Effects of interstitial flow on tumor cell migration

Abstract

Interstitial flow is the convective transport of fluid through tissue extracellular matrix. This creeping fluid flow has been shown to affect the morphology and migration of cells such as fibroblasts, cancer cells, endothelial cells, and mesenchymal stem cells. However, due to limitations in experimental procedures and apparatuses, the mechanism by which cells detect flow and the details and dynamics of the cellular response remain largely unknown. We developed a microfluidic cell culture system in which we can apply stable pressure gradients and fluid flow, and in which we can observe transient responses of breast cancer cells seeded in a 3D collagen type I scaffold. We employed this system to examine cell migration in the presence of interstitial flow to address the hypothesis that interstitial flow increases the metastatic potential of breast cancer cells. By varying the concentration of chemoattractants, we decoupled the mechanisms that provide the migratory stimulus and the directional stimulus to migrating breast cancer cells in the presence of a flow field. We found that cells migrated along streamlines in the presence of flow and that the strength of the flow field determined directional bias of migration along the streamline. We provide evidence that CCR7-dependent autologous chemotaxis is the mechanism by which cells migrate with the flow, while a competing CCR7-independent mechanism leads to migration against the flow. Furthermore, we demonstrate these competing mechanisms are a powerful migrational stimulus, which likely play an important role in development of metastatic disease.