Kahn Targeting the Wnt Pathway in Cancer

1. Auflage 2011
ISBN: 978-1-4419-8023-6
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 240 Seiten

Inappropriate activation of the Wnt signaling pathway is observed in many human cancers and is sufficient to drive tumor initiation and progression in numerous contexts. Multiple mechanisms, such as overexpression of Wnt ligands, inactivation of the APC and Axin tumor suppressors, and mutation of -catenin, are responsible for pathway activation in tumor cells. The development of potent Wnt pathway antagonists for therapeutic use has been a major effort for investigators in both academia and industry in recent years. This book will provide an overview of the Wnt pathway as a therapeutic target for cancer, and discuss the preclinical development of inhibitors specifically directed to upstream and downstream components of the pathway.

Autoren/Hrsg.

Kahn, Michael

Inhaltsverzeichnis

1;Targeting the WntPathway in Cancer;3
1.1;Preface;5
1.2;Contents;7
1.3;Contributors;9
1.4;Chapter 1: An Introduction to Wnt Signaling;13
1.4.1;1.1 The War on Wnt;13
1.4.2;1.2 Wnt Signaling Regulates Genes;14
1.4.3;1.3 Wnt Signaling Causes Human Cancer;15
1.4.4;1.4 Downregulation of Wnt Signaling;19
1.4.5;1.5 Interactions at the Cell Surface;21
1.4.6;1.6 Interactions in the Nucleus;22
1.4.7;1.7 Wnt and Stem Cells;23
1.4.8;1.8 Structural Biology;23
1.4.9;1.9 Conclusion;24
1.4.10;References;24
1.5;Chapter 2: Regulation of Wnt Secretion and Distribution;31
1.5.1;2.1 Introduction;32
1.5.2;2.2 Wnts Are Posttranslationally Modified in the ER;32
1.5.3;2.3 Wls and the Retromer Complex Are Involved in the Intracellular Trafficking of Wnts;34
1.5.4;2.4 Wnts Associate with Lipoproteins in the Dedicated Secretory Route;36
1.5.5;2.5 HSPGs Regulate Extracellular Diffusion and Gradient Formation of Wnts;38
1.5.6;2.6 Concluding Remarks;40
1.5.7;References;41
1.6;Chapter 3: Wnt Signaling in Stem Cells;46
1.6.1;3.1 Introduction;47
1.6.1.1;3.1.1 Stem Cells;47
1.6.1.2;3.1.2 Human Embryonic Stem Cells;48
1.6.1.3;3.1.3 Induced Pluripotent Stem Cells (iPSCs);48
1.6.1.4;3.1.4 Somatic Stem Cells;49
1.6.1.5;3.1.5 Cancer Stem Cells;50
1.6.1.6;3.1.6 Wnt Signaling;51
1.6.1.7;3.1.7 Wnt Signaling in Stem Cells;51
1.6.1.8;3.1.8 Wnt Signaling in Cancer Stem Cells;53
1.6.1.9;3.1.9 Concluding Thoughts;57
1.6.2;References;59
1.7;Chapter 4: Crosstalk of the Wnt Signaling Pathway;62
1.7.1;4.1 Growth Factor Signaling;62
1.7.1.1;4.1.1 EGF;64
1.7.1.2;4.1.2 HGF;66
1.7.1.3;4.1.3 TGFb;67
1.7.1.4;4.1.4 IGF;69
1.7.1.5;4.1.5 VEGF;70
1.7.1.6;4.1.6 FGF;70
1.7.2;4.2 Developmental Pathways;71
1.7.2.1;4.2.1 Notch Pathway;71
1.7.2.2;4.2.2 Hedgehog Pathway;73
1.7.3;4.3 Wnt and Other Networks;74
1.7.3.1;4.3.1 Prostaglandin/Cox-2 Pathway;74
1.7.3.2;4.3.2 PI3K/AKT Pathway;76
1.7.3.3;4.3.3 mTOR;77
1.7.3.4;4.3.4 Ras Pathway;79
1.7.3.5;4.3.5 Miscellaneous Signaling Pathways;80
1.7.4;4.4 Conclusion;80
1.7.5;References;81
1.8;Chapter 5: Dysregulation of the Wnt Pathway in Solid Tumors;92
1.8.1;5.1 Introduction;93
1.8.2;5.2 Colorectal Cancer;97
1.8.2.1;5.2.1 Upregulation of Pathway Activators;97
1.8.2.2;5.2.2 Loss of Pathway Inhibitors;97
1.8.3;5.3 Breast Cancer;98
1.8.3.1;5.3.1 Upregulation of Pathway Activators;98
1.8.3.2;5.3.2 Loss of Pathway Inhibitors;99
1.8.4;5.4 Lung Cancer;100
1.8.4.1;5.4.1 Upregulation of Pathway Activators;100
1.8.4.2;5.4.2 Loss of Pathway Inhibitors;101
1.8.4.3;5.4.3 Mesothelioma;101
1.8.5;5.5 Gastric Cancer;102
1.8.5.1;5.5.1 Upregulation of Pathway Activators;102
1.8.5.2;5.5.2 Loss of Pathway Inhibitors;102
1.8.6;5.6 Head and Neck Cancer;103
1.8.6.1;5.6.1 Upregulation of Pathway Activators;103
1.8.6.2;5.6.2 Loss of Pathway Inhibitors;103
1.8.7;5.7 Prostate Cancer;104
1.8.7.1;5.7.1 Upregulation of Pathway Activators;104
1.8.7.2;5.7.2 Loss of Pathway Inhibitors;104
1.8.8;5.8 Pancreatic Cancer;105
1.8.8.1;5.8.1 Upregulation of Pathway Activators;105
1.8.8.2;5.8.2 Loss of Pathway Inhibitors;105
1.8.9;5.9 Hepatocellular Carcinoma and Hepatoblastoma;106
1.8.9.1;5.9.1 Upregulation of Pathway Activators;106
1.8.9.2;5.9.2 Loss of Pathway Inhibitors;106
1.8.10;5.10 Kidney Cancer;107
1.8.10.1;5.10.1 Upregulation of Pathway Activators;107
1.8.10.2;5.10.2 Loss of Pathway Inhibitors;107
1.8.11;5.11 Bladder Cancer;107
1.8.11.1;5.11.1 Upregulation of Pathway Activators;107
1.8.11.2;5.11.2 Loss of Pathway Inhibitors;108
1.8.12;5.12 Skin Cancer;108
1.8.12.1;5.12.1 Upregulation of Pathway Activators;108
1.8.12.2;5.12.2 Loss of Pathway Inhibitors;109
1.8.13;5.13 Tumors of the Central Nervous System (CNS);109
1.8.13.1;5.13.1 Gliomas;109
1.8.13.2;5.13.2 Medulloblastomas;110
1.8.13.3;5.13.3 Other CNS Tumors;110
1.8.14;5.14 Musculoskeletal Tumors;111
1.8.14.1;5.14.1 Osteosarcoma;111
1.8.14.2;5.14.2 Ewing’s Sarcoma;111
1.8.14.3;5.14.3 Soft Tissue Tumors;111
1.8.15;5.15 Gynecological Cancers;112
1.8.15.1;5.15.1 Ovarian Cancer;112
1.8.15.2;5.15.2 Endometrial Cancer;113
1.8.15.3;5.15.3 Cervical Cancer;113
1.8.16;5.16 Other Tumors;113
1.8.16.1;5.16.1 Esophageal Cancer;113
1.8.16.2;5.16.2 Adrenal Tumors;114
1.8.16.3;5.16.3 Thyroid and Parathyroid Tumors;114
1.8.16.4;5.16.4 Pituitary Tumors;115
1.8.17;5.17 Conclusion;115
1.8.18;References;117
1.9;Chapter 6: WNT/b-Catenin Signaling in Leukemia;140
1.9.1;6.1 WNT/b-Catenin Signaling in Normal Hematopoietic Stem Cells;141
1.9.2;6.2 WNT/b-Catenin Signaling in Lymphopoiesis;142
1.9.3;6.3 WNT Signaling in B-Cell Lineage Acute Lymphoblastic Leukemia;142
1.9.4;6.4 Negative Regulation of WNT/b-Catenin Signaling Through BTK;144
1.9.5;6.5 WNT/b-Catenin Signaling Promotes Leukemogenesis in the T-Cell Lineage;144
1.9.6;6.6 WNT/b-Catenin Signaling is Required for Leukemia-Initiation in Acute Myeloid Leukemia;145
1.9.7;6.7 Role of Prostaglandin E/b-Catenin Signaling in Leukemia Stem Cell Maintenance in AML;146
1.9.8;6.8 WNT Signaling in Chronic Myeloid Leukemia;147
1.9.9;6.9 Perspective;148
1.9.10;References;149
1.10;Chapter 7: Use of Genetically Engineered Mouse Models in Identification and Validation of Therapeutic Targets for Colon Cancer;154
1.10.1;7.1 Introduction;154
1.10.2;7.2 Genetically Engineered Mouse Models for Colonic Adenomas;155
1.10.3;7.3 Therapeutic Targets Identified by Pharmacological Experiments Using Apc Mutant Mice;156
1.10.3.1;7.3.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs);156
1.10.3.2;7.3.2 Compounds that Target the Wnt Signaling;156
1.10.3.2.1;7.3.2.1 ICG-001: CBP/b-Catenin;156
1.10.3.2.2;7.3.2.2 NSAIDs and Other Reagents;161
1.10.3.3;7.3.3 Compounds that Target Other Signaling Pathways;161
1.10.3.3.1;7.3.3.1 RAD001: mTORC1;161
1.10.3.3.2;7.3.3.2 Other Compounds and Their Target Molecules;162
1.10.4;7.4 Putative Therapeutic Targets Proposed by Genetic Experiments Using Apc Mutant Mice;163
1.10.5;7.5 Wnt Signaling Molecules and Its Modifiers;164
1.10.5.1;7.5.1 APC-Stimulated Guanine Nucleotide Exchange Factor (Asef)/Asef2;164
1.10.5.2;7.5.2 Smoothened;164
1.10.5.3;7.5.3 Sirtuin (Silent Mating Type Information Regulation 2 Homolog) 1 (SIRT1);164
1.10.5.4;7.5.4 Krüppel-Like Factor 5 (KLF5);165
1.10.6;7.6 Wnt Targets;165
1.10.6.1;7.6.1 c-Myc, Prox1, Tiam1 CD44, and Mdr1;165
1.10.7;7.7 Epigenetic Regulators;165
1.10.7.1;7.7.1 DNA-Methyl Transferase 3b (Dnmt3b) and Dnmt1;165
1.10.7.2;7.7.2 Methyl-CpG Binding Protein 2 (Mbd2), Kaiso, and Histone Deacetylase 2 (HDAC2);166
1.10.8;7.8 Inflammation;166
1.10.8.1;7.8.1 Cyclooxygenase 2 (COX-2), COX-1, Prostaglandin E2 Receptors (EP2), Cytoplasmic Phospholipase A2 (cPLA2), and Membrane-Bound Prostaglandin E Synthetase 1 (mPGES-1);166
1.10.8.2;7.8.2 Apolipoprotein B mRNA Editing Enzyme, CatalyticPolypeptide 1 (Apobec1), Myeloid DifferentiationPrimary Response Gene 88 (MyD88), Interleukin 6 (IL-6),and Inducible Nitric Oxide Synthase (iNos);167
1.10.9;7.9 Other Signals;167
1.10.9.1;7.9.1 c-Jun, Jagged1, Epidermal Growth Factor Receptor(EGFR), Insulin Receptor Substrate 1 (IRS-1), ProteinKinase C l (PKCl), Eph Receptor A2 (EphA2), and Wip1/PPM1D (Protein Phosphatase 1D Magnesium-Dependent);167
1.10.10;7.10 Environment;168
1.10.10.1;7.10.1 Matrix Metalloproteinase 7 (MMP7), Secreted Protein Acidic, Rich in Cysteine (SPARC), Spermidine/Spermine N1-Acetyltransferase-1 (SSAT) ;168
1.10.11;7.11 Perspectives: Towards Establishing Preclinical Colon Cancer Mouse Models that Develop Metastasis;169
1.10.12;References;169
1.11;Chapter 8: Targeting Wnt Signalling in Cancer;175
1.11.1;8.1 Targeting the Wnt Pathway at the Level of Wnt Ligands;175
1.11.2;8.2 Targeting the Wnt Pathway at the Receptor Level;177
1.11.3;8.3 Targeting b-Catenin Degradation;178
1.11.3.1;8.3.1 Targeting the b-Catenin Turnover Complex;178
1.11.3.2;8.3.2 Alternative Pathways Contributing to b-Catenin Degradation;179
1.11.4;8.4 Targeting Wnt Signalling at the Nuclear Level;180
1.11.4.1;8.4.1 Targeting the b-Catenin/TCF Interaction;181
1.11.4.2;8.4.2 Targeting Transcriptional Co-Activators of the Wnt Pathway;181
1.11.4.3;8.4.3 Targeting Transcriptional Co-Repressors of the Wnt Pathway;182
1.11.5;8.5 Targeting Downstream Wnt Targets;183
1.11.5.1;8.5.1 Targeting the Wnt Pathway in Cancer Stem Cells;185
1.11.6;8.6 Generic Approaches to Targeting Wnt-Mediated Tumourigenesis;186
1.11.6.1;8.6.1 Targeting DNA Methylation;186
1.11.6.2;8.6.2 Targeting Mediators of Histone Modifications;187
1.11.6.3;8.6.3 Non-Steroidal Anti-Inflammatory Drugs;187
1.11.7;8.7 Summary;189
1.11.8;References;189
1.12;Chapter 9: Inhibiting the Wnt Signaling Pathway with Small Molecules;193
1.12.1;9.1 Introduction;194
1.12.2;9.2 Existing Drugs and Natural Compounds;199
1.12.2.1;9.2.1 Effect of Existing Drugs on Wnt Signaling and Anticancer Drug Development;199
1.12.2.1.1;9.2.1.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs);199
1.12.2.1.2;9.2.1.2 Derivatives of NSAIDs;200
1.12.2.1.3;9.2.1.3 Drug Repurposing to Target Wnt Signaling;200
1.12.2.2;9.2.2 Effect of Natural Compounds on Wnt Signaling and Anticancer Drug Development;201
1.12.2.2.1;9.2.2.1 ( 1)-Epigallocatechin-3-Gallate (EGCG);201
1.12.2.2.2;9.2.2.2 Quercetin;202
1.12.2.2.3;9.2.2.3 Resveratrol;202
1.12.2.2.4;9.2.2.4 Curcumin;202
1.12.2.2.5;9.2.2.5 Other Natural Compounds;203
1.12.3;9.3 Targeting Protein–Protein Interactions in Wnt Signaling;203
1.12.3.1;9.3.1 Targeting of b-Catenin Activity;204
1.12.3.1.1;9.3.1.1 Targeting b-Catenin/TCF (LEF) Interaction;204
1.12.3.1.2;9.3.1.2 Targeting of b-Catenin and Its Cofactors;205
1.12.3.2;9.3.2 Targeting of Dishevelled Proteins;206
1.12.4;9.4 Targeting of Enzyme Activity to Inhibit Wnt Signaling in Cancer;208
1.12.4.1;9.4.1 Targeting of Tankyrase;209
1.12.4.2;9.4.2 Targeting of Porcupine;209
1.12.5;9.5 Conclusions and Perspectives;210
1.12.6;References;211
1.13;Chapter 10: Targeting of Wnt Signaling Inside the Nucleus;220
1.13.1;10.1 Constitutive Transactivation of TCF-4 Target Genes is Essential for the Maintenance of Malignant Phenotypes;222
1.13.2;10.2 Targeting of Wnt Signaling;223
1.13.3;10.3 Protein Components of the b-Catenin and TCF-4 Transcriptional Complex;223
1.13.4;10.4 PARP-1;224
1.13.5;10.5 Topo IIa;225
1.13.6;10.6 RanBP2, Ran, RanGAP1, and Ubc9;226
1.13.7;10.7 Traf2- and Nck-Interacting Kinase;230
1.13.8;10.8 Conclusion;230
1.13.9;References;232
1.14;Index;235