Targeting the Wnt Pathway in Cancer (eBook)

Targeting the WntPathway in Cancer 3
Preface 5
Contents 7
Contributors 9
Chapter 1: An Introduction to Wnt Signaling 13
1.1 The War on Wnt 13
1.2 Wnt Signaling Regulates Genes 14
1.3 Wnt Signaling Causes Human Cancer 15
1.4 Downregulation of Wnt Signaling 19
1.5 Interactions at the Cell Surface 21
1.6 Interactions in the Nucleus 22
1.7 Wnt and Stem Cells 23
1.8 Structural Biology 23
1.9 Conclusion 24
References 24
Chapter 2: Regulation of Wnt Secretion and Distribution 31
2.1 Introduction 32
2.2 Wnts Are Posttranslationally Modified in the ER 32
2.3 Wls and the Retromer Complex Are Involved in the Intracellular Trafficking of Wnts 34
2.4 Wnts Associate with Lipoproteins in the Dedicated Secretory Route 36
2.5 HSPGs Regulate Extracellular Diffusion and Gradient Formation of Wnts 38
2.6 Concluding Remarks 40
References 41
Chapter 3: Wnt Signaling in Stem Cells 46
3.1 Introduction 47
3.1.1 Stem Cells 47
3.1.2 Human Embryonic Stem Cells 48
3.1.3 Induced Pluripotent Stem Cells (iPSCs) 48
3.1.4 Somatic Stem Cells 49
3.1.5 Cancer Stem Cells 50
3.1.6 Wnt Signaling 51
3.1.7 Wnt Signaling in Stem Cells 51
3.1.8 Wnt Signaling in Cancer Stem Cells 53
3.1.9 Concluding Thoughts 57
References 59
Chapter 4: Crosstalk of the Wnt Signaling Pathway 62
4.1 Growth Factor Signaling 62
4.1.1 EGF 64
4.1.2 HGF 66
4.1.3 TGFb 67
4.1.4 IGF 69
4.1.5 VEGF 70
4.1.6 FGF 70
4.2 Developmental Pathways 71
4.2.1 Notch Pathway 71
4.2.2 Hedgehog Pathway 73
4.3 Wnt and Other Networks 74
4.3.1 Prostaglandin/Cox-2 Pathway 74
4.3.2 PI3K/AKT Pathway 76
4.3.3 mTOR 77
4.3.4 Ras Pathway 79
4.3.5 Miscellaneous Signaling Pathways 80
4.4 Conclusion 80
References 81
Chapter 5: Dysregulation of the Wnt Pathway in Solid Tumors 92
5.1 Introduction 93
5.2 Colorectal Cancer 97
5.2.1 Upregulation of Pathway Activators 97
5.2.2 Loss of Pathway Inhibitors 97
5.3 Breast Cancer 98
5.3.1 Upregulation of Pathway Activators 98
5.3.2 Loss of Pathway Inhibitors 99
5.4 Lung Cancer 100
5.4.1 Upregulation of Pathway Activators 100
5.4.2 Loss of Pathway Inhibitors 101
5.4.3 Mesothelioma 101
5.5 Gastric Cancer 102
5.5.1 Upregulation of Pathway Activators 102
5.5.2 Loss of Pathway Inhibitors 102
5.6 Head and Neck Cancer 103
5.6.1 Upregulation of Pathway Activators 103
5.6.2 Loss of Pathway Inhibitors 103
5.7 Prostate Cancer 104
5.7.1 Upregulation of Pathway Activators 104
5.7.2 Loss of Pathway Inhibitors 104
5.8 Pancreatic Cancer 105
5.8.1 Upregulation of Pathway Activators 105
5.8.2 Loss of Pathway Inhibitors 105
5.9 Hepatocellular Carcinoma and Hepatoblastoma 106
5.9.1 Upregulation of Pathway Activators 106
5.9.2 Loss of Pathway Inhibitors 106
5.10 Kidney Cancer 107
5.10.1 Upregulation of Pathway Activators 107
5.10.2 Loss of Pathway Inhibitors 107
5.11 Bladder Cancer 107
5.11.1 Upregulation of Pathway Activators 107
5.11.2 Loss of Pathway Inhibitors 108
5.12 Skin Cancer 108
5.12.1 Upregulation of Pathway Activators 108
5.12.2 Loss of Pathway Inhibitors 109
5.13 Tumors of the Central Nervous System (CNS) 109
5.13.1 Gliomas 109
5.13.2 Medulloblastomas 110
5.13.3 Other CNS Tumors 110
5.14 Musculoskeletal Tumors 111
5.14.1 Osteosarcoma 111
5.14.2 Ewing’s Sarcoma 111
5.14.3 Soft Tissue Tumors 111
5.15 Gynecological Cancers 112
5.15.1 Ovarian Cancer 112
5.15.2 Endometrial Cancer 113
5.15.3 Cervical Cancer 113
5.16 Other Tumors 113
5.16.1 Esophageal Cancer 113
5.16.2 Adrenal Tumors 114
5.16.3 Thyroid and Parathyroid Tumors 114
5.16.4 Pituitary Tumors 115
5.17 Conclusion 115
References 117
Chapter 6: WNT/b-Catenin Signaling in Leukemia 140
6.1 WNT/b-Catenin Signaling in Normal Hematopoietic Stem Cells 141
6.2 WNT/b-Catenin Signaling in Lymphopoiesis 142
6.3 WNT Signaling in B-Cell Lineage Acute Lymphoblastic Leukemia 142
6.4 Negative Regulation of WNT/b-Catenin Signaling Through BTK 144
6.5 WNT/b-Catenin Signaling Promotes Leukemogenesis in the T-Cell Lineage 144
6.6 WNT/b-Catenin Signaling is Required for Leukemia-Initiation in Acute Myeloid Leukemia 145
6.7 Role of Prostaglandin E/b-Catenin Signaling in Leukemia Stem Cell Maintenance in AML 146
6.8 WNT Signaling in Chronic Myeloid Leukemia 147
6.9 Perspective 148
References 149
Chapter 7: Use of Genetically Engineered Mouse Models in Identification and Validation of Therapeutic Targets for Colon Cancer 154
7.1 Introduction 154
7.2 Genetically Engineered Mouse Models for Colonic Adenomas 155
7.3 Therapeutic Targets Identified by Pharmacological Experiments Using Apc Mutant Mice 156
7.3.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 156
7.3.2 Compounds that Target the Wnt Signaling 156
7.3.2.1 ICG-001: CBP/b-Catenin 156
7.3.2.2 NSAIDs and Other Reagents 161
7.3.3 Compounds that Target Other Signaling Pathways 161
7.3.3.1 RAD001: mTORC1 161
7.3.3.2 Other Compounds and Their Target Molecules 162
7.4 Putative Therapeutic Targets Proposed by Genetic Experiments Using Apc Mutant Mice 163
7.5 Wnt Signaling Molecules and Its Modifiers 164
7.5.1 APC-Stimulated Guanine Nucleotide Exchange Factor (Asef)/Asef2 164
7.5.2 Smoothened 164
7.5.3 Sirtuin (Silent Mating Type Information Regulation 2 Homolog) 1 (SIRT1) 164
7.5.4 Krüppel-Like Factor 5 (KLF5) 165
7.6 Wnt Targets 165
7.6.1 c-Myc, Prox1, Tiam1 CD44, and Mdr1 165
7.7 Epigenetic Regulators 165
7.7.1 DNA-Methyl Transferase 3b (Dnmt3b) and Dnmt1 165
7.7.2 Methyl-CpG Binding Protein 2 (Mbd2), Kaiso, and Histone Deacetylase 2 (HDAC2) 166
7.8 Inflammation 166
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
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
7.9 Other Signals 167
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
7.10 Environment 168
7.10.1 Matrix Metalloproteinase 7 (MMP7), Secreted Protein Acidic, Rich in Cysteine (SPARC), Spermidine/Spermine N1-Acetyltransferase-1 (SSAT) 168
7.11 Perspectives: Towards Establishing Preclinical Colon Cancer Mouse Models that Develop Metastasis 169
References 169
Chapter 8: Targeting Wnt Signalling in Cancer 175
8.1 Targeting the Wnt Pathway at the Level of Wnt Ligands 175
8.2 Targeting the Wnt Pathway at the Receptor Level 177
8.3 Targeting b-Catenin Degradation 178
8.3.1 Targeting the b-Catenin Turnover Complex 178
8.3.2 Alternative Pathways Contributing to b-Catenin Degradation 179
8.4 Targeting Wnt Signalling at the Nuclear Level 180
8.4.1 Targeting the b-Catenin/TCF Interaction 181
8.4.2 Targeting Transcriptional Co-Activators of the Wnt Pathway 181
8.4.3 Targeting Transcriptional Co-Repressors of the Wnt Pathway 182
8.5 Targeting Downstream Wnt Targets 183
8.5.1 Targeting the Wnt Pathway in Cancer Stem Cells 185
8.6 Generic Approaches to Targeting Wnt-Mediated Tumourigenesis 186
8.6.1 Targeting DNA Methylation 186
8.6.2 Targeting Mediators of Histone Modifications 187
8.6.3 Non-Steroidal Anti-Inflammatory Drugs 187
8.7 Summary 189
References 189
Chapter 9: Inhibiting the Wnt Signaling Pathway with Small Molecules 193
9.1 Introduction 194
9.2 Existing Drugs and Natural Compounds 199
9.2.1 Effect of Existing Drugs on Wnt Signaling and Anticancer Drug Development 199
9.2.1.1 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 199
9.2.1.2 Derivatives of NSAIDs 200
9.2.1.3 Drug Repurposing to Target Wnt Signaling 200
9.2.2 Effect of Natural Compounds on Wnt Signaling and Anticancer Drug Development 201
9.2.2.1 ( 1)-Epigallocatechin-3-Gallate (EGCG) 201
9.2.2.2 Quercetin 202
9.2.2.3 Resveratrol 202
9.2.2.4 Curcumin 202
9.2.2.5 Other Natural Compounds 203
9.3 Targeting Protein–Protein Interactions in Wnt Signaling 203
9.3.1 Targeting of b-Catenin Activity 204
9.3.1.1 Targeting b-Catenin/TCF (LEF) Interaction 204
9.3.1.2 Targeting of b-Catenin and Its Cofactors 205
9.3.2 Targeting of Dishevelled Proteins 206
9.4 Targeting of Enzyme Activity to Inhibit Wnt Signaling in Cancer 208
9.4.1 Targeting of Tankyrase 209
9.4.2 Targeting of Porcupine 209
9.5 Conclusions and Perspectives 210
References 211
Chapter 10: Targeting of Wnt Signaling Inside the Nucleus 220
10.1 Constitutive Transactivation of TCF-4 Target Genes is Essential for the Maintenance of Malignant Phenotypes 222
10.2 Targeting of Wnt Signaling 223
10.3 Protein Components of the b-Catenin and TCF-4 Transcriptional Complex 223
10.4 PARP-1 224
10.5 Topo IIa 225
10.6 RanBP2, Ran, RanGAP1, and Ubc9 226
10.7 Traf2- and Nck-Interacting Kinase 230
10.8 Conclusion 230
References 232
Index 235