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Vascular Targeted Agents for the Treatment of Angiosarcoma

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Vascular Targeted Agents for the Treatment of Angiosarcoma Robin Joseph Young Thesis submitted for the degree of Doctor of Philosophy University of Sheffield Department of Oncology January 2013 Contents Section Title Page I Acknowledgements II Abstract III Abbreviations IV List of tables V List of figures 1 Introduction 1 1.1 Angiogenesis 1 1.1.1 Vascular Endothelial Growth Factors 2 1.1.2 Angiopoietins 3 1.1.3 Platelet Derived Growth Factors 4 1.1.4 Fibroblast Growth Factors 5 1.1.5 Notch 5 1.1.6 VEGF targeted therapy 6 1.1.6.1 Bevacizumab 6 1.1.6.2 Tyrosine kinase inhibitors 7 1.2 Angiosarcomas 11 1.2.1 Epidemiology 11 1.2.2 Aetiology 12 1.2.3 Clinical presentation 13 1.2.4 Pathology 14 1.2.5 Treatment 15 1.2.5.1 Localised disease 16 1.2.5.2 Advanced disease 16 1.2.5.3 Biological agents 17 1.3 The Molecular Pathology of Angiosarcomas 20 1.3.1 Chromosomal abnormalities 20 1.3.2 Immortality 21 1.3.3 Abnormal growth signals 21 1.3.4 Invasion and metastasis 23 1.3.5 Angiogenesis 24 1.4 Hypothesis 27 1.5 Aims 23 2 Methods 28 2.1 Cells 28 2.2 Characterisation Studies 31 2.2.1 Immunocytochemistry characterisation 31 2.2.1.1 Slides 31 2.2.1.2 Immunocytochemistry protocol 31 2.2.1.3 Permanox slides 32 2.2.2 Flow cytometry 33 2.2.3 Dil-Ac-LDL 35 2.3 Functional Assays 36 2.3.1 Growth kinetics 36 2.3.2 Differentiation 36 2.3.3 Migration 38 2.3.4 In vivo tumour formation 40 2.4 Protein Expression Profiling 40 2.4.1 Protein arrays 40 2.4.2 VEGF ELISA 43 2.4.3 Western blot 44 2.5 Drug Studies 49 2.5.1 Chemosensitivity assays 49 2.5.1.1 Cell membrane integrity assay 51 2.5.1.2 MTS assay 52 2.5.2 Functional studies 53 2.5.2.1 Differentiation 53 2.5.2.2 Migration 53 2.5.2.3 Invasion 54 2.6 Tumour Samples 58 2.6.1 Cell line development 58 2.6.2 Angiogenesis related protein array of human tumours 61 2.6.2.1 Protein extraction 62 2.6.2.2 Protein array 62 2.6.3 Immunohistochemistry study of human vascular tumours 62 2.6.3.1 Immunohistochemistry protocol 63 2.6.4 Immunohistochemistry study of canine vascular tumours 64 2.7 Statistical Methods 65 3 Results 66 3.1 Characterisation of Angiosarcoma Cell Lines 66 3.1.1 Cell morphology 66 3.1.2 Immunocytochemistry studies 67 3.1.3 DiL-Ac-LDL 71 3.1.4 Flow cytometry 72 3.1.5 Characterisation of angiosarcoma cell lines 72 3.2 Protein Expression 75 3.2.1 Protein arrays 75 3.2.1.1 Angiogenesis related proteins 75 3.2.1.2 Phosphorylated protein kinases 77 3.2.1.3 Phosphorylated protein kinase receptors 78 3.2.1.4 Protein array summary 79 3.2.2 VEGF ELISA 88 3.2.3 Western blot studies 90 3.2.3.1 VEGF 90 3.2.3.2 VEGFR2 90 3.2.3.4 Protein expression summary 91 3.3 Functional Assays 92 3.3.1 Growth kinetics 92 3.3.2 Differentiation (tubule formation) assay 92 3.3.3 Migration 94 3.3.4 Functional assays summary 95 3.4 Drug Studies 96 3.4.1 Chemotherapeutic agents 96 3.4.2 VEGF targeted agents 100 3.4.2.1 Tyrosine kinase inhibitors 100 3.4.2.1.1 Cell viability studies in the presence of TKI 100 3.4.2.1.2 Cell differentiation studies in the presence of TKI 105 3.4.2.1.3 Cell migration studies in the presence of TKI 106 3.4.2.1.4 Cell invasion studies in the presence of TKI 107 3.4.2.2 Bevacizumab 109 3.4.2.2.1 Cell viability studies in the presence of bevacizumab 110 3.4.2.2.2 Cell differentiation studies in the presence of 112 bevacizumab 3.4.2.2.3 Cell migration studies in the presence of bevacizumab 113 3.4.2.3 VEGF targeted agents in hypoxia 114 3.4.2.3.1 Cell viability in hypoxia 114 3.4.2.3.2 Cell differentiation in hypoxia 116 3.4.2.4 Endothelial cell differentiation with ASM and ISO-HAS 117 conditioned media 3.4.2.5 VEGFR2 phosphorylation status 118 3.4.2.6 Downstream signalling pathways - phosphoERK 119 3.4.3 MEK inhibition 121 3.4.3.1 Cell viability studies with MEK inhibition 122 3.4.3.2 Cell differentiation studies with MEK inhibition 122 3.4.4 mTOR inhibition 123 3.4.4.1 Cell viability studies with mTOR inhibition 124 3.4.5 Summary of studies with VEGF targeted agents 126 3.4.6 Checkpoint II inhibition 126 3.4.6.1 Cell viability studies with checkpoint II inhibition 127 3.4.7 Vascular disrupting agent 128 3.4.7.1 Cell viability studies with vascular disrupting agent 128 3.4.7.2 Cell differentiation studies with vascular disrupting agent 130 3.4.7.3 DMXAA drug mechanisms 131 3.4.7.3.1 TNFα 131 3.4.7.3.2 Apoptosis 132 3.4.7.4 Vascular disrupting agent summary 134 3.5 Human Angiosarcoma Tumour Samples 135 3.5.1 Tumour cell isolates 136 3.5.1.1 STS0510 136 3.5.1.2 STS2110, STS2210 137 3.5.1.3 STS1011 137 3.5.1.3.1 Functional in vitro studies 138 3.5.1.3.1.1 STS1011 cell viability 138 3.5.1.3.1.2 STS1011 cell differentiation 140 3.5.1.4 Tumour cell isolates summary 141 3.5.2 Angiogenesis related protein array of tumour samples 142 3.5.3 Immunohistochemistry studies of tumour samples 146 3.5.3.1 Histological features 147 3.5.3.2 Tumour expression of angiogenesis related proteins 149 3.5.3.3 Immunohistochemistry studies of tumour samples 151 summary 3.5.4 Immunohistochemistry studies of canine vascular tumours 166 4 Discussion 170 4.1 Characterisation Studies 170 4.2 Protein Expression 171 4.2.1 VEGF 175 4.3 Drug Studies 175 4.3.1 VEGF targeted agents 176 4.3.2 VEGF inhibition 178 4.3.3 mTOR inhibition 181 4.3.4 MEK inhibition 182 4.3.5 Checkpoint II inhibition 183 4.3.6 DMXAA 184 4.4 Human Tumour Samples 187 4.4.1 Tumour cell isolates 187 4.4.2 Angiogenesis related protein array study of tumour 187 samples 4.4.3 Immunohistochemistry studies 188 4.4.3.1 VEGF and VEGFRs 189 4.4.3.2 Neuropilins 190 4.4.3.3 bFGF and FGFR1 191 4.4.3.4 Angiopoietins 191 4.4.3.5 HGF and MET 192 4.5 Canine Angiosarcomas 193 4.6 Future Work 194 5 References 197 Appendix Research Ethics Committee approval letters 215 and Published Articles I Acknowledgements First and foremost I am indebted to my two supervisors Penella Woll and Nicola Brown; they have supported and inspired me throughout my research, and continue to do so. I also wish to thank Malcolm Reed and Carolyn Staton for all their advice and support. I wish to thank Yorkshire Cancer Research who funded my clinical research fellowship. I would like to acknowledge Sue Murphy from the Animal Health Trust who generously provided the canine tumour blocks, and Professors Krump-Konvalinkova and Masuzawa who kindly provided the ASM and ISO-HAS cell lines respectively. Pfizer provided axitinib and sunitinib for the drug studies, and Novartis provided DMXAA. Many other people helped me during my research. By inclusion I risk omission, but I would like to specifically thank Carmel Nichols, Sue Higham, Jenny Globe and Claire Greaves for providing technical support and advice. Thanks also to Sue Newton for helping me with the flow cytometry experiments. I woud like to express my thanks to Lynda Wyld for her help in collecting the sarcoma tumour samples, and to the patients who donated their tissue. I would also like to thank David Hughes and Marlee Fernando for their help, with particular thanks to Malee for giving up so much of her time to guide me through the tumour immunohistochemistry analysis. I would also like to thank those with whom I was fortunate enough to share lab time and office space, with special mention to Sapna, Matt, Debayan and Sheila. Finally, I wish to thank my family, especially my wonderful wife Shareen - for sharing the journey and for encouraging me to follow my dreams - and our children, Kamran, Leila and Benjamin. II Abstract Background: Angiogenesis is the process of new blood vessel formation, and is regulated by angiogenic growth factors including vascular endothelial growth factor (VEGF). Angiosarcomas are rare, aggressive vascular tumours. Studies were performed to investigate the expression of angiogenic growth factors in angiosarcoma, and to assess vascular targeted agents for the treatment of angiosarcoma. Methods: In vitro studies compared two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS) with human dermal microvascular endothelial cells (HuDMECs). The cell lines were compared in functional assays, including cell viability, cell differentiaiton and cell migration assays, and protein expression profiled using antibody arrays. Cell responses to vascular targeted agents were compared, including response to bevacizumab an anti-VEGF antibody, axitinib a VEGF receptor (VEGFR) tyrosine kinase inhibitor, selumetinib a MEK inhibitor, and DMXAA a vascular disrupting agent.
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