Scholar
  47. 47.
    Mokry J et al (2004) Nestin expression by newly formed human blood vessels. Stem Cells Dev 13(6):658–664PubMedCrossRefGoogle Scholar
  48. 48.
    Sugawara K et al (2002) Nestin as a marker for proliferative endothelium in gliomas. Lab Invest 82(3):345–351PubMedCrossRefGoogle Scholar
  49. 49.
    Ding B et al (2006) Comparison of cerebral blood volume and permeability in preoperative grading of intracranial glioma using CT perfusion imaging. Neuroradiology 48(10):773–781PubMedCrossRefGoogle Scholar
  50. 50.
    Millar BA et al (2005) Assessing perfusion changes during whole brain irradiation for patients with cerebral metastases. J Neurooncol 71(3):281–286PubMedCrossRefGoogle Scholar
  51. 51.
    Jain R et al (2011) In vivo correlation of tumor blood volume and permeability with histologic and molecular angiogenic markers in gliomas. AJNR Am J Neuroradiol 32(2):388–394PubMedCrossRefGoogle Scholar
  52. 52.
    Budde MD et al (2012) Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain. NMR Biomed 25(5):726–736PubMedCrossRefGoogle Scholar
  53. 53.
    Budde MD et al (2012) Differential microstructure and physiology of brain and bone metastases in a rat breast cancer model by diffusion and dynamic contrast enhanced MRI. Clin Exp Metastasis 29(1):51–62PubMedCrossRefGoogle Scholar
  54. 54.
    Fidler IJ (2011) The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 21(2):107–112PubMedCrossRefGoogle Scholar
  55. 55.
    Zhang RD et al (1992) Differential permeability of the blood–brain barrier in experimental brain metastases produced by human neoplasms implanted into nude mice. Am J Pathol 141(5):1115–1124PubMedGoogle Scholar
  56. 56.
    Peereboom DM (2005) Chemotherapy in brain metastases. Neurosurgery 57(5 (Suppl)):S54–S65, discussion S1-4PubMedGoogle Scholar
  57. 57.
    Colombo T, Zucchetti M, D’Incalci M (1994) Cyclosporin A markedly changes the distribution of doxorubicin in mice and rats. J Pharmacol Exp Ther 269(1):22–27PubMedGoogle Scholar
  58. 58.
    Kemper EM et al (2003) Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. Clin Cancer Res 9(7):2849–2855PubMedGoogle Scholar
  59. 59.
    Sparreboom A et al (1996) Tissue distribution, metabolism and excretion of paclitaxel in mice. Anticancer Drugs 7(1):78–86PubMedCrossRefGoogle Scholar
  60. 60.
    van Asperen J et al (1997) The functional role of P-glycoprotein in the blood–brain barrier. J Pharm Sci 86(8):881–884PubMedCrossRefGoogle Scholar
  61. 61.
    Walbert T, Gilbert MR (2009) The role of chemotherapy in the treatment of patients with brain metastases from solid tumors. Int J Clin Oncol 14(4):299–306PubMedCrossRefGoogle Scholar
  62. 62.
    Taskar KS et al (2012) Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer. Pharm Res 29(3):770–781PubMedCrossRefGoogle Scholar
  63. 63.
    Bakay L et al (1956) Ultrasonically produced changes in the blood–brain barrier. AMA Arch Neurol Psychiatry 76(5):457–467PubMedCrossRefGoogle Scholar
  64. 64.
    Shealy CN, Crafts D (1965) Selective alteration of the blood–brain barrier. J Neurosurg 23(5):484–487PubMedCrossRefGoogle Scholar
  65. 65.
    Lin SR, Kormano M (1977) Cerebral circulation after cardiac arrest. Microangiographic and protein tracer studies. Stroke 8(2):182–188PubMedCrossRefGoogle Scholar
  66. 66.
    Johansson B et al (1970) The effect of acute arterial hypertension on the blood–brain barrier to protein tracers. Acta Neuropathol 16(2):117–124PubMedCrossRefGoogle Scholar
  67. 67.
    da Costa JC (1972) Influence of electroconvulsions on the permeability of the blood–brain barrier to trypan blue. Arq Neuropsiquiatr 30(1):1–7PubMedGoogle Scholar
  68. 68.
    Nemeroff CB, Crisley FD (1975) Monosodium L-glutamate-induced convulsions: temporary alteration in blood–brain barrier permeability to plasma proteins. Environ Physiol Biochem 5(6):389–395PubMedGoogle Scholar
  69. 69.
    Schettler T, Shealy CN (1970) Experimental selective alteration of blood–brain barrier by x-irradiation. J Neurosurg 32(1):89–94PubMedCrossRefGoogle Scholar
  70. 70.
    Dereymaeker A, Claeys L, Sorel L (1970) Experimental study of the blood–brain barrier in the frozen cerebral cortex. Eur Neurol 3(5):293–302PubMedCrossRefGoogle Scholar
  71. 71.
    Uehara H et al (1997) Imaging experimental brain tumors with 1-aminocyclopentane carboxylic acid and alpha-aminoisobutyric acid: comparison to fluorodeoxyglucose and diethylenetriaminepentaacetic acid in morphologically defined tumor regions. J Cereb Blood Flow Metab 17(11):1239–1253PubMedGoogle Scholar
  72. 72.
    Miyagawa T et al (2003) Assessment of treatment response by autoradiography with (14)C-aminocyclopentane carboxylic acid, (67)Ga-DTPA, and (18)F-FDG in a herpes simplex virus thymidine kinase/ganciclovir brain tumor model. J Nucl Med 44(11):1845–1854PubMedGoogle Scholar
  73. 73.
    Schmidt KC, Smith CB (2005) Resolution, sensitivity and precision with autoradiography and small animal positron emission tomography: implications for functional brain imaging in ­animal research. Nucl Med Biol 32(7):719–725PubMedCrossRefGoogle Scholar
  74. 74.
    Ohno K, Pettigrew KD, Rapoport SI (1978) Lower limits of cerebrovascular permeability to nonelectrolytes in the conscious rat. Am J Physiol 235(3):H299–H307PubMedGoogle Scholar
  75. 75.
    Patlak CS, Blasberg RG, Fenstermacher JD (1983) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab 3(1):1–7PubMedCrossRefGoogle Scholar
  76. 76.
    Server A et al (2011) Diagnostic examination performance by using microvascular leakage, cerebral blood volume, and blood flow derived from 3-T dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging in the differentiation of glioblastoma multiforme and brain metastasis. Neuroradiology 53(5):319–330PubMedCrossRefGoogle Scholar
  77. 77.
    Asotra K, Ningaraj N, Black KL (2003) Measurement of blood–brain and blood-tumor barrier permeabilities with [14C]-labeled tracers. Methods Mol Med 89:177–190PubMedGoogle Scholar
  78. 78.
    Blasberg RG et al (1984) Local blood-to-tissue transport in walker 256 metastatic brain tumors. J Neurooncol 2(3):205–218PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Chris E. Adkins
    • 1
  • Rajendar K. Mittapalli
    • 1
  • Kaci A. Bohn
    • 1
  • Amit Bansal
    • 1
  • Vinay K. Venishetty
    • 1
  • Paul R. Lockman
    • 1
    Email author
  1. 1.Department of Pharmaceutical SciencesTexas Tech University Health Sciences CenterAmarilloUSA

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