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Cancer Signaling - From Molecular Biology to Targeted Therapy

Cancer Signaling - From Molecular Biology to Targeted Therapy

von: Christoph Wagener, Carol Stocking, Oliver Müller

Wiley-VCH, 2016

ISBN: 9783527800452 , 360 Seiten

Format: PDF

Kopierschutz: DRM

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Cancer Signaling - From Molecular Biology to Targeted Therapy


 

Cover

1

Title Page

5

Copyright

6

Dedication

7

Contents

9

Preface

17

Acknowledgments

23

List of Abbreviations

25

About the Companion Website

31

Chapter 1 General Aspects of Signal Transduction and Cancer Therapy

33

1.1 General Principles of Signal Transduction

34

1.1.1 Biological Signals have to be Processed

34

1.1.2 What is a Signal Transduction Pathway?

34

1.1.3 Mechanisms of Direct Signal Transduction

36

1.1.4 The Interactome Gives Insight into the Signaling Network

37

1.1.5 Protein Domains for Protein-Protein Interaction and Signal Transduction

38

1.1.6 Functions of Mutated Proteins in Tumor Cells

40

1.2 Drugs against Cancer

42

1.2.1 Terms and Definitions

42

1.2.2 The Steps from a Normal Cell to a Tumor

42

1.2.3 Interference Levels of Therapeutic Drugs

43

1.2.4 Drugs Attacking the Whole Cell

44

1.2.4.1 DNA Alkylating Drugs

45

1.2.5 Process-Blocking Drugs

46

1.2.5.1 Drugs Blocking Synthesis of DNA and RNA

46

1.2.5.2 Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules

47

1.2.5.3 Drugs Blocking Dynamics of Microtubules

48

1.2.6 Innovative Molecule-Interfering Drugs

50

1.2.7 Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse

51

1.2.8 Drug Resistance

51

1.2.8.1 Drugs Circumventing Resistance

51

1.3 Outlook

52

References

53

Chapter 2 Tumor Cell Heterogeneity and Resistance to Targeted Therapy

55

2.1 The Genetic Basis of Tumorigenesis

56

2.2 Clonal Heterogeneity

56

2.2.1 Clonal Origin of Tumors

56

2.2.2 Clonal Evolution

58

2.2.3 The Time Course of Clonal Evolution

62

2.2.4 Clonal Evolution and Resistance to Therapy

64

2.2.5 Targeting Essential Drivers (Driver Addiction)

66

2.2.6 Resistance by Alternative Pathway Activation

68

2.2.7 Overcoming Resistance by Combinatorial Therapies

68

2.3 Tumor Stem Cells and Tumor Cell Hierarchies

69

2.4 Epigenetics and Phenotypic Plasticity

72

2.5 Microenvironment

74

2.6 Outlook

75

References

76

Chapter 3 Cell Cycle of Tumor Cells

79

3.1 Properties of Tumor Cells

80

3.1.1 Differences between Tumor Cells and Normal Cells In vitro

81

3.1.2 Regulation of Cell Number

81

3.2 The Cell Cycle

82

3.2.1 Checkpoints

83

3.2.2 Cyclins

84

3.2.3 Cyclin-Dependent Kinases (CDKs)

85

3.2.4 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle

86

3.2.5 Inhibitors of CDKs

86

3.2.6 Checkpoints and DNA Integrity

87

3.2.7 The Repair Mechanism Depends on the Cell Cycle Phase

89

3.2.8 Tumor-Relevant Proteins in the Cell Cycle

89

3.3 The Cell Cycle as Therapeutic Target

90

3.3.1 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs

91

3.4 Outlook

92

References

93

Chapter 4 Cell Aging and Cell Death

95

4.1 A Cell's Journey through Life

96

4.2 Cellular Aging and Senescence

96

4.2.1 Replicative Senescence

97

4.2.2 Shortening of Chromosomal Telomeres during Replication

99

4.2.3 Chromosomal Telomeres

99

4.2.4 Telomerase

101

4.2.5 Animal Models

104

4.2.6 Overcoming Replicative Senescence in Tumor Cells

104

4.2.7 Nonreplicative Senescence

105

4.3 Cell Death

106

4.4 Morphologies of Dying Cells

107

4.4.1 Morphology of Necrotic Cells

107

4.4.2 Morphologies of Apoptotic and Necroptotic Cells

107

4.4.3 Morphology of Autophagy

108

4.5 Necroptosis

108

4.6 Apoptosis in the Healthy Organism

111

4.6.1 The Four Phases of Apoptosis

112

4.6.2 Extrinsic Initiation

113

4.6.2.1 TNF Pathway

113

4.6.2.2 TNF Receptor Downstream Signaling

114

4.6.2.3 Caspases

114

4.6.3 Intrinsic Initiation

115

4.6.4 Execution Phase

116

4.6.5 Phagocytosis and Degradation

117

4.7 Apoptosis of Tumor Cells

117

4.8 Autophagy

118

4.8.1 Autophagy in Tumor Development

119

4.8.2 Regulation of Autophagy

121

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

121

4.9.1 Induction of Apoptosis by Radiation

121

4.9.2 Induction of Apoptosis by Conventional Anticancer Drugs

122

4.9.3 Innovative Drugs Targeting Aging and Death Pathways

124

4.9.3.1 Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand)

124

4.9.3.2 Targeting Bcl-2

124

4.9.3.3 Simulating the Effects of cIAP Inhibitors

124

4.9.3.4 Targeting Autophagy Pathways

125

4.10 Senescence in Anticancer Therapy

125

4.11 Outlook

126

References

127

Chapter 5 Growth Factors and Receptor Tyrosine Kinases

129

5.1 Growth Factors

130

5.2 Protein Kinases

130

5.2.1 Receptor Protein Tyrosine Kinases

132

5.2.2 Receptor Protein Tyrosine Kinase Activation

134

5.2.3 The Family of EGF Receptors

135

5.2.4 The Family of PDGF Receptors

136

5.2.5 The Insulin Receptor Family and its Ligands

139

5.2.5.1 Prostate-Specific Antigen

139

5.2.6 Signaling from Receptor Protein Tyrosine Kinases

140

5.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins

141

5.2.7.1 Signaling from PDGF and EGF Receptors

144

5.2.8 Constitutive Activation of RTKs in Tumor Cells

145

5.3 Therapy of Tumors with Dysregulated Growth Factors and their Receptors

147

5.3.1 Targeting Growth Factors

147

5.3.2 Targeting EGF Receptors by Antibodies

148

5.3.3 Targeting EGF Receptors by Kinase Inhibitors

149

5.4 Outlook

149

References

149

Chapter 6 The Philadelphia Chromosome and BCR-ABL1

151

6.1 Analysis of Chromosomes

152

6.2 Aberrant Chromosomes in Tumor Cells

153

6.3 The Philadelphia Chromosome

154

6.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene

157

6.4 The BCR-ABL1 Kinase Protein

157

6.4.1 Structural Aspects of BCR-ABL1 Kinase

158

6.4.2 Substrates and Effects of BCR-ABL1 Kinase

160

6.4.3 The BCR-ABL1 Kinase Inhibitor Imatinib

161

6.4.4 Imatinib in Treatment of Tumors Other than CML

162

6.4.5 Mechanism of Imatinib Action

162

6.4.6 Resistance against Imatinib

162

6.4.7 BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation

163

6.4.8 Allosteric Inhibitors of BCR-ABL1

164

6.5 Outlook

165

References

165

Chapter 7 MAPK Signaling

167

7.1 The RAS Gene

168

7.2 The Ras Protein

168

7.2.1 The Ras Protein as a Molecular Switch

170

7.2.2 The GTPase Reaction in Wild-Type and Mutant Ras Proteins

171

7.3 Neurofibromin: The Second RasGAP

175

7.4 Downstream Signaling of Ras

176

7.4.1 The BRaf Protein

177

7.4.2 The BRAF Gene

179

7.4.3 The MAPK Signaling Pathway

179

7.4.4 Mutations in Genes of the MAPK Pathway

180

7.5 Therapy of Tumors with Constitutively Active MAPK Pathway

181

7.5.1 Ras as a Therapeutic Target

182

7.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring of Ras

182

7.5.1.2 Direct Targeting Mutant Ras

184

7.5.1.3 Preventing Ras/Raf Interaction

184

7.5.2 BRaf Inhibitors

184

7.5.2.1 Consequences of BRaf Inhibition by Vemurafenib

186

7.5.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms

186

7.5.2.3 Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms

187

7.5.2.4 Treatment of Vemurafenib-Resistant Tumors

187

7.6 Outlook

188

References

188

Chapter 8 PI3K-AKT-mTOR Signaling

191

8.1 Discovery of the PI3K-AKT-mTOR Pathway

192

8.2 Phosphatidylinositol-3-Kinase (PI3K)

193

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

195

8.3.1 Protein Kinase C (PKC)

195

8.3.2 Activation and Functions of PKC

197

8.4 AKT (Protein Kinase B)

197

8.5 mTOR

200

8.5.1 mTORC1: Inputs

202

8.5.2 mTORC2: Inputs

203

8.5.3 mTORC1: Outputs

203

8.5.4 mTORC2: Outputs

204

8.5.5 Feedback Controls

204

8.6 PTEN

204

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

205

8.7.1 Sporadic Carcinomas

205

8.7.2 Hamartoma Syndromes

206

8.8 PKC in Cancer

207

8.9 Therapy

208

8.10 Outlook

210

References

212

Chapter 9 Hypoxia-Inducible Factor (HIF)

215

9.1 Responses of HIF to Hypoxia and Oncogenic Pathways

216

9.2 HIF Functional Domains

217

9.3 Regulation of HIF

218

9.3.1 Regulation of HIF under Normoxic Conditions

218

9.3.2 Regulation of HIF under Hypoxic Conditions

221

9.3.3 Oxygen-Independent Regulation of HIF

221

9.3.4 Context-Dependence of HIF Regulation

222

9.4 Regulation of HIF in Malignant Disease

223

9.4.1 Expression of HIF in Human Tumors

223

9.4.2 von Hippel-Lindau Disease

223

9.5 HIF Targets in Cancer

224

9.5.1 Target Genes of HIF1?????? and HIF2??????

224

9.5.2 HIF Target Genes Affecting Tumor Growth

225

9.5.3 HIF Target Genes Affecting Metabolism

227

9.5.3.1 Glucose Uptake and Metabolism

227

9.5.3.2 HIF1?????? and the Warburg Effect

229

9.5.3.3 The Warburg Paradox

229

9.6 TCA Cycle Intermediates and Tumor Syndromes

232

9.7 Drugs Targeting HIFs

232

9.8 Outlook

234

References

235

Chapter 10 NF-??????B Pathways

237

10.1 NF-??????B Signaling in Inflammation, Growth Control, and Cancer

238

10.2 The Core of NF-??????B Signaling

239

10.3 Family of I??????B Proteins

241

10.4 Canonical NF-??????B Signaling from TNF Receptor 1

242

10.5 B-Cell Receptor Signaling

245

10.6 Other Receptors Activating the Canonical Pathway

246

10.7 Alternative NF-??????B Pathway

246

10.8 Terminating the NF-??????B Response

247

10.9 Ubiquitinylation in NF-??????B Signaling

249

10.10 Transcriptional Regulation

251

10.11 Physiological Role of NF-??????B Transcription Factors

253

10.12 Mutational Activation of NF-??????B Pathways in Malignant Disease

254

10.12.1 B-Cell Lymphomas

254

10.12.2 Multiple Myeloma

255

10.12.3 Activation of NF-??????B Pathways by Polycomb-Mediated Loss of microRNA-31 in Adult T-Cell Leukemia/Lymphoma

257

10.12.4 Carcinomas

259

10.13 Cross Talk between Mutant KRas and NF-??????B

259

10.14 Inflammation, NF-??????B, and Cancer

260

10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases

262

10.16 Targeting NF-??????B Pathways

264

10.16.1 B-Cell Malignancies

264

10.16.2 Carcinomas

265

10.16.3 Anti-Inflammatory Drugs

265

10.17 Outlook

265

References

266

Chapter 11 Wnt Signaling

269

11.1 The History of Wnt

270

11.2 The Canonical Wnt Pathway

270

11.2.1 The Nonactivated Wnt Pathway

271

11.2.2 The Physiologically Activated Wnt Pathway

273

11.2.3 The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal

274

11.3 The Wnt Network

275

11.4 Proteins of the Wnt Pathway with Diverse Functions

275

11.4.1 APC (Adenomatous Polyposis Coli Protein)

275

11.4.2 ??????-Catenin

277

11.4.3 Axin

277

11.5 The Wnt Targetome

278

11.5.1 The Three Levels of the Wnt Targetome

279

11.5.2 Biological Effects of Wnt Target Genes

280

11.6 The Wnt Pathway as Therapeutic Target

282

11.6.1 Strategies to Identify Anti-Wnt Drugs

282

11.6.2 Molecules Interfering with the Wnt Pathway

285

11.7 Outlook

286

References

287

Chapter 12 Notch Signaling

289

12.1 Introduction

290

12.2 Determination of Cell Fate Decisions

290

12.3 Notch Proteins and Notch Ligands

291

12.4 Notch Signaling

293

12.4.1 The Notch Signaling Pathway

293

12.4.2 Regulation of Notch Signaling by Posttranslational Modification

296

12.4.2.1 Ubiquitinylation

296

12.4.2.2 Glycosylation of Notch

297

12.5 Notch Signaling in Malignant Disease

298

12.5.1 Acute T-Cell Leukemia (T-ALL)

298

12.5.2 Chronic Lymphocytic Leukemia

300

12.5.3 Chronic Myelomonocytic Leukemia (CMML)

301

12.5.4 Breast Cancer

301

12.5.5 Cholangiocellular Carcinoma (CCC)

302

12.5.6 Squamous Cell Carcinomas (SCCs)

303

12.5.7 Small-Cell Lung Cancer (SCLC)

304

12.5.8 Angiogenesis

304

12.6 Drugs Targeting the Notch Pathway

305

12.7 Outlook

307

References

307

Chapter 13 Hedgehog Signaling

309

13.1 Overview of Hedgehog Signaling

310

13.2 Hedgehog Ligands

311

13.3 The Primary Cilium

312

13.4 Patched (Ptch) and Smoothened (Smo)

315

13.5 Gli Transcription Factors

315

13.6 Signaling in the Absence of Hedgehog

316

13.7 Signaling after Binding of Hedgehog to Patched

316

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

317

13.9 Noncanonical Activation of Hedgehog-Responsive Genes

320

13.9.1 KRas

320

13.9.2 Atypical Protein Kinase-Lambda/Iota (aPKC??????)

320

13.9.3 PI3-Kinase-AKT (PI3K-AKT)

321

13.9.4 mTOR

322

13.10 Paracrine Activation of Hedgehog Signaling

323

13.11 Pharmacological Inhibition of the Hedgehog Pathway

324

13.11.1 Inhibition of Hh Binding to Ptch

325

13.11.2 Inhibitors of Smoothened

325

13.11.3 Inhibition of Cilial Trafficking

326

13.11.4 Inhibition of Gli

326

13.11.5 Resistance against Direct Inhibitors of Smoothened

327

13.12 Outlook

328

References

328

Chapter 14 TGF?????? Signaling

331

14.1 The TGF?????? Superfamily

332

14.2 Structure and Processing of TGF?????? Superfamily Members

333

14.3 The TGF?????? Signaling Pathway

334

14.4 Transcriptional Regulation by TGF?????? Superfamily Members

337

14.5 Regulation of Stem Cells by TGF?????? Superfamily Members

339

14.6 TGF?????? Superfamily Members as Tumor Suppressors in Human Cancer

341

14.7 Active role of TGF?????? in Tumor Progression

342

14.8 Drugs Interfering with TGF?????? Signaling

344

14.9 TGF?????? Superfamily Members in Tumor Cachexia

345

14.10 Outlook

347

Nomenclature

348

References

349

Index

351

EULA

357