Cancer, which has become the second-most prevalent health issue globally, is essentially a malfunction of cell signaling. Understanding how the intricate signaling networks of cells and tissues allow cancer to thrive - and how they can be turned into potent weapons against it - is the key to managing cancer in the clinic and improving the outcome of cancer therapies. In their ground-breaking textbook, the authors provide a compelling story of how cancer works on the molecular level, and how targeted therapies using kinase inhibitors and other modulators of signaling pathways can contain and eventually cure it.
The first part of the book gives an introduction into the cell and molecular biology of cancer, focusing on the key mechanisms of cancer formation. The second part of the book introduces the main signaling transduction mechanisms responsible for carcinogenesis and compares their function in healthy versus cancer cells. In contrast to the complexity of its topic, the text is easy to read. 32 specially prepared teaching videos on key concepts and pathways in cancer signaling are available online for users of the print edition and have been integrated into the text in the enhanced e-book edition.
Christoph Wagener is Professor of Clinical Biochemistry and former director of the Institute of Clinical Chemistry at the University Medical Center Hamburg-Eppendorf, Germany. His areas of research are the interaction of tumor cells with their microenvironment, and molecular approaches to tumor diagnosis. Professor Wagener has authored more than 100 original scientific publications, 15 scientific reviews and 13 book chapters. Together with Oliver Muller, he published the text book 'Molekulare Onkologie' and the 'Onkoview Videos', which can be viewed on YouTube. Book and videos have received excellent reviews from readers and viewers.
Carol Stocking is Head of the Research Group Retroviral Pathogenesis at the Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology in Hamburg, Germany. She is a highly regarded expert in the field of leukemogenesis and hematology. Her areas of research are gene regulation, molecular control of differentiation, and hematopoietic stem cells. Dr. Stocking has authored more than 120 original publications in top international journals and 20 book chapters.
Oliver Muller is Professor for Applied Life Sciences at the University for Applied Sciences Kaiserslautern, Germany. He holds academic degrees in both biochemistry and medicine. His areas of research are the intracellular signal transduction and the genes and proteins involved in carcinogenesis. Professor Muller is author of more than 80 original articles, 11 patents, 15 scientific reviews and 4 book chapters. His work was honoured by several science awards.
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
1.1.1 Biological Signals have to be Processed 2
1.1.2 What is a Signal Transduction Pathway? 2
1.1.3 Mechanisms of Direct Signal Transduction 4
1.1.4 The Interactome Gives Insight into the Signaling Network 5
1.1.5 Protein Domains for ProteinProtein Interaction and Signal Transduction 6
1.1.6 Functions of Mutated Proteins in Tumor Cells 8
1.2 Drugs against Cancer 10
1.2.1 Terms and Definitions 10
1.2.2 The Steps from a Normal Cell to a Tumor 10
1.2.3 Interference Levels ofTherapeutic Drugs 11
1.2.4 Drugs Attacking the Whole Cell 12
1.2.4.1 DNA Alkylating Drugs 13
1.2.5 Process-Blocking Drugs 14
1.2.5.1 Drugs Blocking Synthesis of DNA and RNA 14
1.2.5.2 Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules 15
1.2.5.3 Drugs Blocking Dynamics of Microtubules 16
1.2.6 Innovative Molecule-Interfering Drugs 18
1.2.7 Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse 19
1.2.8 Drug Resistance 19
1.2.8.1 Drugs Circumventing Resistance 19
1.3 Outlook 20
2 Tumor Cell Heterogeneity and Resistance to Targeted Therapy 23
2.1 The Genetic Basis of Tumorigenesis 24
2.2 Clonal Heterogeneity 24
2.2.1 Clonal Origin of Tumors 24
2.2.2 Clonal Evolution 26
2.2.3 The Time Course of Clonal Evolution 30
2.2.4 Clonal Evolution and Resistance toTherapy 32
2.2.5 Targeting Essential Drivers (Driver Addiction) 34
2.2.6 Resistance by Alternative Pathway Activation 36
2.2.7 Overcoming Resistance by Combinatorial Therapies 36
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
3 Cell Cycle of Tumor Cells 47
3.1 Properties of Tumor Cells 48
3.1.1 Differences between Tumor Cells and Normal Cells In vitro 49
3.1.2 Regulation of Cell Number 49
3.2 The Cell Cycle 50
3.2.1 Checkpoints 51
3.2.2 Cyclins 52
3.2.3 Cyclin-Dependent Kinases (CDKs) 53
3.2.4 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle 54
3.2.5 Inhibitors of CDKs 54
3.2.6 Checkpoints and DNA Integrity 55
3.2.7 The Repair Mechanism Depends on the Cell Cycle Phase 57
3.2.8 Tumor-Relevant Proteins in the Cell Cycle 57
3.3 The Cell Cycle as Therapeutic Target 58
3.3.1 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs 59
3.4 Outlook 60
4 Cell Aging and Cell Death 63
4.1 A Cells Journey through Life 64
4.2 Cellular Aging and Senescence 64
4.2.1 Replicative Senescence 65
4.2.2 Shortening of Chromosomal Telomeres during Replication 67
4.2.3 Chromosomal Telomeres 67
4.2.4 Telomerase 69
4.2.5 Animal Models 72
4.2.6 Overcoming Replicative Senescence in Tumor Cells 72
4.2.7 Nonreplicative Senescence 73
4.3 Cell Death 74
4.4 Morphologies of Dying Cells 75
4.4.1 Morphology of Necrotic Cells 75
4.4.2 Morphologies of Apoptotic and Necroptotic Cells 75
4.4.3 Morphology of Autophagy 76
4.5 Necroptosis 76
4.6 Apoptosis in the Healthy Organism 79
4.6.1 The Four Phases of Apoptosis 80
4.6.2 Extrinsic Initiation 81
4.6.2.1 TNF Pathway 81
4.6.2.2 TNF Receptor Downstream Signaling 82
4.6.2.3 Caspases 82
4.6.3 IntrinsicInitiation 83
4.6.4 Execution Phase 84
4.6.5 Phagocytosis and Degradation 85
4.7 Apoptosis of Tumor Cells 85
4.8 Autophagy 86
4.8.1 Autophagy in Tumor Development 87
4.8.2 Regulation of Autophagy 89
4.9 Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment 89
4.9.1 Induction of Apoptosis by Radiation 89
4.9.2 Induction of Apoptosis by Conventional Anticancer Drugs 90
4.9.3 Innovative Drugs Targeting Aging and Death Pathways 92
4.9.3.1 Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand) 92
4.9.3.2 Targeting Bcl-2 92
4.9.3.3 Simulating the Effects of cIAP Inhibitors 92
4.9.3.4 Targeting Autophagy Pathways 93
4.10 Senescence in Anticancer Therapy 93
4.11 Outlook 94
5 Growth Factors and Receptor Tyrosine Kinases 97
5.1 Growth Factors 98
5.2 Protein Kinases 98
5.2.1 Receptor Protein Tyrosine Kinases 100
5.2.2 Receptor Protein Tyrosine Kinase Activation 102
5.2.3 The Family of EGF Receptors 103
5.2.4 The Family of PDGF Receptors 104
5.2.5 The Insulin Receptor Family and its Ligands 107
5.2.5.1 Prostate-Specific Antigen 107
5.2.6 Signaling from Receptor Protein Tyrosine Kinases 108
5.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins 109
5.2.7.1 Signaling from PDGF and EGF Receptors 112
5.2.8 Constitutive Activation of RTKs in Tumor Cells 113
5.3 Therapy of Tumors with Dysregulated Growth Factors and their Receptors 115
5.3.1 Targeting Growth Factors 115
5.3.2 Targeting EGF Receptors by Antibodies 116
5.3.3 Targeting EGF Receptors by Kinase Inhibitors 117
5.4 Outlook 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
6.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene 125
6.4 The BCR-ABL1 Kinase Protein 125
6.4.1 Structural Aspects of BCR-ABL1 Kinase 126
6.4.2 Substrates and Effects of BCR-ABL1 Kinase 128
6.4.3 The BCR-ABL1 Kinase Inhibitor Imatinib 129
6.4.4 Imatinib in Treatment of Tumors Other than CML 130
6.4.5 Mechanism of Imatinib Action 130
6.4.6 Resistance against Imatinib 130
6.4.7 BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation 131
6.4.8 Allosteric Inhibitors of BCR-ABL1 132
6.5 Outlook 133
7 MAPK Signaling 135
7.1 The RAS Gene 136
7.2 The Ras Protein 136
7.2.1 The Ras Protein as a Molecular Switch 138
7.2.2 The GTPase Reaction inWild-Type and Mutant Ras Proteins 139
7.3 Neurofibromin: The Second RasGAP 143
7.4 Downstream Signaling of Ras 144
7.4.1 The BRaf Protein 145
7.4.2 The BRAF Gene 147
7.4.3 The MAPK Signaling Pathway 147
7.4.4 Mutations in Genes of the MAPK Pathway 148
7.5 Therapy of Tumors with Constitutively Active MAPK Pathway 149
7.5.1 Ras as aTherapeutic Target 150
7.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring of Ras 150
7.5.1.2 Direct Targeting Mutant Ras 152
7.5.1.3 Preventing Ras/Raf Interaction 152
7.5.2 BRaf Inhibitors 152
7.5.2.1 Consequences of BRaf Inhibition by Vemurafenib 154
7.5.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms 154
7.5.2.3 Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms 155
7.5.2.4 Treatment of Vemurafenib-Resistant Tumors 155
7.6 Outlook 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
8.3.1 Protein Kinase C (PKC) 163
8.3.2 Activation and Functions of PKC 165
8.4 AKT (Protein Kinase B) 165
8.5 mTOR 168
8.5.1 mTORC1: Inputs 170
8.5.2 mTORC2: Inputs 171
8.5.3 mTORC1: Outputs 171
8.5.4 mTORC2: Outputs 172
8.5.5 Feedback Controls 172
8.6 PTEN 172
8.7 Activation of the PI3K/AKT/mTOR Pathway in Cancer 173
8.7.1 Sporadic Carcinomas 173
8.7.2 Hamartoma Syndromes 174
8.8 PKC in Cancer 175
8.9 Therapy 176
8.10 Outlook 178
9 Hypoxia-Inducible Factor (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
9.3.1 Regulation of HIF under Normoxic Conditions 186
9.3.2 Regulation of HIF under Hypoxic Conditions 189
9.3.3 Oxygen-Independent Regulation of HIF 189
9.3.4 Context-Dependence of HIF Regulation 190
9.4 Regulation of HIF in Malignant Disease 191
9.4.1 Expression of HIF in Human Tumors 191
9.4.2 von HippelLindau Disease 191
9.5 HIF Targets in Cancer 192
9.5.1 Target Genes of HIF1 and HIF2 192
9.5.2 HIF Target Genes Affecting Tumor Growth 193
9.5.3 HIF Target Genes Affecting Metabolism 195
9.5.3.1 Glucose Uptake and Metabolism 195
9.5.3.2 HIF1 and theWarburg Effect 197
9.5.3.3 The Warburg Paradox 197
9.6 TCA Cycle Intermediates and Tumor Syndromes 200
9.7 Drugs Targeting HIFs 200
9.8 Outlook 202
10 NF-B Pathways 205
10.1 NF-B Signaling in Inflammation, Growth Control, and Cancer 206
10.2 The Core of NF-B Signaling 207
10.3 Family of IB Proteins 209
10.4 Canonical NF-B 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-B Pathway 214
10.8 Terminating the NF-B Response 215
10.9 Ubiquitinylation in NF-B Signaling 217
10.10 Transcriptional Regulation 219
10.11 Physiological Role of NF-B Transcription Factors 221
10.12 Mutational Activation of NF-B Pathways in Malignant Disease 222
10.12.1 B-Cell Lymphomas 222
10.12.2 Multiple Myeloma 223
10.12.3 Activation of NF-B Pathways by Polycomb-Mediated Loss of microRNA-31 in Adult T-Cell Leukemia/Lymphoma 225
10.12.4 Carcinomas 227
10.13 Cross Talk between Mutant KRas and NF-B 227
10.14 Inflammation, NF-B, and Cancer 228
10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases 230
10.16 Targeting NF-B Pathways 232
10.16.1 B-Cell Malignancies 232
10.16.2 Carcinomas 233
10.16.3 Anti-Inflammatory Drugs 233
10.17 Outlook 233
11 Wnt Signaling 237
11.1 The History of Wnt 238
11.2 The Canonical Wnt Pathway 238
11.2.1 The Nonactivated Wnt Pathway 239
11.2.2 The Physiologically Activated Wnt Pathway 241
11.2.3 The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal 242
11.3 TheWnt Network 243
11.4 Proteins of the Wnt Pathway with Diverse Functions 243
11.4.1 APC (Adenomatous Polyposis Coli Protein) 243
11.4.2 -Catenin 245
11.4.3 Axin 245
11.5 The Wnt Targetome 246
11.5.1 The Three Levels of the Wnt Targetome 247
11.5.2 Biological Effects of Wnt Target Genes 248
11.6 The Wnt Pathway as Therapeutic Target 250
11.6.1 Strategies to Identify Anti-Wnt Drugs 250
11.6.2 Molecules Interfering with the Wnt Pathway 253
11.7 Outlook 254
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
12.4.1 The Notch Signaling Pathway 261
12.4.2 Regulation of Notch Signaling by Posttranslational Modification 264
12.4.2.1 Ubiquitinylation 264
12.4.2.2 Glycosylation of Notch 265
12.5 Notch Signaling in Malignant Disease 266
12.5.1 Acute T-Cell Leukemia (T-ALL) 266
12.5.2 Chronic Lymphocytic Leukemia 268
12.5.3 Chronic Myelomonocytic Leukemia (CMML) 269
12.5.4 Breast Cancer 269
12.5.5 Cholangiocellular Carcinoma (CCC) 270
12.5.6 Squamous Cell Carcinomas (SCCs) 271
12.5.7 Small-Cell Lung Cancer (SCLC) 272
12.5.8 Angiogenesis 272
12.6 Drugs Targeting the Notch Pathway 273
12.7 Outlook 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
13.9.1 KRas 288
13.9.2 Atypical Protein Kinase-Lambda/Iota (aPKC) 288
13.9.3 PI3-Kinase-AKT (PI3K-AKT) 289
13.9.4 mTOR 290
13.10 Paracrine Activation of Hedgehog Signaling 291
13.11 Pharmacological Inhibition of the Hedgehog Pathway 292
13.11.1 Inhibition of Hh Binding to Ptch 293
13.11.2 Inhibitors of Smoothened 293
13.11.3 Inhibition of Cilial Trafficking 294
13.11.4 Inhibition of Gli 294
13.11.5 Resistance against Direct Inhibitors of Smoothened 295
13.12 Outlook 296
14 TGF Signaling 299
14.1 The TGF Superfamily 300
14.2 Structure and Processing of TGF Superfamily Members 301
14.3 The TGF Signaling Pathway 302
14.4 Transcriptional Regulation by TGF Superfamily Members 305
14.5 Regulation of Stem Cells by TGF Superfamily Members 307
14.6 TGF Superfamily Members as Tumor Suppressors in Human Cancer 309
14.7 Active role of TGF in Tumor Progression 310
14.8 Drugs Interfering with TGF Signaling 312
14.9 TGF Superfamily Members in Tumor Cachexia 313
14.10 Outlook 315
Nomenclature 316
Index 319
