Abstract 5207: Vascular remodeling is associated with increased permeability of experimental brain metastases of breast cancer

Abstract

Abstract Approximately 1 in 8 women will develop breast cancer. Of these women, a subset develop metastatic breast cancer, of which 10-16% develop brain metastases. Treatment options are limited. The blood-brain barrier (BBB) serves as a physical barrier, limiting drug entry into the brain, as well as the active efflux of drugs by P-Glycoprotein, Breast Cancer Resistance Protein, and/or Multidrug Resistance-associated Protein located on the capillary endothelial cell membranes composing the BBB. Active remodeling occurs when cancer cells extravasate through the BBB and begin to metastasize forming fully colonized tumors, creating the Blood-Tumor Barrier (BTB). In order for active remodeling to occur, induction of angiogenesis must be initiated, resulting in formation of new blood vessels. These new blood vessels undergo active remodeling, and are associated with increased permeability when compared to intact BBB. By measuring vascular density, our goals were to understand permeability as it relates to vascular density, determine if increases in lesion permeability facilitate paclitaxel uptake into the lesion, and evaluate permeability as it relates to vascular remodeling. In this study, we utilize two experimental models (murine: 4T1-BR5; and human: MDA-MB-231-BR-Her2) to analyze permeability, drug uptake and vascular characteristics. In an analysis of over 2,000 metastatic lesions, we observed an increased permeability (a range over 30 fold) of nearly all lesions, with paclitaxel concentrations elevated (p< 0.05) in 85% of the lesions; however, only ∼10% of the lesions received enough paclitaxel to induce cytotoxicity (greater than 10-fold and 1000 ng/g) within the lesion. Analysis of the lesion vasculature revealed decreased vessel density (n = 86 for Her2 and n = 40 for 4T1), as well as the presence of tortuous and abnormal vessels, with nearly all blood vessels associated with the metastatic lesions showing structural changes to some extent. Furthermore, with immunofluorescent analysis, we observed a decreased (∼1.5 fold) expression of the vascular endothelial tight junction protein zonula occludens-1 (p<0.05), and increased expression of two vascular proteins: nestin (25% in permeable lesions compared with non-permeable) and plasmalemma vesicle associated protein-1 (∼18 ± 2% in permeable lesions compared to non-permeable lesions at ∼8.5 ± 2%, p<0.05). When plotting nestin expression versus fold increase in permeability, a correlation of r2 = 0.33, p<0.05 was observed. Increased expression of nestin and plasmalemma vesicle associated protein-1, and decreased expression of zonula occludes-1 correlate to increased permeability. We hypothesize the changes in these vascular proteins are a contributory cause to vascular destabilization and/or vascular remodeling in brain metastases of breast cancer, resulting in an increased permeability of the BTB. Citation Format: Kaci A. Bohn, Tori B. Terrell-Hall, Chris E. Adkins, Rajendar K. Mittapalli, Mohamed I. Nounou, Afroz S. Mohammad, Paul R. Lockman. Vascular remodeling is associated with increased permeability of experimental brain metastases of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5207. doi:10.1158/1538-7445.AM2015-5207