Stem Cells and Cancer (eBook)

Contents 5
Contributors 7
Introduction to Stem Cells and Cancer 10
References 13
Stem Cells and Cancer: An Introduction 14
1 Stem Cell Origin of Cancer 15
1.1 Cancer Is a Problem of Developmental Biology 15
1.1.1 Normal Tissue Renewal and Cancer 17
1.1.2 Skin Cell Renewal 17
1.1.3 Skin Cancer 17
1.1.4 Malignant Cells May Become Benign 19
1.1.5 Comparison of Normal Tissue Renewal to Growth of Cancers 19
1.1.6 Normal Tissue Contains Stem Cells with Malignant Potential 20
1.2 Theories of the Cellular Origin of Cancer 20
1.2.1 Embryonal Rest Theory of Cancer 20
1.2.2 De-differentiation Theory of Cancer 21
1.3 Teratocarcinoma, Stem Cells, and Cancer 22
1.3.1 Teratocarcinomas Contain Pluripotent Stem Cells 22
1.3.2 Teratocarcinomas Arise from Stem Cells 23
1.3.3 What Have We Learned from Teratocarcinomas? 23
1.4 Chemical Hepatocarcinogenesis and the Stem Cell Origin of Cancer 24
1.4.1 Oval Cells 24
1.4.2 Cellular Changes in the Liver Preceding Development of Liver Cancer 25
1.5 Skin Cancers Arise in Self-Renewing Stem Cells (Initiation and Promotion) 25
2 Cancer Stem Cells 26
2.1 Properties of Cancer Stem Cells 26
2.1.1 Transplantability 27
2.1.2 Growth In Vitro 27
2.1.3 Resistance to Therapy 27
2.2 Isolation of Cancer Stem Cells? 28
2.2.1 Breast Cancer 28
2.2.2 Liver Cancer 29
2.2.3 Cancer Stem Cell Isolation and Transplantability 29
2.3 Cancer Stem Cells or Resting Cancer Cells 29
2.4 Differentiation Therapy 30
2.4.1 Leukemia 31
The Leukemic Stem Cell 31
Maturation Arrest Is the Critical Lesion in Leukemia 32
Leukemic Stem Cells and Response to Therapy 33
Differentiation Therapy for Leukemia 33
Chronic Myeloid Leukemia 33
Acute Promyelocytic Leukemia 34
Acute Myeloid Leukemia 34
Leukemic Stem Cells and Differentiation Therapy 34
Lessons Learned from Leukemia 35
3 Cancer Stem Cell-Directed Therapy 35
3.1 Normal and Cancer Stem Cell Signals 36
3.2 Cancer Stem Cell Inhibition 36
3.3 Inhibitory RNA 36
3.4 Molecular Inhibitors 37
4 Conclusions 38
References 39
Molecular Regulation of the State of Embryonic Stem Cells 45
1 Introduction 45
2 Extrinsic Factors 47
3 ‘‘Core’’ Transcription Factors 51
4 Pluripotency Genomics and Proteomics 54
5 Extended Transcriptional Network: ChIP-ChIP 56
6 Epigenetics in ESCs 60
7 State of ESCs 62
References 62
MicroRNAs in Stem Cells and Cancer Stem Cells 73
1 Biogenesis of miRNAs 74
1.1 The miRNA-Protein Complex 76
2 Mechanisms of miRNA Function 77
2.1 Translational Repression 77
2.1.1 Pre-initiation Repression of Translation 77
2.1.2 Post-initiation Repression of Translation 78
2.2 Destabilization of mRNA (mRNA Deadenylation and Decay) 78
2.3 Sequestration of mRNA into Sub-cellular Locations 78
3 Stem Cells and miRNA 79
3.1 Embryonic Stem Cells and miRNA 79
4 The Role of miRNAs in Gene Expression 82
5 MicroRNAs and Cancer 83
5.1 miRNA-Mediated Mechanisms in Cancer 85
5.1.1 Epigenetics and miRNAs 85
5.1.2 miRNAs in Cancer-Associated Genomic Regions (CAGRs) 85
5.1.3 miRNA Processing 86
5.2 Specific miRNAs in Cancer 86
5.2.1 Loss of miRNA Function and Cancer 87
5.2.2 Gain of miRNA Function and Cancer 88
5.2.3 Gain or Loss of miRNA Function and Cancer 88
6 Cancer Stem Cells and miRNA 89
7 Potential Therapeutic Targets 90
8 Conclusions 91
References 92
Cancer Stem Cells and Metastasis: Emerging Themes and Therapeutic Implications 102
1 Introduction 103
2 Acquisition of Metastatic Character During Tumor Development 103
3 Tumor Subpopulations, Metastatic Origin, and pCSCs 105
4 Cancer Stem Cells and the Metastatic Cascade 109
5 The Pre-metastatic Microenvironment and mCSCs 110
6 mCSCs: Novel Opportunities for Therapeutic Intervention 113
6.1 Targeting the (Pre-)metastasis Niche 115
6.2 Transition of Quiescence (Micrometastasis) to Proliferation (Macrometastasis) 116
6.3 Targeting CSC Surface Markers 116
7 Conclusion 117
References 117
Stem Cells in Leukemia and Other Hematological Malignancies 121
1 Hematopoietic Stem Cells and Normal Hematopoiesis 122
1.1 Early Evidence for the Existence of HSCs 123
1.2 Techniques for Studying Stem Cells in the Hematopoietic System 124
2 Leukemia Stem Cells 126
2.1 Myeloid Leukemias 126
2.2 Acute Lymphoblastic Leukemia 129
2.3 Candidate LSCs in Chronic Lymphoproliferative Disorders 129
3 Committed Progenitor Cells as Candidate LSCs 130
4 Targeting Self-Renewal in LSC: Potential Therapeutic Strategies 131
4.1 Wnt Signaling in Leukemia 131
4.2 The Hedgehog Pathway in Leukemia 132
4.3 The Notch Pathway in Leukemia 133
4.4 NF-kappaB in Leukemia 133
4.5 The HOX Gene Family in Leukemia 133
4.6 The Polycomb Gene BMI-1 in Leukemia 134
4.7 The Role of PTEN in Leukemia 134
4.8 Telomerase in Leukemia 135
5 The Importance of Developing Targeted Stem Cell Therapies in Leukemia: The CML Story 135
5.1 BCR-ABL Tyrosine Kinase Inhibitors in CML 136
5.2 CML Stem Cell Modeling 136
6 Future Challenges in Targeting LSCs 138
References 139
Prostate Cancer Stem Cells 147
1 Introduction 148
1.1 Prostate Cancer and Treatment 148
1.2 The Prostate Gland Architecture and Morphogenesis 149
1.3 The Cancer Stem Cell 151
1.4 Properties of Normal Stem Cells vs. Cancer Stem Cells 152
2 The Cell of Origin of Normal and Cancerous Prostatic Stem Cells 153
3 Identification and Isolation of Cancer Stem Cells 154
3.1 Side Populations as a Means of Stem Cell Enrichment 155
3.2 Enrichment of Prostatic CSCs by Culturing Non-adherent Spheres 156
3.3 Identification of Prostatic Cancer Stem Cells Through Surface Markers 157
3.3.1 Normal Prostate Stem Cell Markers 157
3.3.2 Prostate Cancer Stem Cell Markers 158
4 Signaling Pathways Important in Prostate CSCs 159
4.1 Wnt/beta-Catenin Pathway 159
4.2 Hedgehog Signaling 161
4.3 Notch Signaling 162
4.4 Nanog, Oct3/4, and Sox2 Transcriptional Network 163
5 Targeting of CSCs 164
5.1 Targeting ABC Transporters 164
5.2 Targeting the Sonic Hedgehog Pathway 165
5.3 Targeting the Notch Pathway 165
5.4 Targeting the Niche of Stem Cells 165
5.5 Targeting Stem Cell Differentiation 166
6 Future Directions 166
7 List of Abbreviations 167
References 168
Breast Cancer Stem Cells 176
1 Introduction 177
2 Breast Anatomy 178
3 Breast Embryology 179
4 Cancer as a Microcosm of Embryogenesis 180
4.1 Soil and Seed 180
4.2 Metastasis 181
4.3 Elimination, Equilibrium, and Escape 182
5 Central Importance of the Stroma 183
6 Breast Cancer Stem Cells 183
7 Multistep Carcinogenesis and DNA Repair 184
8 The Origins of the Tumor-Initiating Cell 185
9 Activation of Stem Cells and Cancer 186
10 Tumor Suppressor Genes and Cancer-Initiating Cells 187
11 Stem Cell Activation and Specific Cancers 188
12 SP Cells in Tumors and Cell Lines 189
13 Major Cancers and Risk Factors 190
13.1 Cancer Therapy ‘‘Causes’’ Cancers 191
14 How the Stem Cell Paradigm Suggests New Approaches 191
15 Future Research 193
16 Conclusions 193
References 194
Stem Cells and Lung Cancer 202
1 Introduction 203
2 Embryological Signaling Pathways in Lung Cancer 204
2.1 The Wnt Signaling Pathway in Lung Cancer 205
2.1.1 The Canonical Wnt Pathway 205
2.1.2 The Non-canonical Wnt Pathway 207
2.1.3 Wnt Ligands 208
2.1.4 Wnt Receptors and Antagonists 208
2.2 The Hedgehog Signaling Pathway in Lung Cancer 208
2.3 The Notch Signaling Pathway in Lung Cancer 210
2.4 The Importance of Communication Between Developmental Pathways 211
3 The Stem Cell Niche 213
3.1 Niche Infrastructure: The Extracellular Matrix 213
3.2 Paracrine Signals Within the Niche 214
3.3 The Concept of Stem Cells and Cancer Stem Cells 215
3.3.1 Pulmonary Stem Cell Niches 217
3.3.2 Identification of Pulmonary Cancer Stem Cells 218
Cell Surface Markers 219
CD117 (c-Kit) 219
CD44 220
CD133 (Prominin-1) 220
Miscellaneous Markers 220
4 Conclusions 221
References 222
Cancer Stem Cells in Colorectal Cancer 232
1 Introduction 233
2 Normal Colon Stem Cells 234
2.1 Identification of Colonic Stem Cells 234
2.2 Morphogenetic Pathways Regulate Colonic Epithelial Cell Fate 235
2.2.1 Wnt Signaling 235
2.2.2 Notch Signaling 236
2.2.3 TGFbeta Family Signaling 237
2.2.4 Hedgehog Signaling 238
2.3 Clonal Stem Cell Expansion in Colonic Epithelial Damage and Repair 238
3 Colorectal Carcinogenesis and Origin of the Colon-Cancer Stem Cell 239
3.1 Clonal Stem or Precursor Cell Expansion Initiates Adenoma Formation 240
3.2 Identification of Initiators of Clonal Growth 240
3.2.1 APC Mutations and Adenoma Initiation 241
3.2.2 BMP and Receptor Tyrosine Kinase Signaling and Hamartoma Initiation 241
3.3 Adenoma to Carcinoma Transition 242
4 Identification of Colon-Cancer Stem Cells 243
4.1 Colon-Cancer Stem Cells: Definition and Methods 243
4.2 Colon-Cancer Stem Cell Markers 244
4.3 In Vivo Differentiation 246
4.4 Caveats 247
5 In Vitro Expansion of Colon-Cancer Stem Cells 248
6 Origin of the Colon-Cancer Stem Cell 250
7 Cancer Stem Cells in Metastasis 251
8 Consequences of the Cancer Stem Cell Model for Therapy 252
8.1 Minimal Residual Disease 253
8.2 Chemoresistance of Colon-Cancer Stem Cells 253
8.3 Development of New Therapies 253
9 Synthesis 254
References 255
Cancer Stem Cells and Skin Cancer 260
1 Introduction 260
1.1 Stem Cells in the Skin 261
2 Cancer Stem Cells and Stemness Signature in the Skin 266
3 Pharmacological Perspectives 268
References 271
Lineage Relationships Connecting Germinal Regions to Brain Tumors 277
1 Development of Rodent Ventricular and Subventricular Zones 278
2 Unique Organization of the Human Subventricular Zone 279
3 Glial Progenitors in the Subcortical White Matter 280
4 Emergence of the Cancer Stem Cell Hypothesis 280
5 Susceptibility of Stem and Progenitor Cells to Transformation 281
6 Shared Immature Expression Profiles Among Brain Tumors and Stem Cell Niches 282
6.1 Cytoskeletal Proteins 282
6.2 Tumor Suppressor Genes 283
6.3 Growth Factors 284
6.4 Vascular Niches 285
6.5 Transcription Factors 285
7 Transit-Amplifying Type C Cells as a Glioma Cell-of-Origin 286
8 Implications for Brain Tumor Therapy 288
9 Conclusions 289
References 289
Index 295