Macrophages are known contributors to cancer progression in the primary site, but significantly less is known about their roles in secondary tumor formation. They are likely involved in tumor cell adhesion and transmigration of endothelial cells in the secondary site since macrophages are integral conductors of immune cell recruitment during the immune response and experimental evidence indicates that macrophages recruited to the secondary site before the arrival of tumor cells. However, current model systems are limited in their ability to observe and quantify these early interactions. We have developed a tunable, microfluidic model system consisting of an endotheilalized vessel channel perfusing a 3D collagen matrix that can be seeded with macrophages to recapitulate the basic structure of the extravasation site. We will use this model to quantify human macrophage-endothelial cell interactions in the context of metastasis by measuring permeability, tumor cell adhesion, and tumor cell transmigration. By treating devices with tumor cell conditioned media before the addition of tumor cells, we will quantify how macrophages change tumor cells extravasation phenotypes. We will also use M1 and M2 polarizing molecules to determine if macrophage polarization can create tumor-inhibitory or tumor-promoting responses. Since tumor cell adhesion and extravasation may depend on leukocyte adhesion mechanisms, we also developed a microfluidic model that can measure changes in leukocyte adhesion and velocity to endothelial cells in healthy and thrombotic states. We demonstrate that this model system may be used with endothelial and blood cells from a single patient, highlighting its utility in personalized medicine. Additionally, this model can be used to evaluate tumor cell-blood interactions and how these influence initial tumor cell adhesion in extravasation. As both these systems can probe and quantify early extravasation events, they can be used in tandem to gain a better understanding of the mechanisms driving tumor cell extravasation.
University of Minnesota Ph.D. dissertation. February 2020. Major: Biomedical Engineering. Advisor: David Wood. 1 computer file (PDF); ix, 128 pages.
Microfluidic Model Systems to Evaluate Endothelial Cell Phenotype in Disease.
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