Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer. Its high mortality rate is associated with difficulties in early detection, which is crucial to survival. The onset of CRC is marked by macroscopic changes in intestinal tissue, originating from a deviation in the healthy cell dynamics of glands known as the crypts of Lieberkuhn. It is believed that accumulated genetic alterations confer on mutated cells the ability to persist in the crypts, which can lead to the formation of a benign tumour through localised proliferation. Stress on the crypt walls can lead to buckling, or crypt fission, and the further spread of mutant cells. Elucidating the initial perturbations in crypt dynamics is not possible experimentally, but such investigations could be made using a predictive, computational model. This thesis proposes a new discrete crypt model, which focuses on the interaction between cell- and tissue-level behaviour, while incorporating key subcellular components. The model contains a novel description of the role of the surrounding tissue and musculature, which allows the shape of the crypt to evolve and deform. A two-dimensional (2D) cross-sectional geometry is considered. Simulation results reveal how the shape of the crypt base may contribute mechanically to the asymmetric division events typically associated with the stem cells in this region. The model predicts that epithelial cell migration may arise due to feedback between cell loss at the crypt collar and density-dependent cell division, an hypothesis which can be investigated in a wet lab. Further, in silico experiments illustrate how this framework can be used to investigate the spread of mutations, and conclude that a reduction in cell migration is key to confer persistence on mutant cell populations. A three-dimensional (3D) model is proposed to remove the spatial restrictions imposed on cell migration in 2D, and preliminary simulation results agree with the hypotheses generated in 2D. Computational limitations that currently restrict extension to a realistic 3D geometry are discussed. These models enable investigation of the role that mechanical forces play in regulating tissue homeostasis, and make a significant contribution to the theoretical study of the onset of crypt deformation under pre-cancerous conditions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:580911 |
| Date | January 2011 |
| Creators | Dunn, Sara-Jane Nicole |
| Contributors | Gavaghan, D. J.; Chapman, S. J.; Byrne, H.; Osborne, J. M. |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:c3c9440a-52ac-4a3d-8e1c-5dc276b8eb6c |
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