Metastasis-on-chip: Exploring the effect of vascular endothelial growth factor (VEGF) on cancer cell extravasation in vitro

<bold>Introduction</bold> Lung cancer is associated with the highest cancer-associated mortality rate, largely due to the occurrence of metastasis. After establishing a primary tumor, lung cancer cells shed from the tumor and enter the bloodstream. A distinct population of these circulating tumor cells (CTCs) extravasate to form a secondary tumor site. To model this process, we investigated the role of VEGF on the extravasation dynamics of two A549 lung adenocarcinoma subpopulations, holoclones and paraclones, with an epithelial and a mesenchymal phenotype, respectively, on a 3D pulmonary microvasculature-on-chip system. <bold>Material & Methods</bold> A microfluidic platform was used to co-culture primary human umbilical vein endothelial cells and normal human lung fibroblasts in a fibrin hydrogel to form a functional microvasculature network as previously reported (S. Zeinali, et al., Angiogenesis 2018, 4:861-871). After formation of the mature microvasculature network, A549 holoclones and paraclones were introduced into the network and their metastatic potential evaluated, either with or without VEGF. The CTCs were then incubated for 24 hours to investigate their kinetics and extravasation potential and vascular permeability was assessed as well. <bold>Results & Discussion</bold> We found out that epithelial-like holoclones enhance vessel permeability, while remaining inside the microvasculature. However, mesenchymal-like paraclones migrate at higher velocity within the microvasculature and extravasate. Further, without VEGF, paraclones ceased to extravasate, suggesting a VEGF-dependent mechanism in this phenotypical distinct A549 subpopulation.