Nonlinear Simulations of Solid Tumor Growth Using a Mixture Model: Invasion and Branching

J Math Biol. 2009 Apr;58(4-5):723-63. doi: 10.1007/s00285-008-0215-x. Epub 2008 Sep 12.

Abstract

We develop a thermodynamically consistent mixture model for avascular solid tumor growth which takes into account the effects of cell-to-cell adhesion, and taxis inducing chemical and molecular species. The mixture model is well-posed and the governing equations are of Cahn-Hilliard type. When there are only two phases, our asymptotic analysis shows that earlier single-phase models may be recovered as limiting cases of a two-phase model. To solve the governing equations, we develop a numerical algorithm based on an adaptive Cartesian block-structured mesh refinement scheme. A centered-difference approximation is used for the space discretization so that the scheme is second order accurate in space. An implicit discretization in time is used which results in nonlinear equations at implicit time levels. We further employ a gradient stable discretization scheme so that the nonlinear equations are solvable for very large time steps. To solve those equations we use a nonlinear multilevel/multigrid method which is of an optimal order O(N) where N is the number of grid points. Spherically symmetric and fully two dimensional nonlinear numerical simulations are performed. We investigate tumor evolution in nutrient-rich and nutrient-poor tissues. A number of important results have been uncovered. For example, we demonstrate that the tumor may suffer from taxis-driven fingering instabilities which are most dramatic when cell proliferation is low, as predicted by linear stability theory. This is also observed in experiments. This work shows that taxis may play a role in tumor invasion and that when nutrient plays the role of a chemoattractant, the diffusional instability is exacerbated by nutrient gradients. Accordingly, we believe this model is capable of describing complex invasive patterns observed in experiments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Algorithms
  • Animals
  • Body Water / physiology
  • Cell Adhesion / physiology
  • Cell Proliferation
  • Humans
  • Linear Models
  • Mathematical Concepts
  • Models, Biological*
  • Neoplasm Invasiveness / pathology*
  • Neoplasm Invasiveness / physiopathology
  • Neoplasms / pathology*
  • Neoplasms / physiopathology
  • Nonlinear Dynamics
  • Spheroids, Cellular / pathology
  • Thermodynamics
  • Tumor Cells, Cultured