Localisation of breast cancer resistance protein in microvessel endothelium of human brain

Cooray, Hiran C; Blackmore, Colin G.; Maskell, L.; Barrand, Margery A.

doi:10.1097/00001756-200211150-00014

Cited by 366 publications

(249 citation statements)

References 15 publications

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“…Further analysis revealed that the porcine BCRP was expressed in brain tissue in vivo and was predominantly localized within the endothelial cells isolated from brain capillaries. The presence of BCRP in the luminal surface of the endothelium of human brain microvessels was recently demonstrated by immunofluorescence confocal microscopy (Cooray et al, 2002). This suggests that BCRP, like Pgp and MRP1, contributes to the blood-brain barrier.…”

Section: Expression Of Bcrp In Normal Tissuesmentioning

confidence: 85%

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential 'side population' stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

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Section: Expression Of Bcrp In Normal Tissuesmentioning

confidence: 85%

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

2003

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“…Multidrug resistance-associated proteins (MRPs), transporting conjugated metabolites such as glutathione-and glucuronideconjugates (Loe et al 1996;Kusuhara et al 1998), are expressed and localized on the basal membrane of testis Sertolli cells and the basolateral membrane of lung epithelial cells (Wijnholds et al 1998;Wright et al 1998) but no expression of MRPs was detected on isolated human brain capillaries (Seetharaman et al 1998) and no significant staining was found in mouse brain (Wijnholds et al 2000). Breast Cancer Related Protein (BCRP) is located at the BBB, mainly at the luminal surface of microvessel endothelium (Cooray et al 2002). The preferential binding of EM-1 and EM-2 on the basolateral membrane in our polarized cell model suggests an efflux transporter located on the abluminal side of the BBB.…”

Section: Discussionmentioning

confidence: 99%

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Vı́gh

Kastin

Liao

et al. 2004

Experimental Brain Research

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Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) are two highly selective mu-opiate receptor agonists. We recently demonstrated that EM-1 and EM-2 have a saturable transport system from brain-to-blood in vivo. Since the endothelial cells are the main component of the non-fenestrated microvessels of the blood-brain barrier (BBB), we examined whether these endogenous tetrapeptides have a saturable transport system in cultured cerebral endothelial cells. EM-1 and EM-2 binding and transport were studied in a transwell system in which primary mouse endothelial cells were co-cultured with rat glioma cells. We found that binding of both endomorphins was greater on the basolateral than the apical cell surface. Flux of EM-1 and EM-2 occurred predominantly in the basolateral to apical direction, each showing self-inhibition with an excess of the respective endomorphin. Transport was not influenced by the addition of the Pglycoprotein inhibitor, cyclosporin A. Neither the mu-opiate receptor agonist DAMGO nor the delta-opiate receptor agonist DPDPE had any effect on the transport. Thus, the results show that a saturable transport system for EM-1 and EM-2 occurs at the level of endothelial cells of the BBB, and unlike β-endorphin and morphine, P-glycoprotein is not needed for the brain-to-blood transport. Cross-inhibition of the transport of each endomorphin by the other suggests a shared transport system that is different from mu-or delta-opiate receptors. As endormorphins are mainly produced in the CNS, the presence of the efflux system at the BBB could play an important role in pain modulation and neuroendocrine control.

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“…The levels of integrin β1 expression were decreased in SAC group, and the lowest levels were seen in the NAC population. ABCG2 mRNA, a newly proposed stem cell marker (Cooray et al, 2002;Scharenberg et al, 2002;Zhou et al, 2001) was expressed at the highest level by the RAC group, while ALL cells and SAC population expressed much lower levels of ABCG2 mRNA, with undetectable expression by the NAC population (Fig. 5B).…”

Section: Rapidly Adherent Cells Express the Highest Levels Of Integrimentioning

confidence: 95%

Partial enrichment of a population of human limbal epithelial cells with putative stem cell properties based on collagen type IV adhesiveness

Chen

Song

et al. 2005

Experimental Eye Research

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The concept that corneal epithelium stem cells reside in limbus has been recognized for more than a decade, but isolation of these stem cells has not been accomplished. This study was an initial attempt to isolate a population of human limbal epithelial cells enriched for certain putative stem cell properties based on their phenotype. Epithelial cells harvested from fresh human limbal rings and their primary cultures were allowed to adhere to collagen IV-coated dishes for 20 min and 2 hr, sequentially. The rapidly adherent cells (RAC), slowly adherent cells and non-adherent cells were evaluated for certain stem cell properties: (a) BrdU-label retention, (b) expression of basal cell (integrin β1, p63, ABCG2) and differentiation (involucrin, keratin 12) markers, and (c) colony forming efficiency (CFE) and growth capacity on a 3T3 fibroblast feeder layer. Among unfractionated cells and the three selected populations, the RAC, accounting for about 10% of whole population, were enriched 5-fold in BrdU label-retaining cells, displayed the highest number of integrin β1 and p63 positive and involucrin negative cells, expressed high levels of ΔNp63 and ABCG2 mRNA, and lacked involucrin and K12 expression, and possessed the greatest CFE and growth capacity. These findings demonstrated for the first time that human limbal epithelial cells with stem cell properties can be partially enriched by their adhesiveness to collagen IV. The RAC population enriched for certain putative stem cell properties may prove useful in the future for transplantation to diseased and damaged corneas with limbal stem cell deficiency.

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Localisation of breast cancer resistance protein in microvessel endothelium of human brain

Cited by 366 publications

References 15 publications

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)

Endomorphins exit the brain by a saturable efflux system at the basolateral surface of cerebral endothelial cells

Partial enrichment of a population of human limbal epithelial cells with putative stem cell properties based on collagen type IV adhesiveness

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