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Obstacles to Brain Tumor Therapy: Key ABC Transporters.

ABSTRACT: The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood-brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is only recently that the important transporter components, expressed in the tightly knit capillary endothelial cells, have been deciphered. These transporters are ATP-binding cassette (ABC) transporters and, so far, the major clinically important ones that functionally contribute to the blood-brain barrier are ABCG2 and ABCB1. A further limitation to cancer therapy of brain tumors or brain metastases is the blood-tumor barrier, where tumors erect a barrier of transporters that further impede drug entry. The expression and regulation of these two transporters at these barriers, as well as tumor derived alteration in expression and/or mutation, are likely obstacles to effective therapy.

SUBMITTER: Wijaya J

PROVIDER: S-EPMC5751147 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Obstacles to Brain Tumor Therapy: Key ABC Transporters.

Wijaya Juwina J Fukuda Yu Y Schuetz John D JD

International journal of molecular sciences 20171127 12

The delivery of cancer chemotherapy to treat brain tumors remains a challenge, in part, because of the inherent biological barrier, the blood-brain barrier. While its presence and role as a protector of the normal brain parenchyma has been acknowledged for decades, it is only recently that the important transporter components, expressed in the tightly knit capillary endothelial cells, have been deciphered. These transporters are ATP-binding cassette (ABC) transporters and, so far, the major clin ...[more]

PMID: 29186899

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Project description:The low permeability and high selectivity of the blood vessels of the brain and central nervous system (CNS) characterize the blood-brain barrier (BBB). Tight junctions, a lack of fenestrations, and low rates of transcytosis in the endothelial cells of the vasculature prevent passive diffusion of most molecules other than water, gases and some lipid soluble molecules (Obermeier, Daneman, & Ransohoff, 2013). Any additional nutrients must be transported across the barrier with the help of transporter proteins. Two protein families account for most transporters. ABC transporters use ATP to power primary-active transport to move molecules across the BBB against an electrochemical gradient, frequently excluding drugs from entering the brain. Some SLC transporters facilitate transport of solutes along an electrochemical gradient, while others permit secondary-active transport by coupling the flow of a solute traveling down the electrochemical gradient to power another solute against its electrochemical gradient. Brain microvessel endothelial cells (BMEC) from human cerebral cortex were enriched through a homogenization and centrifugation procedure. Two BMEC and two tissue were sequenced with paired-end reads on a SOLiD 5500 Wildfire. Raw data was aligned using LifeScope Genomic Analysis, gene expression determined through Cufflinks, and splice junctions identified by aligning to a custom database of known to known and known to novel junctions. We found numerous examples of transporters with enriched expression in the isolated BMECs compared to whole brain tissue. In total, 131 transporter genes or pseudogenes (109 SLC, 22 ABC) are enriched at least 1.25 fold in BMEC enriched samples, and 57 of these are enriched over 2-fold (50 SLC, 7 ABC). Thirteen genes were found to have at least twice as many counts in BMEC enriched samples than in whole tissue for at least one alternative splice junction. Inversely, 23 genes were found to have at least one alternative splice junction with half as many counts in BMEC enriched samples than in whole tissue.

Project description:Atherosclerosis, driven by inflamed lipid-laden lesions, can occlude the coronary arteries and lead to myocardial infarction. This chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete cholesterol and other lipids, thus preventing atherosclerosis by a process termed reverse cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of ABC transporter loci. In Tangier disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis. Likewise, sitosterolemia is another inherited syndrome associated with premature atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting cholesterol and plant sterols, including sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes cholesterol and dietary sterols back into the gut, while ABCA1 functions to export excess cell cholesterol and phospholipid during the biogenesis of HDL. Interestingly, a third protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer cholesterol to mature HDL particles. Here we review the relationship between the lipid transport activities of these proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface cholesterol levels and inhibit its partitioning into lipid rafts. Given lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another HDL receptor, may directly act as anti-inflammatory receptors independent of their lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of lipids through the RCT pathway.

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Dataset Information

Obstacles to Brain Tumor Therapy: Key ABC Transporters.

Publications

Obstacles to Brain Tumor Therapy: Key ABC Transporters.

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