Development of a Blood Brain Barrier (BBB) Mimetic to Study Breast-Brain Metastasis
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Date
2017-05
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The Ohio State University
Abstract
Cancer metastasis is a highly complex process that causes 90% of all solid tumor deaths. With recent advances in diagnostic modalities and treatment options, the occurrence of brain metastasis has been rising over the last decade. Since many therapeutics are unable to cross the blood brain barrier (BBB), a protective layer separating the vascular system and the brain, brain metastases are notoriously difficult to treat. In certain types of cancer, tumor cells can invade the brain by crossing the BBB from the circulatory system through a process known as extravasation. Brain metastasis in breast cancer leads to poor prognosis with mean survival rate of 2 years. Studying the mechanism of the extravasation of breast cancer into the brain is critical for the elucidation of the pathways driving this metastatic process. Current methods used to study this invasion process cannot fully recapitulate physiological conditions. The gold standard method uses Transwell® inserts that have a non-physiological membrane separating the ‘blood’ and the ‘brain stroma’, which can cause non-physiological behaviors in migration studies. Thus, we developed a three dimensional (3D) 3-layer hydrogel model to study the invasion of breast cancer into the brain. To develop this model, the physical effects of composite Hyaluronic acid (HA) / collagen matrices used as brain stroma mimetics in breast-brain metastasis were investigated. HA was chosen because it is one of the most common glycosaminoglycans found in the brain extracellular matrix (ECM) 5 and collagen was chosen because it is a major component of the basement membrane of the BBB.6 In this study, highly invasive MDA-MB231 breast cancer cells were either encapsulated in or suspended on the surface of the composite hydrogels and the migration velocity was ascertained. It was found that cell proliferation was inhibited by HA concentrations higher than 0.5wt%. Adhesion of cells onto the gel surface and cell migration velocity were decreased with increasing concentration of HA in gel composites. Moreover, cell migration velocity appeared to increasing with time (i.e., it is higher on day 5 than on day 1 of the study), potentially indicating remodeling of the ECM by cancer cells or altered chemical signaling from the composite hydrogel matrix. These results suggest that the HA/collagen composite hydrogel is adequate in modelling the brain stroma and further studies optimizing our proposed BBB mimetic are proposed. If successful, this model could lead to better therapeutics that could help hinder or even prevent brain metastases from occurring.
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Keywords
Breast-brain metastasis, In vitro model, hydrogel, cancer invasion assay