Cancer Stem Cells

Contributors xi

Preface xiii

1 Cancer Stem Cells: Similarities and Variations in the Theme of Normal Stem Cells 1 Sharmila Bapat, Anne Collins, Michael Dean, Kenneth Nephew, and Suraiya Rasheed

1.1 Introduction 1

1.2 Stem Cells in the Life of an Organism 2

1.2.1 Stem Cells in Early Development and Fetal Life 3

1.2.2 Stem Cells in the Adult Organism 4

1.3 Cancer Stem Cells 7

1.3.1 Activation of Stem Cells and Cancer 7

1.3.2 Isolation and Identification of Cancer Stem Cells 10

1.3.3 De Novo Generation of a New Organ (Tumor) by Transformed Stem Cells 12

1.4 Self-Renewal and Differentiation in CSCs 13

1.5 CSC Plasticity as Regulated by Intrinsic and Extrinsic Stem Cell Factors 14

1.5.1 Stem Cell Intrinsic Factors: Genetic and Epigenetic Effects 14

1.5.2 Stem Cell Extrinsic Effects: Niche Effects and Microenvironmental Signaling 16

1.6 Conclusions and Future Perspectives 18

References 20

2 Leukemic Stem Cells 27 Sharmila Bapat

2.1 Introduction 27

2.2 Dysregulation of Hematopoiesis in Leukemia 28

2.2.1 Normal Hematopoietic Stem Cell Hierarchies 28

2.2.2 Understanding Aberrant Hierarchies in Leukemia 30

2.2.3 Types of Leukemia 31

2.3 Identification and isolation of Cancer-Initiating Cells in Leukemia 35

2.4 Molecular Regulation of Aberrant Hierarchies 36

2.4.1 Signaling Pathways Deregulated in Leukemia 37

2.4.2 Self-Renewal of Normal and Leukemic Stem Cells 39

2.4.3 Epigenetic Effects 40

2.4.4 MicroRNA in Leukemia Development 42

2.5 Conclusions and Future Perspectives 44

References 45

3 Isolation and Characterization of Breast and Brain Cancer Stem Cells 57 Meera Saxena and Annapoorni Rangarajan

3.1 Introduction 57

3.2 Breast Cancer Stem Cells 58

3.2.1 Mammary Gland Architecture and Cell Types 58

3.2.2 Breast Cancer 59

3.2.3 Identification of Breast Cancer Stem Cells 59

3.2.4 Putative Breast Cancer Stem Cells that Exhibit the CD44⁺ CD24^-/low Lin^- Marker Profile 61

3.2.5 ESA⁺ Subpopulation of CD24^-low Lin^- Cells Enriched by Tumorigenicity 61

3.2.6 Tumorigenic Breast Cells Displaying Properties of Stem Cells 61

3.2.7 In Vitro Propagation of Breast Cancer Stem Cells as Mammospheres 62

3.3 Brain Cancer Stem Cells 64

3.3.1 Brain Architecture and Cell Types 64

3.3.2 Brain Cancers 65

3.3.3 Brain Stem Cells 66

3.3.4 Brain Cancer Stem Cells 66

3.3.5 Brain Cancer-Derived Cells that Generate Tumor Spheres 67

3.4 Conclusions and Future Perspectives 69

References 70

4 Cancer Stem Cell Side Populations 73 Danuta Balicki and Raymond Beaulieu

4.1 Introduction 73

4.2 Stem Cell Side Populations 75

4.3 Side Populations in Normal Tissue 78

4.4 Side Populations in Tumors 79

4.5 Overcoming Side Population Limitations 80

4.6 Conclusions and Future Perspectives 81

References 82

5 Evidence for Cancer Stem Cells in Retinoblastoma 87 Gail M. Seigel

5.1 Introduction 87

5.2 Elusive Origins of Retinoblastoma 87

5.3 Sources of Retinoblastoma Cells for Study 88

5.4 Precedent for Cancer Stem Cells 88

5.5 Side Populations in Retinoblastoma 89

5.6 Immunoreactivity to Stem Cell Markers in Retinoblastoma 89

5.7 Conclusions and Future Perspectives 91

References 92

6 Ovarian Stem Cell Biology and the Emergence of Ovarian Cancer Stem Cells 95 Anjali Kusumbe and Sharmila Bapat

6.1 Introduction 95

6.2 Overview of the Human Ovary 95

6.2.1 Histological Landmarks 95

6.2.2 Ovarian Development: The Story Before Birth 96

6.2.3 The Mammalian Oogenesis Dogma 98

6.3 Stem/Progenitor Cells in the Adult Mammalian Ovary 98

6.3.1 Historical Perspective 98

6.3.2 The Oogenesis Dogma Revisited 99

6.4 Is Ovarian Cancer a Stem Cell Disease? 104

6.4.1 Putative Role of Stem/Progenitor Cells in Ovarian Cancer 104

6.4.2 Tumor as an Aberrant Organ Initiated by Cancer Stem Cells 105

6.4.3 Ovarian Cancer Stem Cells Isolated as a Side Population 106

6.4.4 New Challenge: Targeting Ovarian Cancer Stem Cells 106

References 107

7 Prostate Cancer Stem Cells 111 Stefanie Hager, Norman J. Maitland, and Anne Collins

7.1 Introduction 111

7.2 Human Prostate Biology Gland Architecture, and Pathological Alterations 111

7.3 Prostate Epithelial Stem Cells 113

7.3.1 Evidence for Prostate Epithelial Stem Cells 113

7.3.2 Isolation of Human Prostate Epithelial Stem Cells and Demonstration of Their Stem Cell Character 116

7.3.3 Epithelial Stem Cells in the Murine Prostate 118

7.3.4 Other Markers of Prostate Epithelial Stem Cells 119

7.4 Prostate Cancer Stem Cells 120

7.4.1 Role of Stem Cells in Prostate Cancer 120

7.4.2 Prospective Isolation of Prostate Cancer Stem Cells from Human Tissue Samples 122

7.4.3 Role of the Stem Cell Niche in Prostate Cancer 124

7.4.4 Putative Markers of Prostate Cancer Stem Cells 124

7.5 Stem Cell Tracking in the Prostate 125

7.6 Conclusions and Future Perspectives 127

References 127

8 Molecular Signatures of Highly Malignant Melanoma Stem Cells 135 Suraiya Rasheed

8.1 General Properties of Human Melanomas 135

8.2 Characteristics of Stem Cell-Derived Melanomas 136

8.3 The Cat Model System for Stem Cell Melanomas 137

8.3.1 Biological Characteristics of Highly Malignant Stem Cell Melanomas 138

8.3.2 Trans-differentiation of the Malignant Cat Melanoma into Neuronal Cells 139

8.3.3 Proteins Associated with Neuronal Cell Differentiation 140

8.3.4 Cell Cycle Dysregulation and Antitumorigenic Effects During Cell Differentiation 144

8.3.5 Molecular Signatures of Self Renewal and Long-Term Proliferation of Tumor Cells 145

8.3.6 Proteins Involved in Tumorigenesis and Metastasis 147

8.3.7 Expression of Germline and Embryonic Proteins in Cat Melanomas 149

8.3.8 Naturally Occurring Protein-Protein Interaction Complexes in Melanomas 149

8.3.9 Networks of Protein Interaction Pathways 152

8.4 Challenges of Research in Cancer Stem Cellsand Therapeutics 152

8.5 Conclusions and Future Perspectives 154

References 156

9 Invasion Program of Normal and Cancer Stem Cells 167 David Olmeda, Gema Moreno-Bueno, David Sarrió, José Palacios, and Amparo Cano

9.1 Introduction 167

9.2 Basics of Tumor Progression: Invasion and Metastasis 168

9.3 Epithelial-to-Mesenchymal Transition in Development and Its Relation to The Invasive Process 169

9.4 Regulation of EMT: From Signals to Molecular Pathways 172

9.5 EMT and Cancer Stem Cells 176

9.6 Can Stem Cell Properties Be Extensive to Invasive Tumor Cells? 177

9.7 Is There a Unique EMT Program Linked to Invasion? 178

9.8 Evidence of EMT in Human Clinical Tumors 180

9.9 Expression of Mesenchymal Markers and Cadherin Switching in Carcinomas 181

9.10 Expression of EMT Inducers in Human Tumors 183

9.11 Occurrence of EMT in a Specific Subset of Breast Carcinomas 185

9.12 Conclusions and Future Perspectives 186 References 187

10 Epigenetics in Cancer Stem Cell Development 197 Kenneth Nephew, Curt Balch, Tim H.-M. Huang, Zhang Shu, Michael Chan, and Pearlly Yan

10.1 Introduction 197

10.2 Characterization of Candidate Cancer Stem Cells 198

10.3 Possible Origins of Cancer Stem Cells 198

10.4 Epigenetics in Normal Development 199

10.5 Epigenetic Regulation of the Cancer Stem Cell Phenotype 200

10.6 Contributions of Epigenetics to Drug Resistance in Cancer Stem Cells 204

10.7 Genome-Wide Interrogation of Epigenetic Modifications in Cancer Stem Cells 206

10.8 Epigenetic Therapies Against Poorly Differentiated Cancer Cells 207

10.9 Conclusions and Future Perspectives 208

References 209

11 Cancer Stem Cells and New Therapeutic Approaches 217 Michael Dean

11.1 Cancer Stem Cells 217

11.2 Activation of Stem Cells and Cancer 218

11.2.1 Initiation and Promotion Revised 219

11.2.2 Stem Cell Activation and Specific Cancers 221

11.3 Major Cancers and Risk Factors 223

11.3.1 Liver Cancer 223

11.3.2 Lung Cancer 224

11.3.3 Gastric Cancer 224

11.3.4 Pancreatic Cancer 224

11.3.5 Cervical Cancer 225

11.4 Treatment Implications 225

11.5 Future Perspectives 227

11.6 Conclusions 228

References 243

12 Immunobiology of Cancer Stem Cells 233 Shubhada V. Chiplunkar

12.1 Cancer Stem Cells 233

12.2 Cancer Stem Cells and Lymphocytes 234

12.3 Trafficking of Normal Stem Cells and Metastasis of Cancer Stem Cells 236

References 238

Index 243