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Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

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Abstract

The blood–brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers 14C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.

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Abbreviations

BBB:

Blood–brain barrier

BTB:

Blood–tumor barrier

AIB:

Aminoisobutyric acid

TRD:

Texas red dextran

CNS:

Central nervous system

TEER:

Transendothelial electrical resistance

MRI:

Magnetic resonance imaging

VEGF:

Vascular endothelial growth factor

eNOS:

Endothelial nitric oxide synthase

TGFß:

Transforming growth factor beta

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Acknowledgments

This research was supported by Grants from the National Cancer Institute (R01CA166067-01A1) and National Institute of General Medical Sciences (P30GM103488, and GM103434). Additional support for this research was provided by WVCTSI through the National Institute of General Medical Sciences of the National Institutes of Health under Award Number U54GM104942. A portion of this work was completed at each institution mentioned in the author affiliations.

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Authors and Affiliations

  1. Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA

    Chris E. Adkins, Afroz S. Mohammad, Tori B. Terrell-Hall, Emma L. Dolan, Neal Shah, Emily Sechrest, Jessica Griffith & Paul R. Lockman

  2. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA

    Chris E. Adkins, Afroz S. Mohammad, Tori B. Terrell-Hall & Paul R. Lockman

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  1. Chris E. Adkins
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Correspondence to Paul R. Lockman.

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Adkins, C.E., Mohammad, A.S., Terrell-Hall, T.B. et al. Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer. Clin Exp Metastasis 33, 373–383 (2016). https://doi.org/10.1007/s10585-016-9784-z

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