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

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

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)373-383
Number of pages11
JournalClinical and Experimental Metastasis
Volume33
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2016, Springer Science+Business Media Dordrecht.

Keywords

  • Blood–brain barrier
  • Blood–tumor barrier
  • Brain metastasis
  • Breast cancer
  • Permeability

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