Cancer Cell Signalling

As our understanding of tumour biology has developed, molecules involved in disrupting normal cell signalling and driving cells towards a more cancerous phenotype have provided the basis for new drug targets, and a number of targeted biological therapies now exist for the treatment of tumours. However, many cancer patients have tumours that are either refractory to treatment, or that develop resistance. The amount of research into this area has provided a wealth of information about cross–talk between signalling pathways and compensatory signalling. The aim of this book is to introduce a number of cell signalling pathways that are both well characterised and reported to play central roles in the development of a number of different tumour types. Each chapter focuses on an individual pathway, its key components and dysregulation in tumour development, in the context of both current therapies and future strategies.  The final chapter is devoted to signalling cross–talk. Interactions between signalling pathways, compensatory signalling and tumour related issues are presented so that the reader will not only develop a better appreciation for the role of signalling in disease, but also begin to understand the relevance of cross–talk. Cancer Cell Signalling will prove invaluable for advanced undergraduates and postgraduates studying and researching within this fast moving and complex field. A focused, accessible introduction to cell signalling, its role in cancer development and implications for current and future therapeutic opportunities.  Covers the individual cell signalling pathways that are known to be involved in cancer development, and includes the cross–interactions between the pathways together with the current therapeutic approaches. Includes colour figures throughout, to illustrate the key pathways explored within the text.

List of contributors ix Acknowledgements xi Introduction xiii About the companion website xvi 1 Epidermal growth factor receptor family 1 Amanda Harvey 1.1 ErbB receptors and their structure 1 1.2 ErbB ligands 2 1.3 Downstream signalling molecules and events 5 1.4 Signalling regulation 8 1.5 Dysregulation of signalling in cancer 10 1.6 Therapeutic opportunities 13 References 17 2 Insulin and the insulin–like growth factor (IGF) family 25 Maria Thorpe, Erald Shehu and Amanda Harvey 2.1 Receptors 25 2.2 Ligands 28 2.3 Downstream signalling molecules and events 30 2.4 Dysregulation of signalling in cancer 32 2.5 Therapeutic opportunities 34 References 37 3 Transforming growth factor–β receptor signalling 45 Gudrun Stenbeck 3.1 TGFβ receptors 45 3.2 Ligands 48 3.3 Downstream signalling molecules and events 49 3.4 Signalling regulation 53 3.5 Dysregulation of signalling in cancer 56 3.6 Therapeutic opportunities 58 References 60 4 Wnt signalling 67 David Tree 4.1 Introduction and overview 67 4.2 The ligands: Wnt proteins, their modification and secretion 69 4.3 The receptors: Frizzleds and LRPs, multiple receptors and combinations 70 4.4 Regulation of signalling 71 4.5 When good signalling goes bad: Wnt signalling in diseases 79 4.6 Taming the beast: drugs and small molecule inhibitors targeting Wnt signalling 80 4.7 Conclusion and perspectives 81 References 82 5 Mammalian target of rapamycin (mTOR) signalling 93 Maria Thorpe and Emmanouil Karteris 5.1 Discovery of mTOR 93 5.2 mTOR complexes 94 5.3 mTOR dysregulation in disease 99 5.4 Therapeutic opportunities 104 References 107 6 c–Met receptor signalling 115 Stephen Hiscox 6.1 Historical context – identification of the MET gene 115 6.2 c–Met expression, activation and signal transduction 119 6.3 Physiological roles of c–Met 121 6.4 c–Met and cancer 123 6.5 c–Met as a potential therapeutic target in malignancy 128 6.6 Summary 130 References 130 7 Vascular endothelial growth factor and its receptor family 139 Katarzyna Leszczynska, Christopher Hillyar and Ester M. Hammond 7.1 VEGF receptors 139 7.2 Ligands 140 7.3 Downstream signalling molecules and events 143 7.4 Signalling regulation 150 7.5 Dysregulation of signalling in cancer 152 7.6 Therapeutic opportunities 153 References 158 8 Progesterone receptor signalling in breast cancer models 171 Andrea R. Daniel, Todd P. Knutson, Christy R. Hagan and Carol A. Lange 8.1 Progesterone receptor function 172 8.2 Model systems: context for studying PR biochemistry 174 8.3 Progesterone receptor signalling 175 8.4 Regulation of signalling 176 8.5 Tissue specific PR actions (breast versus reproductive tract) 181 8.6 Progesterone receptor and cancer 183 8.7 Summary 183 References 184 9 Signalling cross–talk 193 Amanda Harvey 9.1 Introduction 193 9.2 Examples of cross–talk 195 9.3 Convergence of signalling at downstream foci 197 9.4 Common signalling components 198 9.5 Compensatory signalling 202 9.6 Summary 203 References 203 Index 207