Tiffany Lyle, DVM, PhD, DACVPA
Assistant Professor of Anatomic Pathology
Department of Comparative Pathology
Purdue University College of Veterinary Medicine

The Blood-Tumor Barrier in Brain Metastases of Breast Cancer: Insights from Pre-Clinical Models

Brain metastases of breast cancer are increasing in incidence; chemotherapy is generally ineffective due to poor overall uptake, and heterogeneous permeability.  We have characterized functional components of the blood-brain barrier (BBB) and blood-tumor barrier (BTB) 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 and BTB permeability was analyzed.  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.  Interestingly, increased expression of the desmin+ subpopulation of pericytes was associated with highly permeable metastases compared to poorly permeable metastases in the 231-BR6, JIMT-1-BR3, and SUM190-BR3 models.  This increase was accompanied by a decrease in CD13+ pericytes in all 3 experimental 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.