Pancreatic Ductal Adenocarcinoma (PDA) is one of the most lethal solid malignancies primarily because it is staunchly resistant to conventional cytotoxic chemotherapies. Xenograft models are typically not sophisticated enough to reproduce the complex pathophysiology of the clinical disease. This is the main reason why treatments that have shown promise in preclinical mouse models have not translated into improvements in median survival in the clinic. Genetically engineered KPC mice develop PDA in situ which recapitulates the genetic, molecular and pathophysiological features of human PDA. Spontaneous KPC tumours are also chemoresistant and this mouse model therefore provides an ideal platform from which to study the biology of PDA. Recent evidence suggests that poor perfusion and extensive fibrosis may prevent the delivery of cytotoxic agents to neoplastic PDA cells and are therefore at least in part responsible for the chemoresistance demonstrated by human PDA tumours and spontaneous KPC tumours. In this thesis we use non-invasive Magnetic Resonance Imaging techniques (Dynamic ContrastEnhanced (DCE-) MRI, Magnetisation Transfer Imaging (MTI)) and SHG microscopy to evaluate the perfusion properties and fibrosis of three different mouse models of PDA: spontaneous KPC tumours, allografts initiated by transplantation of pancreatic tumour cells derived from a KPC tumour, and allografts initiated by co-transplantation of these cells with pancreatic stellate cells (fibrotic allografts). Using DCE-MRI and MTI we showed that the perfusion of spontaneous KPC tumours and fibrotic allografts decreases with increasing tumour volume while the tumour macromolecular content increases with increasing tumour volume. This is in contrast to the viable portion of non-fibrotic allografts which have a low macromolecular content and exhibit sustained moderate perfusion irrespective of tumour volume. Ex viva SHG microscopy clearly showed differences in the type, distribution and magnitude of fibrosis in these models. Using MTI, we showed a differential between spontaneous and transplanted tumours, but not between fibrotic and non-fibrotic allografts. We subsequently investigated the ability of MTI to detect treatment-induced depletion of the stroma in spontaneous KPC tumours, to assess its possible application as a non-invasive biomarker for treatment response in the clinic. However, we were unable to detect such depletion by MTI, although ex viva SHG microscopy confirmed that it did occur. In summary, our results contribute to the body of know_ledge on the biology of PDA and strengthen the evidence that early detection of PDA would be required to improve the chances of effective drug delivery to PDA tumours.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:648145 |
| Date | January 2013 |
| Creators | Bell, Leanne Katherine |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.repository.cam.ac.uk/handle/1810/265615 |
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