Localization of breast cancer resistance protein (BCRP) in microvessel endothelium of human control and epileptic brain

被引:142
作者
Aronica, E
Gorter, JA
Redeker, S
van Vliet, EA
Ramkema, M
Scheffer, GL
Scheper, RJ
van der Valk, P
Leenstra, S
Baayen, JC
Spliet, WGM
Troost, D
机构
[1] Univ Amsterdam, Acad Med Ctr, Dept Neuropathol, NL-1105 AZ Amsterdam, Netherlands
[2] Univ Amsterdam, Acad Med Ctr, Dept Neurosurg, NL-1105 AZ Amsterdam, Netherlands
[3] Univ Amsterdam, Swammerdam Inst Life Sci, Amsterdam, Netherlands
[4] Stichting Epilepsie Instellingen Nederland, Heemstede, Netherlands
[5] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands
[6] Vrije Univ Amsterdam Med Ctr, Dept Neurosurg, Amsterdam, Netherlands
[7] Univ Med Ctr Utrecht, Dept Pathol, Utrecht, Netherlands
关键词
epilepsy; hippocampus; glioma; glioneuronal tumors; blood vessels; endothelium;
D O I
10.1111/j.1528-1167.2005.66604.x
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Purpose: Breast cancer resistance protein (BCRP) is a half adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed on cellular membranes and included in the group of multidrug resistant (MDR)-related proteins. Recently, upregulation of different MDR proteins has been shown in human epilepsy-associated conditions. This study investigated the expression and cellular distribution of BCRP in human control and epileptic brain, including a large number of both neoplastic and nonneoplastic specimens from patients with chronic pharmacoresistant epilepsy. Methods: Several epileptogenic pathologies, such as hippocampal sclerosis (HS), focal cortical dysplasia (FCD), dysembryoplastic neuroepithelial tumor, oligodendroglioma astrocytoma, and glioblastoma multiforme were studied by using Western blot and immunocytochemistry. Results: With Western blot, we could demonstrate the presence of BCRP in both normal and epileptic human brain tissue. In contrast to P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, BCRP expression levels did not change in tissue from patients with HS, compared with control hippocampus. No BCRP immunoreactivity was observed in glial or neuronal cells, including reactive astrocytes and dysplastic neurons in FCD. BCRP expression was, however, increased in tumor brain tissue. Immunocytochemistry demonstrated that BCRP was exclusively located in blood vessels and was highly expressed at the luminal cell surface and in newly formed tumor capillaries. This localization closely resembles that of P-gp. The higher expression observed in astrocytomas by Western blot analysis was related to the higher vascular density within the tumor tissue. Conclusions: These results indicate a constitutive expression of BCRP in human endothelial cells, representing an important barrier against drug access to the brain. In particular, the strong BCRP expression in the microvasculature of epileptogenic brain tumors could critically influence the bioavailability of drugs within the tumor and contribute to pharmacoresistance.
引用
收藏
页码:849 / 857
页数:9
相关论文
共 37 条
  • [11] Characterisation of the brain multidrug resistance protein (BMDP/ABCG2/BCRP) expressed at the blood-brain barrier
    Eisenblätter, T
    Hüwel, S
    Galla, HJ
    [J]. BRAIN RESEARCH, 2003, 971 (02) : 221 - 231
  • [12] Cyclooxygenase-2 and inducible nitric oxide synthase expression in human astrocytic gliomas: correlation with angiogenesis and prognostic significance
    Hara, A
    Okayasu, I
    [J]. ACTA NEUROPATHOLOGICA, 2004, 108 (01) : 43 - 48
  • [13] Kleindorfer P. R., 2000, Proceedings of the 33rd Annual Hawaii International Conference on Systems Sciences
  • [14] Differential cellular expression of neurotrophins in cortical tubers of the tuberous sclerosis complex
    Kyin, R
    Hua, Y
    Baybis, M
    Scheithauer, B
    Kolson, D
    Uhlmann, E
    Gutmann, D
    Crino, PB
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2001, 159 (04) : 1541 - 1554
  • [15] Lage H, 2000, Lancet Oncol, V1, P169, DOI 10.1016/S1470-2045(00)00032-2
  • [16] Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy
    Lazarowski, A
    Sevlever, G
    Taratuto, A
    Massaro, M
    Rabinowicz, A
    [J]. PEDIATRIC NEUROLOGY, 1999, 21 (04) : 731 - 734
  • [17] From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance
    Litman, T
    Druley, TE
    Stein, WD
    Bates, SE
    [J]. CELLULAR AND MOLECULAR LIFE SCIENCES, 2001, 58 (07) : 931 - 959
  • [18] Role of multidrug transporters in pharmacoresistance to antiepileptic drugs
    Löscher, W
    Potschka, H
    [J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2002, 301 (01) : 7 - 14
  • [19] Maliepaard M, 2001, CANCER RES, V61, P3458
  • [20] Terminology and classification of the cortical dysplasias
    Palmini, A
    Najm, I
    Avanzini, G
    Babb, T
    Guerrini, R
    Foldvary-Schaefer, N
    Jackson, G
    Lüders, HO
    Prayson, R
    Spreafico, R
    Vinters, HV
    [J]. NEUROLOGY, 2004, 62 (06) : S2 - S8