Competing tumor cell migration mechanisms caused by interstitial fluid flow.

In the seminal work by Swartz and collaborators (Shields et al., 2007) it was discovered that autologously secreted or activated (ECM-bound) chemokine forms local pericellular diffusion gradients skewed by fluid convection, and the cells subsequently chemotact up the flow-directed gradient. However, in (Polacheck et al., 2011) Kamm and collaborators found that there is a competing downstream and upstream migration transport mechanism. Their study showed that both mechanisms are present at the same time and the relative strength of these two stimuli governs the directional bias in migration for a cell population and is a function of cell density, interstitial flow rate, and CCR7 receptor availability. The main objective of this work is to give a possible explanation of these two different concurrent cell migration mechanisms by means of a theoretical model. Relying on multiphase modelling, separate momentum balance equations are formulated, respectively, for the cell phase and the interstitial fluid (IF) phase. In order to represent proteolytic activity and autologous chemotaxis a non-moving ECM component is included, as well as proteases secreted by the cancer cells and chemokine that can be released from ECM. The cell and IF momentum balance equations include cell-ECM and fluid-ECM resistance force terms (i.e., classical Darcy's equation terms), but also a cell-fluid interaction term that can account for a more indirect effect that fluid-generated stress may have on cancer cells. We illustrate how the cancer cells can work through this term and effectively avoid being pushed in the flow direction, and even create upstream migration by controlling its magnitude and sign. We think of this as the mathematical interpretation of the experimental observation by Kamm and collaborators that the fluid generated matrix adhesion tension on the upstream side of cells activates integrin adhesion complexes, resulting in activation of focal adhesion (FA) proteins. The model predicts that generally the strength of the upstream migration mechanism is sensitive to the cell volume fraction: a lower density of cells is subject to a weaker upstream migration effect; a higher density of cancer cells can more effectively generate upstream migration. This behavior is a result of the nonlinear coupling between cell-ECM, fluid-ECM, and cell-fluid interaction terms that naturally are involved in the mathematical expression for the net cell velocity.