MOLECULAR ANALYSIS OF THE BLOOD‐TUMOR BARRIER IN BRAIN METASTASIS FROM BREAST CANCER

Brain metastases of breast cancer are increasing in incidence; chemotherapy is generally ineffective due to poor overall uptake, and heterogeneous permeability. Herein, functional components of the blood‐brain barrier (BBB)/blood‐tumor barrier (BTB) were characterized in highly permeable and poorly permeable experimental brain metastases from breast cancer. Brain seeking variants of 3 breast cancer cell lines, MDA‐MB‐231‐BR6, JIMT‐1‐BR3, and SUM190‐BR3 were injected into the left cardiac ventricle of mice to produce brain metastases. Mice were injected with 3kd Texas Red dextran and sterilely perfused; highly permeable metastases were identified by exudation of red dye. Immunofluorescence expression of BTB functional components was quantified in uninvolved brain, highly permeable metastases, and poorly permeable metastases. We report a significant increase in endothelial cell and neuroinflammatory components in brain metastases compared to uninvolved brain in all 3 models. There was no trend in these markers in highly permeable versus poorly permeable metastases. Interestingly, increased expression of the desmin+ subpopulation of pericytes was associated with highly permeable metastases compared to poorly permeable metastases in the 231‐BR6 (p=0.0002), JIMT‐1‐BR3 (p=0.004), and SUM190‐BR3 (p=0.008) models. This increase was accompanied by a decrease in CD13+ pericytes in the 231‐BR6 (p=0.014), JIMT‐1‐BR3 (0.002), and SUM190‐BR3 (p=ns) models. Findings for both pericytes populations were corroborated in human craniotomy specimens. Preliminary functionality experiments demonstrated increased permeability in an in vitro model of the BTB with desmin+ pericytes compared to CD13+ pericytes. These alterations provide testable hypotheses for the development of new targeted therapeutic strategies to increase chemotherapeutic delivery to brain metastatic lesions.