Enhanced cancer cell invasion caused by fibroblasts when fluid flow is present

Abstract

It has been demonstrated that interstitial fluid (IF) flow can play a crucial role in tumor cell progression. Swartz and collaborators (Cancer Cell 11: 526-538, Shields et al. 2007) demonstrated that cells that secrete the lymphoid homing chemokines CCL21/CCL19 and express their receptor CCR7 could use flow to bias the secreted chemokine, causing pericellular gradients that stimulate cells to migrate in the direction of the flow. In a further work by Shieh et al. (Cancer Res 71: 790-800, 2011), a synergetic enhancement of tumor cell invasion caused by interaction between tumor cells and fibroblasts in the presence of fluid flow was reported. In the present work, we extend a previous proposed cell-fluid mathematical model for autologous chemotaxis (Chem Eng Sci 191: 268-287, Waldeland and Evje 2018) to also include fibroblasts. This results in a cell-fibroblast-fluid model. Motivated by the experimental findings by Shieh et al, the momentum balance equation for the fibroblasts involves (1) a stress term that accounts for chemotaxis in the direction of positive gradients in secreted growth factor TGF-[Formula: see text]; (2) a fibroblast-ECM interaction term; (3) a cancer cell-fibroblast interaction term. Imposing reasonable simplifying assumptions, we derive an explicit expression for the cancer cell velocity [Formula: see text] that reveals a balance between a fluid-generated stress term, a chemotactic-driven migration term (autologous chemotaxis), and a new term that accounts for the possible mechanical interaction between fibroblasts and cancer cells. Similarly, the model provides an expression for the fibroblast velocity [Formula: see text] as well as the IF velocity [Formula: see text]. The three-phase model is then used for comparison of the simulated output with experimental results to elucidate some of the possible mechanism(s) behind the reported fibroblast-enhanced tumor cell invasion.

Keywords: Autologous chemotaxis; Cell migration; Chemokine; Fibroblast; Growth factor; Interstitial fluid; Interstitial fluid pressure; Multiphase flow; Protease.