Nonlinear studies of tumor morphological stability using a two-fluid flow model

We consider the nonlinear dynamics of an avascular tumor at the tissue scale using a two-fluid flow Stokes model, where the viscosity of the tumor and host microenvironment may be different. The viscosities reflect the combined properties of cell and extracellular matrix mixtures. We perform a linear morphological stability analysis of the tumors, and we investigate the role of nonlinearity using boundary-integral simulations in two dimensions. The tumor is non-necrotic, although cell death may occur through apoptosis. We demonstrate that tumor evolution is regulated by a reduced set of nondimensional parameters that characterize apoptosis, cell-cell/cell-extracellular matrix adhesion, vascularization and the ratio of tumor and host viscosities. A novel reformulation of the equations enables the use of standard boundary integral techniques to solve the equations numerically. Nonlinear simulation results are consistent with linear predictions for nearly circular tumors. As perturbations develop and grow, the linear and nonlinear results deviate and linear theory tends to underpredict the growth of perturbations. Simulations reveal two basic types of tumor shapes, depending on the viscosities of the tumor and microenvironment. When the tumor is more viscous than its environment, the tumors tend to develop invasive fingers and a branched-like structure. As the relative ratio of the tumor and host viscosities decreases, the tumors tend to grow with a more compact shape and develop complex invaginations of healthy regions that may become encapsulated in the tumor interior. Although our model utilizes a simplified description of the tumor and host biomechanics, our results are consistent with experiments in a variety of tumor types that suggest that there is a positive correlation between tumor stiffness and tumor aggressiveness.