Localized Modeling of Biochemical and Flow Interactions during Cancer Cell Adhesion.

This work focuses on one component of a larger research effort to develop a simulation tool to model populations of flowing cells. Specifically, in this study a local model of the biochemical interactions between circulating melanoma tumor cells (TC) and substrate adherent polymorphonuclear neutrophils (PMN) is developed. This model provides realistic three-dimensional distributions of bond formation and attendant attraction and repulsion forces that are consistent with the time dependent Computational Fluid Dynamics (CFD) framework of the full system model which accounts local pressure, shear and repulsion forces. The resulting full dynamics model enables exploration of TC adhesion to adherent PMNs, which is a known participating mechanism in melanoma cell metastasis. The model defines the adhesion molecules present on the TC and PMN cell surfaces, and calculates their interactions as the melanoma cell flows past the PMN. Biochemical rates of reactions between individual molecules are determined based on their local properties. The melanoma cell in the model expresses ICAM-1 molecules on its surface, and the PMN expresses the ß-2 integrins LFA-1 and Mac-1. In this work the PMN is fixed to the substrate and is assumed fully rigid and of a prescribed shear-rate dependent shape obtained from micro-PIV experiments. The melanoma cell is transported with full six-degrees-of-freedom dynamics. Adhesion models, which represent the ability of molecules to bond and adhere the cells to each other, and repulsion models, which represent the various physical mechanisms of cellular repulsion, are incorporated with the CFD solver. All models are general enough to allow for future extensions, including arbitrary adhesion molecule types, and the ability to redefine the values of parameters to represent various cell types. The model presented in this study will be part of a clinical tool for development of personalized medical treatment programs.

Multi-scale biological and physical modelling of the tumour micro-environment.

Paced by advances in high performance computing, and algorithms for multi-physics and multi-scale simulation, a number of groups have recently established numerical models of flowing blood systems, where cell-scale interactions are explicitly resolved. To be biologically representative, these models account for some or all of: (1) fluid dynamics of the carrier flow, (2) structural dynamics of the cells and vessel walls, (3) interaction and transport biochemistry, and, (4) methods for scaling to physiologically representative numbers of cells. In this article, our interest is the modelling of the tumour micro-environment. We review the broader area of cell-scale resolving blood flow modelling, while focusing on the particular interactions of tumour cells and white blood cells, known to play an important role in metastasis.