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Cancer Signaling, Enhanced Edition - From Molecular Biology to Targeted Therapy
Christoph Wagener, Carol Stocking, Oliver Müller
Verlag Wiley-VCH, 2016
ISBN 9783527800452 , 360 Seiten
Format PDF
Kopierschutz DRM
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