Multiscale modeling of solid stress and tumor cell invasion in response to dynamic mechanical microenvironment.

Mathematical models can provide a quantitatively sophisticated description of tumor cell (TC) behaviors under mechanical microenvironment and help us better understand the role of specific biophysical factors based on their influences on the TC behaviors. To this end, we propose an off-lattice cell-based multiscale mathematical model to describe the dynamic growth-induced solid stress during tumor progression and investigate the influence of the mechanical microenvironment on TC invasion. At the cellular level, cell-cell and cell-matrix interactive forces depend on the mechanical properties of the cells and the cancer-associated fibroblasts in the stroma, respectively. The constitutive relationship between the interactive forces and cell migrations obeys the Hooke's law and damping effects. At the tissue level, the integrated growth-induced forces caused by proliferating cells within the simulation region are balanced by the external forces applied by the surrounding host tissues. Then, the cell movements are calculated according to the Newton's second law of motion, and the morphology of TC invasion is updated. The simulation results reveal the continuous changes of the macroscopic mechanical forces due to the interactions among the structural components and the microscopic environmental factors. Moreover, the simulation results demonstrate the adverse effect of the stiffness of tumor tissue on tumor growth and invasion. A decrease in the stiffness of tumor and matrix can promote TCs to proliferate at a much faster rate and invade into the surrounding healthy tissue more easily, whereas an increase in the stiffness can lead to an aggressive morphology of tumor invasion. We envision that the proposed model can be served as a quantitative theoretical platform to study the underlying biophysical role of the mechanical microenvironmental factors during tumor invasion and metastasis.