Cancer Signaling: from molecular biology to targeted therapy
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| Beteiligte Personen: | , , |
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| Format: | Buch |
| Sprache: | Englisch |
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Weinheim
Wiley-VCH Verlag GmbH & Co. KGaA
[2017]
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| Umfang: | XXIX, 324 Seiten Illustrationen, Diagramme |
| ISBN: | 9783527336586 3527336583 |
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| 264 | 1 | |a Weinheim |b Wiley-VCH Verlag GmbH & Co. KGaA |c [2017] | |
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Datensatz im Suchindex
| _version_ | 1819360340569227264 |
|---|---|
| adam_text | Titel: Cancer signaling
Autor: Wagener, Christoph
Jahr: 2017
VII
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
1.1.1 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 Protein-Protein 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 of Therapeutic 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
References 21
VIII Contents
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 to Therapy 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 Stern 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 Cydeof 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
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
4.2.1 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
Contents IX
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 ofNecrotic 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 Intrinsic Initiation 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
References 95
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 ofEGF 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
X Contents
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
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
6.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene 125
6.4 The BCR-ABL1 Kinase Protein 125
6.4.1 Structural Aspects ofBCR-ABLl 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
References 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 in Wild-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 a Therapeutic Target 150
7.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring
ofRas 150
Contents XI
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
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
8.3.1 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 mTORCl: Inputs 170
8.5.2 mTORC2: Inputs 171
8.5.3 mTORCl: 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
References 180
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 Hypoxie 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
XII | Contents
9.4.2 von Hippel-Lindau Disease 191
9.5 HIF Targets in Cancer 192
9.5.1 Target Genes of HIFla and HIF2a 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 HIFla and the Warburg 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
References 203
10 NF-kB Pathways 205
10.1 NF-kB Signaling in Inflammation, Growth Control, and
Cancer 206
10.2 The Core of NF-kB Signaling 207
10.3 Family of IkB Proteins 209
10.4 Canonical NF-kB 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-kB Pathway 214
10.8 Terminating the NF-kB Response 215
10.9 Ubiquitinylation in NF-kB Signaling 217
10.10 Transcriptional Regulation 219
10.11 Physiological Role of NF-kB Transcription Factors 221
10.12 Mutational Activation of NF-kB Pathways in Malignant
Disease 222
10.12.1 B-Cell Lymphomas 222
10.12.2 Multiple Myeloma 223
10.12.3 Activation of NF-kB 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-kB 227
10.14 Inflammation, NF-kB, and Cancer 228
10.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer
Metastases 230
10.16 Targeting NF-kB 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
References 234
Contents XIII
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 The Wnt 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 ß-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
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
12.4.1 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
References 275
XIV | Contents
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 (aPKCi) 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
References 296
14 TGFß Signaling 299
14.1 The TGFß Superfamily 300
14.2 Structure and Processing of TGFß Superfamily Members 301
14.3 The TGFß Signaling Pathway 302
14.4 Transcriptional Regulation by TGFß Superfamily Members 305
14.5 Regulation of Stern Cells by TGFß Superfamily Members 307
14.6 TGFß Superfamily Members as Tumor Suppressors in Human
Cancer 309
14.7 Active role of TGFß in Tumor Progression 310
14.8 Drugs Interfering with TGFß Signaling 312
14.9 TGFß Superfamily Members in Tumor Cachexia 313
14.10 Outlook 315
Nomenclature 316
References 317
Index 319
|
| any_adam_object | 1 |
| author | Wagener, Christoph 1947- Müller, Oliver 1965- Stocking, Carol |
| author_GND | (DE-588)139510036 (DE-588)1035139936 |
| author_facet | Wagener, Christoph 1947- Müller, Oliver 1965- Stocking, Carol |
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| bvnumber | BV043756827 |
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| id | DE-604.BV043756827 |
| illustrated | Illustrated |
| indexdate | 2024-12-20T17:44:22Z |
| institution | BVB |
| institution_GND | (DE-588)16179388-5 |
| isbn | 9783527336586 3527336583 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-029168274 |
| oclc_num | 909797012 |
| open_access_boolean | |
| owner | DE-11 DE-20 DE-578 |
| owner_facet | DE-11 DE-20 DE-578 |
| physical | XXIX, 324 Seiten Illustrationen, Diagramme |
| publishDate | 2017 |
| publishDateSearch | 2017 |
| publishDateSort | 2017 |
| publisher | Wiley-VCH Verlag GmbH & Co. KGaA |
| record_format | marc |
| spellingShingle | Wagener, Christoph 1947- Müller, Oliver 1965- Stocking, Carol Cancer Signaling from molecular biology to targeted therapy Onkologie (DE-588)4075658-0 gnd Pharmakotherapie (DE-588)4076066-2 gnd Signaltransduktion (DE-588)4318717-1 gnd Krebs Medizin (DE-588)4073781-0 gnd |
| subject_GND | (DE-588)4075658-0 (DE-588)4076066-2 (DE-588)4318717-1 (DE-588)4073781-0 |
| title | Cancer Signaling from molecular biology to targeted therapy |
| title_auth | Cancer Signaling from molecular biology to targeted therapy |
| title_exact_search | Cancer Signaling from molecular biology to targeted therapy |
| title_full | Cancer Signaling from molecular biology to targeted therapy Christoph Wagener, Carol Stocking, and Oliver Müller |
| title_fullStr | Cancer Signaling from molecular biology to targeted therapy Christoph Wagener, Carol Stocking, and Oliver Müller |
| title_full_unstemmed | Cancer Signaling from molecular biology to targeted therapy Christoph Wagener, Carol Stocking, and Oliver Müller |
| title_short | Cancer Signaling |
| title_sort | cancer signaling from molecular biology to targeted therapy |
| title_sub | from molecular biology to targeted therapy |
| topic | Onkologie (DE-588)4075658-0 gnd Pharmakotherapie (DE-588)4076066-2 gnd Signaltransduktion (DE-588)4318717-1 gnd Krebs Medizin (DE-588)4073781-0 gnd |
| topic_facet | Onkologie Pharmakotherapie Signaltransduktion Krebs Medizin |
| url | http://deposit.dnb.de/cgi-bin/dokserv?id=5249464&prov=M&dok_var=1&dok_ext=htm http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029168274&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT wagenerchristoph cancersignalingfrommolecularbiologytotargetedtherapy AT mulleroliver cancersignalingfrommolecularbiologytotargetedtherapy AT stockingcarol cancersignalingfrommolecularbiologytotargetedtherapy AT wileyvch cancersignalingfrommolecularbiologytotargetedtherapy |