Claudia Tanja Mierke
 

Soft Matter Physics Division, Institute of Experimental Physics I, University of Leipzig, Linnéstraße 5, 04103 Leipzig, Germany

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Metastasis is a key event of malignant tumor progression. The capability of tumors to metastasize depends on the cancer cell`s ability to migrate into connective tissue, adhere, and possibly transmigrate through the endothelium. Previously, we reported that the endothelium does not generally act as barrier for cancer cells to migrate in 3D extracellular matrices (3D-ECMs). Moreover, the endothelium acted as an enhancer or promoter for the invasiveness of certain cancer cells. How invasive cancer cells diminished the endothelial barrier function remains still elusive. Therefore, this study investigated whether invasive cancer cells can decrease the endothelial barrier function through alteration of endothelial biomechanical properties. To address this, MDA-MB-231 breast cancer cells were used. They invaded deeper and more numerous into 3D-ECMs when co-cultured with microvascular endothelial cells. Using magnetic tweezer measurements MDA-MB-231 cells were found to alter mechanical properties of endothelial cells by reducing their stiffness. Using spontaneous bead diffusion actin cytoskeletal remodeling dynamics were shown to be increased in co-cultured compared to mono-cultured endothelial cells. In addition, knock-down of the alpha5 integrin subunit in highly-transmigrating alpha5beta1high cells abolished the endothelial invasion enhancing effect comparable to the inhibition of myosin light chain kinase indicating that the endothelial invasion enhancing effect is alpha5beta1 integrin dependent. In conclusion, decreased stiffness and increased cytoskeletal remodeling dynamics of endothelial cells can explain the break-down of endothelial barrier function indicating that biomechanical alterations were sufficient to facilitate transmigration and invasion of invasive cancer cells into 3D-ECMs.