Angiogenesis is the formation of new blood vessels from existing ones, and is a key characteristic of tumour progression. The purpose of antiangiogenic (AA) cancer therapies is to disrupt the tumour's blood supply in order to inhibit the delivery of oxygen and nutrients. However, such therapies have demonstrated limited benet to cancer patients: although they delay tumour progression for some types of cancer, they do not consistently improve survival. Several preclinical experimental studies have reported that AA therapies lead to a period of vessel normalisation, during which vessels transition from the leaky, tortuous state that is typical of tumour vasculature to a more stable state where blood perfusion is increased. It has been suggested that normalisation is the reason why some AA therapies lack effcacy. In this thesis, we develop and study mathematical models of various aspects of angiogenesis and vessel normalisation, and we use our results to suggest effective AA therapy regimens. Our first model represents the biochemical interactions and cellular dynamics involved in neovascularisation: we incorporate biological hypotheses to develop a spatially averaged ODE model of vessel formation, and we show that the model admits a number of vascular phenotypes characterised by their degrees of vessel normalisation. We showed that these phenotypes respond differently to different AA treatments. In our second model, we use preclinical tumour size data to develop and parametrise a mixed effects model of vascular tumour growth including vessel normalisation. We use our prediction about the timing of the transient normalisation window to further predict the potential benefits of combining chemotherapy and AA therapy. Lastly, we extend an existing PDE model of vascular tumour growth to incorporate AA therapy and vessel normalisation. We demonstrate that the oscillatory behaviour that arises in the spatially averaged version of the model induces spatial heterogeneity in the spatially extended version, and show that the vessel kill and normalisation parameters (among other parameters) can modulate tumour heterogeneity.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:729870 |
| Date | January 2017 |
| Creators | Hutchinson, Lucy |
| Contributors | Gaffney, Eamonn ; Maini, Philip ; Byrne, Helen |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://ora.ox.ac.uk/objects/uuid:0c1034ee-ff8e-4ed4-b168-f559f93f9142 |
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