Angiogenesis, the process by which new vessels form from existing ones, is a key event in the development of a large and malignant vascularised tumour. A rapid expansion in in vivo and in vitro angiogenesis research in recent years has led to increased knowledge about the processes underlying angiogenesis and to promising steps forward in the development of anti-angiogenic therapies for the treatment of various cancers. However, substantial gaps in knowledge persist and the development of effective treatments remains a major challenge. In this thesis we study tumour-induced angiogenesis within the context of a highly controllable experimental environment: the cornea micropocket assay. Using a multidisciplinary approach that combines experiments, image processing and analysis, and mathematical and computational modelling, we aim to provide mechanistic insight into the action of two angiogenic factors which are known to play central roles during tumour-induced angiogenesis: vascular endothelial growth factor A (VEGF-A) and basic fibroblast growth factor (bFGF). Image analysis techniques are used to extract quantitative data, which are both spatially and temporally resolved, from experimental images. These data are then used to develop and parametrise mathematical models describing the evolution of the corneal vasculature in response to both VEGF-A and bFGF. The first models developed in this thesis are one-dimensional continuum models of angiogenesis in which VEGF-A and/or bFGF are released from a pellet implanted into a mouse cornea. We also use an object-oriented framework, designed to facilitate the re-use and extensibility of hybrid multiscale models of angiogenesis and vascular tumour growth, to develop a complementary three-dimensional hybrid model of the same system. The hybrid model incorporates a new non-local cell sensing model which facilitates the formation of well-perfused and functional vascular networks in three dimensions. The continuum models are used to assess the utility of the cornea micropocket assay as a quantitative assay for angiogenesis, to characterise proposed synergies between VEGF-A and bFGF, and to generate experimentally testable predictions regarding the effect of anti-VEGF-A therapies on bFGF-induced angiogenesis. Meanwhile, the hybrid model is used to provide context for the comparison that is drawn between the continuum models and the data, to study the relative distributions of perfused and unperfused vessels in the evolving neovasculature, and to investigate the impact of tip cell sensing dysregulation on the angiogenic response in the cornea. We have found that by exploiting a close link with quantitative data we have been able to extend the predictive and hypothesis-testing capabilities of our models. As such, this thesis demonstrates the potential for integrating mathematical modelling with image analysis techniques to increase insight into the mechanisms underlying angiogenesis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:692866 |
| Date | January 2014 |
| Creators | Connor, Anthony J. |
| Contributors | Maini, Philip K. ; Byrne, Helen M. ; Cooper, Jonathan ; Quaiser, Tom ; Shochat, Eliezer |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:f6b6c496-3adb-43c4-a3b3-aaf4d1b866b4 |
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