Cancer Signaling

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 XVAcknowledgments XXIList of Abbreviations XXIIIAbout the Companion Website XXIX1 General Aspects of Signal Transduction and Cancer Therapy 11.1 General Principles of Signal Transduction 21.1.1 Biological Signals have to be Processed 21.1.2 What is a Signal Transduction Pathway? 21.1.3 Mechanisms of Direct Signal Transduction 41.1.4 The Interactome Gives Insight into the Signaling Network 51.1.5 Protein Domains for Protein–Protein Interaction and Signal Transduction 61.1.6 Functions of Mutated Proteins in Tumor Cells 81.2 Drugs against Cancer 101.2.1 Terms and Definitions 101.2.2 The Steps from a Normal Cell to a Tumor 101.2.3 Interference Levels ofTherapeutic Drugs 111.2.4 Drugs Attacking the Whole Cell 121.2.4.1 DNA Alkylating Drugs 131.2.5 Process-Blocking Drugs 141.2.5.1 Drugs Blocking Synthesis of DNA and RNA 141.2.5.2 Drugs Blocking the Synthesis of DNA and RNA Precursor Molecules 151.2.5.3 Drugs Blocking Dynamics of Microtubules 161.2.6 Innovative Molecule-Interfering Drugs 181.2.7 Fast-Dividing Normal Cells and Slowly Dividing Tumor Cells: Side Effects and Relapse 191.2.8 Drug Resistance 191.2.8.1 Drugs Circumventing Resistance 191.3 Outlook 202 Tumor Cell Heterogeneity and Resistance to Targeted Therapy 232.1 The Genetic Basis of Tumorigenesis 242.2 Clonal Heterogeneity 242.2.1 Clonal Origin of Tumors 242.2.2 Clonal Evolution 262.2.3 The Time Course of Clonal Evolution 302.2.4 Clonal Evolution and Resistance toTherapy 322.2.5 Targeting Essential Drivers (Driver Addiction) 342.2.6 Resistance by Alternative Pathway Activation 362.2.7 Overcoming Resistance by Combinatorial Therapies 362.3 Tumor Stem Cells and Tumor Cell Hierarchies 372.4 Epigenetics and Phenotypic Plasticity 402.5 Microenvironment 422.6 Outlook 433 Cell Cycle of Tumor Cells 473.1 Properties of Tumor Cells 483.1.1 Differences between Tumor Cells and Normal Cells In vitro 493.1.2 Regulation of Cell Number 493.2 The Cell Cycle 503.2.1 Checkpoints 513.2.2 Cyclins 523.2.3 Cyclin-Dependent Kinases (CDKs) 533.2.4 The Retinoblastoma-Associated Protein Rb as Regulator of the Cell Cycle 543.2.5 Inhibitors of CDKs 543.2.6 Checkpoints and DNA Integrity 553.2.7 The Repair Mechanism Depends on the Cell Cycle Phase 573.2.8 Tumor-Relevant Proteins in the Cell Cycle 573.3 The Cell Cycle as Therapeutic Target 583.3.1 Small Compounds Inhibiting Cell-Cycle-Dependent Kinases as Anticancer Drugs 593.4 Outlook 604 Cell Aging and Cell Death 634.1 A Cell’s Journey through Life 644.2 Cellular Aging and Senescence 644.2.1 Replicative Senescence 654.2.2 Shortening of Chromosomal Telomeres during Replication 674.2.3 Chromosomal Telomeres 674.2.4 Telomerase 694.2.5 Animal Models 724.2.6 Overcoming Replicative Senescence in Tumor Cells 724.2.7 Nonreplicative Senescence 734.3 Cell Death 744.4 Morphologies of Dying Cells 754.4.1 Morphology of Necrotic Cells 754.4.2 Morphologies of Apoptotic and Necroptotic Cells 754.4.3 Morphology of Autophagy 764.5 Necroptosis 764.6 Apoptosis in the Healthy Organism 794.6.1 The Four Phases of Apoptosis 804.6.2 Extrinsic Initiation 814.6.2.1 TNF Pathway 814.6.2.2 TNF Receptor Downstream Signaling 824.6.2.3 Caspases 824.6.3 Intrinsic Initiation 834.6.4 Execution Phase 844.6.5 Phagocytosis and Degradation 854.7 Apoptosis of Tumor Cells 854.8 Autophagy 864.8.1 Autophagy in Tumor Development 874.8.2 Regulation of Autophagy 894.9 Cell Death and Cell Aging as Therapeutic Targets in Cancer Treatment 894.9.1 Induction of Apoptosis by Radiation 894.9.2 Induction of Apoptosis by Conventional Anticancer Drugs 904.9.3 Innovative Drugs Targeting Aging and Death Pathways 924.9.3.1 Targeting TRAIL (TNF-Related Apoptosis-Inducing Ligand) 924.9.3.2 Targeting Bcl-2 924.9.3.3 Simulating the Effects of cIAP Inhibitors 924.9.3.4 Targeting Autophagy Pathways 934.10 Senescence in Anticancer Therapy 934.11 Outlook 945 Growth Factors and Receptor Tyrosine Kinases 975.1 Growth Factors 985.2 Protein Kinases 985.2.1 Receptor Protein Tyrosine Kinases 1005.2.2 Receptor Protein Tyrosine Kinase Activation 1025.2.3 The Family of EGF Receptors 1035.2.4 The Family of PDGF Receptors 1045.2.5 The Insulin Receptor Family and its Ligands 1075.2.5.1 Prostate-Specific Antigen 1075.2.6 Signaling from Receptor Protein Tyrosine Kinases 1085.2.7 Association of PDGF and EGF Receptors with Cytoplasmic Proteins 1095.2.7.1 Signaling from PDGF and EGF Receptors 1125.2.8 Constitutive Activation of RTKs in Tumor Cells 1135.3 Therapy of Tumors with Dysregulated Growth Factors and their Receptors 1155.3.1 Targeting Growth Factors 1155.3.2 Targeting EGF Receptors by Antibodies 1165.3.3 Targeting EGF Receptors by Kinase Inhibitors 1175.4 Outlook 1176 The Philadelphia Chromosome and BCR-ABL1 1196.1 Analysis of Chromosomes 1206.2 Aberrant Chromosomes in Tumor Cells 1216.3 The Philadelphia Chromosome 1226.3.1 Molecular Diagnosis of the BCR-ABL1 Fusion Gene 1256.4 The BCR-ABL1 Kinase Protein 1256.4.1 Structural Aspects of BCR-ABL1 Kinase 1266.4.2 Substrates and Effects of BCR-ABL1 Kinase 1286.4.3 The BCR-ABL1 Kinase Inhibitor Imatinib 1296.4.4 Imatinib in Treatment of Tumors Other than CML 1306.4.5 Mechanism of Imatinib Action 1306.4.6 Resistance against Imatinib 1306.4.7 BCR-ABL1 Kinase Inhibitors of the Second and the Third Generation 1316.4.8 Allosteric Inhibitors of BCR-ABL1 1326.5 Outlook 1337 MAPK Signaling 1357.1 The RAS Gene 1367.2 The Ras Protein 1367.2.1 The Ras Protein as a Molecular Switch 1387.2.2 The GTPase Reaction inWild-Type and Mutant Ras Proteins 1397.3 Neurofibromin: The Second RasGAP 1437.4 Downstream Signaling of Ras 1447.4.1 The BRaf Protein 1457.4.2 The BRAF Gene 1477.4.3 The MAPK Signaling Pathway 1477.4.4 Mutations in Genes of the MAPK Pathway 1487.5 Therapy of Tumors with Constitutively Active MAPK Pathway 1497.5.1 Ras as aTherapeutic Target 1507.5.1.1 Inhibiting Posttranslational Modification and Membrane Anchoring of Ras 1507.5.1.2 Direct Targeting Mutant Ras 1527.5.1.3 Preventing Ras/Raf Interaction 1527.5.2 BRaf Inhibitors 1527.5.2.1 Consequences of BRaf Inhibition by Vemurafenib 1547.5.2.2 Resistance against BRaf Inhibitors Based on BRaf Dependent Mechanisms 1547.5.2.3 Resistance against BRaf Inhibitors Based on BRaf Independent Mechanisms 1557.5.2.4 Treatment of Vemurafenib-Resistant Tumors 1557.6 Outlook 1568 PI3K-AKT-mTOR Signaling 1598.1 Discovery of the PI3K-AKT-mTOR Pathway 1608.2 Phosphatidylinositol-3-Kinase (PI3K) 1618.3 Inositol Trisphosphate, Diacylglycerol, and Protein Kinase C (PKC) 1638.3.1 Protein Kinase C (PKC) 1638.3.2 Activation and Functions of PKC 1658.4 AKT (Protein Kinase B) 1658.5 mTOR 1688.5.1 mTORC1: Inputs 1708.5.2 mTORC2: Inputs 1718.5.3 mTORC1: Outputs 1718.5.4 mTORC2: Outputs 1728.5.5 Feedback Controls 1728.6 PTEN 1728.7 Activation of the PI3K/AKT/mTOR Pathway in Cancer 1738.7.1 Sporadic Carcinomas 1738.7.2 Hamartoma Syndromes 1748.8 PKC in Cancer 1758.9 Therapy 1768.10 Outlook 1789 Hypoxia-Inducible Factor (HIF) 1839.1 Responses of HIF to Hypoxia and Oncogenic Pathways 1849.2 HIF Functional Domains 1859.3 Regulation of HIF 1869.3.1 Regulation of HIF under Normoxic Conditions 1869.3.2 Regulation of HIF under Hypoxic Conditions 1899.3.3 Oxygen-Independent Regulation of HIF 1899.3.4 Context-Dependence of HIF Regulation 1909.4 Regulation of HIF in Malignant Disease 1919.4.1 Expression of HIF in Human Tumors 1919.4.2 von Hippel–Lindau Disease 1919.5 HIF Targets in Cancer 1929.5.1 Target Genes of HIF1α and HIF2α 1929.5.2 HIF Target Genes Affecting Tumor Growth 1939.5.3 HIF Target Genes Affecting Metabolism 1959.5.3.1 Glucose Uptake and Metabolism 1959.5.3.2 HIF1α and theWarburg Effect 1979.5.3.3 The Warburg Paradox 1979.6 TCA Cycle Intermediates and Tumor Syndromes 2009.7 Drugs Targeting HIFs 2009.8 Outlook 20210 NF-κB Pathways 20510.1 NF-κB Signaling in Inflammation, Growth Control, and Cancer 20610.2 The Core of NF-κB Signaling 20710.3 Family of IκB Proteins 20910.4 Canonical NF-κB Signaling from TNF Receptor 1 21010.5 B-Cell Receptor Signaling 21310.6 Other Receptors Activating the Canonical Pathway 21410.7 Alternative NF-κB Pathway 21410.8 Terminating the NF-κB Response 21510.9 Ubiquitinylation in NF-κB Signaling 21710.10 Transcriptional Regulation 21910.11 Physiological Role of NF-κB Transcription Factors 22110.12 Mutational Activation of NF-κB Pathways in Malignant Disease 22210.12.1 B-Cell Lymphomas 22210.12.2 Multiple Myeloma 22310.12.3 Activation of NF-κB Pathways by Polycomb-Mediated Loss of microRNA-31 in Adult T-Cell Leukemia/Lymphoma 22510.12.4 Carcinomas 22710.13 Cross Talk between Mutant KRas and NF-κB 22710.14 Inflammation, NF-κB, and Cancer 22810.15 Activation of Osteoclasts in Multiple Myeloma and Breast Cancer Metastases 23010.16 Targeting NF-κB Pathways 23210.16.1 B-Cell Malignancies 23210.16.2 Carcinomas 23310.16.3 Anti-Inflammatory Drugs 23310.17 Outlook 23311 Wnt Signaling 23711.1 The History of Wnt 23811.2 The Canonical Wnt Pathway 23811.2.1 The Nonactivated Wnt Pathway 23911.2.2 The Physiologically Activated Wnt Pathway 24111.2.3 The Nonphysiologically Activated Wnt Pathway in the Absence of the Wnt Signal 24211.3 TheWnt Network 24311.4 Proteins of the Wnt Pathway with Diverse Functions 24311.4.1 APC (Adenomatous Polyposis Coli Protein) 24311.4.2 β-Catenin 24511.4.3 Axin 24511.5 The Wnt Targetome 24611.5.1 The Three Levels of the Wnt Targetome 24711.5.2 Biological Effects of Wnt Target Genes 24811.6 The Wnt Pathway as Therapeutic Target 25011.6.1 Strategies to Identify Anti-Wnt Drugs 25011.6.2 Molecules Interfering with the Wnt Pathway 25311.7 Outlook 25412 Notch Signaling 25712.1 Introduction 25812.2 Determination of Cell Fate Decisions 25812.3 Notch Proteins and Notch Ligands 25912.4 Notch Signaling 26112.4.1 The Notch Signaling Pathway 26112.4.2 Regulation of Notch Signaling by Posttranslational Modification 26412.4.2.1 Ubiquitinylation 26412.4.2.2 Glycosylation of Notch 26512.5 Notch Signaling in Malignant Disease 26612.5.1 Acute T-Cell Leukemia (T-ALL) 26612.5.2 Chronic Lymphocytic Leukemia 26812.5.3 Chronic Myelomonocytic Leukemia (CMML) 26912.5.4 Breast Cancer 26912.5.5 Cholangiocellular Carcinoma (CCC) 27012.5.6 Squamous Cell Carcinomas (SCCs) 27112.5.7 Small-Cell Lung Cancer (SCLC) 27212.5.8 Angiogenesis 27212.6 Drugs Targeting the Notch Pathway 27312.7 Outlook 27513 Hedgehog Signaling 27713.1 Overview of Hedgehog Signaling 27813.2 Hedgehog Ligands 27913.3 The Primary Cilium 28013.4 Patched (Ptch) and Smoothened (Smo) 28313.5 Gli Transcription Factors 28313.6 Signaling in the Absence of Hedgehog 28413.7 Signaling after Binding of Hedgehog to Patched 28413.8 Activation of the Canonical Hedgehog Pathway in Basal Cell Carcinoma and Medulloblastoma 28513.9 Noncanonical Activation of Hedgehog-Responsive Genes 28813.9.1 KRas 28813.9.2 Atypical Protein Kinase-Lambda/Iota (aPKCι) 28813.9.3 PI3-Kinase-AKT (PI3K-AKT) 28913.9.4 mTOR 29013.10 Paracrine Activation of Hedgehog Signaling 29113.11 Pharmacological Inhibition of the Hedgehog Pathway 29213.11.1 Inhibition of Hh Binding to Ptch 29313.11.2 Inhibitors of Smoothened 29313.11.3 Inhibition of Cilial Trafficking 29413.11.4 Inhibition of Gli 29413.11.5 Resistance against Direct Inhibitors of Smoothened 29513.12 Outlook 29614 TGFβ Signaling 29914.1 The TGFβ Superfamily 30014.2 Structure and Processing of TGFβ Superfamily Members 30114.3 The TGFβ Signaling Pathway 30214.4 Transcriptional Regulation by TGFβ Superfamily Members 30514.5 Regulation of Stem Cells by TGFβ Superfamily Members 30714.6 TGFβ Superfamily Members as Tumor Suppressors in Human Cancer 30914.7 Active role of TGFβ in Tumor Progression 31014.8 Drugs Interfering with TGFβ Signaling 31214.9 TGF β Superfamily Members in Tumor Cachexia 31314.10 Outlook 315Nomenclature 316Index 319