Cancer signaling : from molecular biology to targeted therapy / Christoph Wagener, Carol Stocking, and Oliver Müller. -- Weinheim : Wiley-VCH Verlag GmbH & Co. KGaA, c2017. – (58.17114 /W131)

Contents

Preface  xv

Acknowledgments  XXI

List of Abbreviations  XXIII

About the Companion Website  XXIX

1    General Aspects of Signal Transduction and Cancer Therapy  1

1.1  General Principles of Signal Transduction  2

1.2  Drugs against Cancer  10

1.3  Outlook  20

     References  21

2    Tumor Cell Heterogeneity and Resistance to Targeted Therapy  23

2.1  The Genetic Basis of Tumorigenesis  24

2.2  Clonal Heterogeneity  24

2.3  Tumor Stem Cells and Tumor Cell Hierarchies  37

2.4  Epigenetics and Phenotypic Plasticity  40

2.5  Microenvironment  42

2.6  Outlook  43

     References  44

3    Cell Cycle of Tumor Cells  47

3.1  Properties of Tumor Cells  48

3.2  The Cell Cycle  50

3.3  The Cell Cycle as Therapeutic Target  58

3.4  Outlook 60

     References  61

4    Cell Aging and Cell Death  63

4.1  A Cell's Journey,through Life  64

4.2  Cellular Aging and Senescence  64

4.3  Cell Death  74

4.4  Morphologies of Dying Cells  75

4.5  Necroptosis  76

4.6  Apoptosis in the Healthy Organism  79

4.7  Apoptosis of Tumor Cells  85

4.8  Autophagy  86

4.9  Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment  89

4.10  Senescence in Anticancer Therapy  93

4.11  Outlook  94

      References  95

5    Growth Factors and Receptor Tyrosine Kinases  97

5.1  Growth Factors  98

5.2  Protein Kinases  98

5.3  Therapy of Tumors with Dysregulated Growth Factors and their Receptors  115

5.4  Outlook  117

     References  117

6    The Philadelphia Chromosome and BCR-ABL1  119

6.1  Analysis of Chromosomes  120

6.2  Aberrant Chromosomes in Tumor Cells  121

6.3  The Philadelphia Chromosome  122

6.4  The BCR-ABL1 Kinase Protein  125

6.5  Outlook  133

     References  133

7    MAPK Signaling  135

7.1  The RAS Gene  136

7.2  The Ras Protein  136

7.3  Neurofibromin: The Second RasGAP  143

7.4  Downstream Signaling of Ras  144

7.5  Therapy of Tumors with Constitutively Active MAPK Pathway  149

7.6  Outlook  1S6

     References  156

8    PI3K-AKT-mTOR Signaling  159

8.1  Discovery of the PI3K-AKT-mTOR Pathway  160

8.2  Phosphatidylinositol-3-Kinase (PI3K)  161

8.3  Inositol Trisphosphate, Diacylglycerol, and Protein Kinase C(PKC) 163

8.4  AKT (Protein Kinase B)  16S

8.5  mTOR  168

8.6  PTEN  172

8.7  Activation of the PI3K/AKT/mTOR Pathway in Cancer  173

8.8  PKC in Cancer  17S

8.9  Therapy  176

8.10  Outlook  178

      References  180

9    Hypoxia-lnducibleFactor (HIF)  183

9.1  Responses of HIF to Hypoxia and Oncogenic Pathways  184

9.2  HIF Functional Domains  185

9.3  Regulation of HIF  186

9.4  Regulation of HIF in Malignant Disease  191

9.5  HIF Targets in Cancer  192

9.6  TCA Cycle Intermediates and Tumor Syndromes  200

9.7  Drugs Targeting HIFs  200

9.8  Outlook  202

     References  203

10    NF-κB Pathways  205

10.1  NF-κB Signaling in Inflammation, Growth Control, and Cancer  206

10.2  The Core of NF-κB Signaling  207

10.3  FamilyoflKB Proteins  209

10.4  Canonical NF-κB  Signaling from TNF Receptor 1  210

10.5  B-Cell Receptor Signaling  213

10.6  Other Receptors Activating the Canonical Pathway  214

10.7  Alternative NF-κB  Pathway  214

10.8  Terminating the NF-κB  Response  215

10.9  Ubiquitinylation in NF-κB  Signaling  217

10.10  Transcriptional Regulation  219

10.11  Physiological Role of NF-κB  Transcription Factors  221

10.12  Mutational Activation of NF-KB Pathways in Malignant Disease  222

10.13  Cross Talk between Mutant KRas and NF-κB   227

10.14  Inflammation, NF-κB , and Cancer  228

10.15  Activation of Osteoelasts in Multiple Myeloma and Breast Cancer Metastases

10.16  Targeting NF-κB  Pathways  232

10.17  Outlook  233

       References  234

11    Wnt Signaling  237

11.1  The History of Wnt  238

11.2  The Canonical Wnt Pathway  238

11.3  The Wnt Network  243

11.4  Proteins of the Wnt Pathway with Diverse Functions  243

11.5  The Wnt Targetome  246

11.6  The Wnt Pathway as Therapeutic Target  250

11.7  Outlook  254

      References  255

12    Notch Signaling  257

12.1  Introduction  258

12.2  Determination of Cell Fate Decisions  258

12.3  Notch Proteins and Notch Ligands  259

12.4  Notch Signaling  261

12.5  Notch Signaling in Malignant Disease  266

12.6  Drugs Targeting the Notch Pathway  273

12.7  Outlook  275

      References  275

13    Hedgehog Signaling  277

13.1  Overview of Hedgehog Signaling  278

13.2  Hedgehog Ligands  279

13.3  The Primary Cilium  280

13.4  Patched (Ptch) and Smoothened (Smo)  283

13.5  Gli Transcription Factors  283

13.6  Signaling in the Absence of Hedgehog  284

13.7  Signaling after Binding of Hedgehog to Patched  284

13.8  Activation of the Canonical Hedgehog Pathway in Basal Cell Carcinoma and Medulloblastoma  285

13.9   Noncanonical Activation of Hedgehog-Responsive Genes  288

13.10  Paracrine Activation of Hedgehog Signaling  291

13.11  Pharmacological Inhibition of the Hedgehog Pathway  292

13.12  Outlook  296

       References  296

14     TGFβ Signaling  299

14.1   The TGFβ Superfamily  300

14.2   Structure and Processing of TGFβ Superfamily Members  301

14.3   The TGFβ Signaling Pathway  302

14.4   Transcriptional Regulation by TGFβ Superfamily Members  305

14.5   Regulation of Stem Cells by TGFβ Superfamily Members  307

14.6   TGFβ Superfamily Members as Tumor Suppressors in Human Cancer  309

14.7   Active role of TGFβ in Tumor Progression  310

14.8   Drugs Interfering with TGFβ Signaling  312

14.9   TGFβ Superfamily Members in Tumor Cachexia  313

14.10  Outlook  315

       Nomenclature  316

       References  31.7

       Index  319