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Targeting Tumour Angiogenesis in Colorectal Cancer Liver Metastases

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Targeting Tumour Angiogenesis in Colorectal Cancer Liver Metastases Targeting Tumour Angiogenesis in Colorectal Cancer Liver Metastases Peter John Webster Submitted in accordance with the requirements for the degree of Doctor of Philosophy The University of Leeds Faculty of Medicine and Health December 2016 - ii - The candidate confirms that the work submitted is his own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Peter John Webster to be identified as Author of this work has been asserted by him in accordance with the Copyright, Designs and Patents Act 1988. © 2016 The University of Leeds and Peter John Webster - iii - Acknowledgements I would like to thank the following people, without whom this work would not have been possible: Professor David Beech for the opportunity to conduct research in his laboratory as well as all his sound advice, support and guidance throughout my studies. Mr Dermot Burke for all his supervision both in my academic studies and clinical work. I hope it has not been too difficult supervising your first PhD student! Dr Richard Young, Dr Jing Li, Dr Heather Martin and Dr Darren Tomlinson for their RNA interference screening work, which helped form the basis for this project. Dr Sally Boxall for all her knowledge and help with flow cytometry studies. Leeds Teaching Hospitals Charitable Foundation for their generous funding to enable me to undertake this research. All patients who selflessly donated tissue at St. James’s University Hospital, Leeds. Sadly, some of these patients have already passed away and I hope that through their donations this research will help improve outcomes for future patients. Mr Raj Prasad and Professor Peter Lodge, without whom I would not have been able to acquire patient tissue samples. - iv - Hannah Gaunt for all her help. From accidentally throwing my cells in the bin to teaching me how to do the perfect western blot, I have really appreciated her support and friendship throughout this PhD. Dr Baptiste Rode for his help with the Piezo1 mice and love of all things Yorkshire! Anna Littlejohns for all her work and enthusiasm as an intercalating medical student and keen WEE1 investigator. Elizabeth Gabriel for helping to rationalise the proteomics data. Nicola (Nikki) Blythe, Katie Musialowski, Elizabeth (Beth) Evans, Adam Hyman, Dr Nick Moss, Dr Hollie Appleby and Dr Lara Morley who themselves are all at various stages of the PhD process. They have all helped make this PhD a great experience. Mum, Dad, James and Murts for their love, support and never-ending encouragement in everything I do. My Gran sadly passed away during my PhD studies and were she still alive I know she would be happily telling everyone about this work and what I’ve achieved! Sarah for all her love and unwavering support as my girlfriend. Although you going away to New Zealand to work for a year enabled me to complete most of this PhD, it was also a lonely time and I couldn’t wait for you to come back! I hope that when you read this you are proud and finally understand what WEE1 is all about. - v - Abstract Colorectal cancer liver metastases (CLM) remain a significant cause of cancer- related morbidity and mortality. Central to their survival and growth is the process of tumour angiogenesis. Current clinical anti-angiogenic therapies target vascular endothelial growth factor signalling, but resistance to therapy is problematic. The aim of this study was to identify proteins critical for CLM endothelial cell (CLMEC) survival that could be targeted for the development of new anti-angiogenic therapies. CLMECs and endothelial cells of normal adjacent liver (LECs) were isolated from patients undergoing curative resection. The two cell types were superficially similar, exhibiting markers and functional characteristics expected of endothelial cells. However, a number of differences in protein expression were identified, one of which was the previously unrecognised upregulation of the WEE1 checkpoint- kinase, a target of the small molecule WEE1 inhibitor AZD1775, currently in clinical trials. AZD1775 monotherapy was shown to inhibit proliferation and migration of CLMECs. Investigation of the underlying mechanism suggested induction of double-stranded DNA (DS-DNA) breaks due to a critical nucleotide shortage, which then led to caspase-3 dependent apoptosis. The implication for CLMEC tube formation was striking, with AZD1775 inhibiting branching tube formation by 83%. AZD1775 also had direct anti-cancer activity in a p53-mutated colorectal cancer cell line (HT29). In combination with 5-FU it caused increased caspase-3 dependent apoptosis because of DS-DNA breaks, not premature mitosis, which is thought to be the mechanism of AZD1775 toxicity when used in combination with DNA- damaging agents. - vi - Proteomic screening of matched LECs and CLMECs identified a further 157 differentially expressed proteins, including up-regulation of the established endogenous angiogenesis inhibitors thrombospondin-1 and vascular endothelial growth factor receptor-1. The mechanosensitive, Ca2+ permeable ion channel Piezo1 was identified as another potential anti-angiogenic target in CLMECs. Modulation of the Piezo1 channel with the newly discovered Piezo1 activator Yoda1 is demonstrated for the first time in CLMECs and shown to induce phosphorylation of endothelial nitric oxide synthase. This study has identified a number of proteins that are differentially expressed in CLMECs, which could be targeted for the development of anti-angiogenic therapies in the treatment of CLM. AZD1775 has anti-angiogenic activity in CLMECs and Piezo1 represents another target which can be investigated in future studies. - vii - Table of Contents Acknowledgements .................................................................................. iii Abstract ...................................................................................................... v Table of Contents ..................................................................................... vii List of Tables ............................................................................................xiv List of Figures .......................................................................................... xv List of Publications and Communications ...........................................xviii Abbreviations ...........................................................................................xxi Chapter 1: Introduction.............................................................................. 1 1.1 Historical Perspective .................................................................... 1 1.2 Current Treatment of Colorectal Cancer ........................................ 3 1.3 Failure of Treatment ...................................................................... 7 1.3.1 Local Recurrence ............................................................... 7 1.3.2 Metastatic Disease ............................................................. 7 1.4 Development of Colorectal Cancer Liver Metastases .................... 8 1.4.1 Colorectal Cancer Biology .................................................. 8 1.4.2 The Metastatic Cascade ................................................... 10 1.4.3 Progression of Colorectal Cancer Liver Metastases ......... 13 1.5 Treatment of Colorectal Cancer Liver Metastases ....................... 16 1.5.1 Conservative ..................................................................... 16 1.5.2 Surgical Resection ............................................................ 16 1.5.3 Systemic Neoadjuvant Chemotherapy ............................... 17 1.5.4 Systemic Adjuvant Chemotherapy ..................................... 17 1.5.5 Regional Adjuvant Chemotherapy ..................................... 18 1.5.6 Systemic Palliative Chemotherapy .................................... 18 1.5.7 Radiofrequency Ablation ................................................... 19 1.5.8 Transarterial Chemoembolisation ...................................... 19 1.5.9 Microwave Hyperthermia and Interstitial Laser Ablation .... 20 1.5.10 Percutaneous Ethanol Injection ....................................... 21 1.5.11 Cryotherapy ..................................................................... 21 1.5.12 Hepatic Transplant .......................................................... 21 1.5.13 Biological Agents ............................................................. 23 - viii - 1.6 Angiogenesis................................................................................ 25 1.6.1 The Cardiovascular System .............................................. 25 1.6.2 The Endothelium ............................................................... 26 1.6.3 Sprouting Angiogenesis..................................................... 28 1.6.3.1 The Role of Hypoxia ............................................... 28 1.6.3.2 The Role of Vascular Endothelial Growth Factor .... 29 1.6.3.3 Endothelial Tip, Stalk and Phalanx Cells ................ 31 1.6.3.4 DLL4-Notch Signalling ............................................ 32 1.6.3.5 Maturation of Blood Vessels ................................... 34 1.6.4 Intussusceptive Angiogenesis ........................................... 36 1.6.5 Tumour Angiogenesis ....................................................... 37 1.6.5.1 Characteristics of Tumour Blood
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