A multiscale model for colorectal cancer (CRC) is being developed within the framework of the international Integrative Biology (IB) project [1], which brings together computer scientists, modellers and experimental researchers. Whereas existing models for CRC are generally very simple and largely focus on a simple time and length scale [2], the IB hybrid cellular automaton approach aims to embrace all levels of organisation from molecule to tissue. At the subcellular level, deterministic continuum models are used to characterise biochemical networks.

During my talk, for instance, I will introduce a new model for the Wnt signalling pathway [3] and explain how we are exploiting it to gain understanding of the interactions between beta-catenin's adhesive and transcriptional functions and to study the impact of mutations commonly observed in CRCs. Within the multiscale model, the outputs of the subcellular models determine the position-dependent rates of cell migration, division, differentiation and death within the intestinal crypts.

Under normal conditions, these cellular processes are tightly regulated by intra- and extra-cellular cues, and the number of cells remains approximately constant. Under aberrant conditions, in contrast, loss of control can cause increased proliferation and/or decreased differentiation and cell death. The resulting proliferative excess can have serious implications for the maintenance of the integrity of the crypt, as the associated biomechanical stress can force the crypt to deform and undergo fission to accommodate the newborn cells, leading to polyp formation. Integrating the hierarchy of processes occurring at different levels of organisation into a multiscale model, the IB-team aims to be able to investigate possible interactions between such processes, to combine biochemical, histological and clinical data and, eventually, to test drugs in silico on the system as a whole.

(van Leeuwen, University of Nottingham)

[1] IMM van Leeuwen, CM Edwards, M Ilyas and HM Byrne, 2007. Towards a multiscale model of colorectal cancer, World J Gastroenterol, 13(9): 1399-1407.
[2] IMM van Leeuwen, HM Byrne, OE Jensen and JR King, 2006. Crypt dynamics and colorectal cancer: advances in mathematical modelling, Cell Proli, 39(3): 157-181.
[3] IMM van Leeuwen, HM Byrne, OE Jensen and JR King, 2007. Elucidating the interactions between the adhesive and transcriptional functions of beta-catenin in normal and cancerous cells, J Theor Biol, 247(1): 77-102.