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

摘要

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-beta; (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 uc 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 uf as well as the IF velocity uw. 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.