Comparative Therapeutic Validation of a Microfluidic Metastasis Model: Cimetidine but Not Cilengitide Inhibits Physiological Tumor Cell Extravasation

Interactions between tumor cells and the endothelial lining of blood vessels under flow conditions are essential for successful metastasis. These interactions are mainly facilitated by adhesive proteins, like integrins or selectins and by proteases. While expression of specific integrins (αvβ3 and αvβ5) and selectins correlate with tumor progression in cancer and seem to mediate tumor cell adhesion, analysis of a therapeutic intervention in these processes is frequently limited to systems lacking physiological cell–cell interactions. In this study on the adhesion of different tumor cell types in monoculture and in coculture on endothelial cell layers was evaluated under different conditions, i.e., different static setups and under flow conditions in a microfluidic device and under treatment with the integrin inhibitor Cilengitide and the selectin inhibitor Cimetidine. This careful comparative experimental validation revealed that while Cilengitide inhibits H838-, HCT116- and U87-tumor cell adhesion in tumor cell monocultures in all assay set-ups its effect is abolished by the presence of endothelial cells. In contrast, Cimetidine, a Histamine 2 receptor antagonist and E-selectin inhibitor significantly reduced H838 lung carcinoma cell adhesion and trans-endothelial migration suggesting a significant role of E-selectin in tumor progressions and metastasis.