Bone and Cancer (eBook)

Series Editors of Topics in Bone Biology are: Professors Felix Bronner, PhD - University of Connecticut Health Center, Farmington, CT, USA, and Dr Mary C. Farach-Carson, PhD - the Department of Biology, University of Delaware, Newark, DE, USA

Preface 6
Contents 12
Contributors 14
1 Blood0Bone Axis and Bone Marrow Microenvironment 20
1.1 Introduction 20
1.2 The HSC Niche in Marrow 21
1.3 Components of the Niche 22
1.4 Endosteal Niches 22
1.5 Vascular Niches 26
1.6 Other Marrow Niches 26
1.7 Reticular Cells 27
1.8 HSC Homing to the Marrow and Occupancy 27
1.9 Parasitism of the Niche by Cancers 28
1.10 Conclusions 29
1.11 Acknowledgments 30
2 Genetics of Osteosarcoma 37
2.1 Histopathology of Osteosarcoma 37
2.2 Unconventional Osteosarcoma Subtypes 38
2.3 Head and Neck Osteosarcoma 39
2.4 Osteosarcoma and Bilateral Retinoblastoma 40
2.5 Osteosarcoma and LiFraumeni Syndrome 41
2.6 Osteosarcoma and RothmundThomson Syndrome 41
2.7 Osteosarcoma and Pagets Disease of Bone 41
2.8 Genetics of Osteosarcoma 42
2.9 RB1 and Osteosarcoma 42
2.10 TP53 and Osteosarcoma 43
2.11 Wnt Signaling Pathway 43
2.12 Ezrin and Metastasis 43
2.13 FAS and FASL Signaling 44
2.14 erbB2/HER2 and Its Role in Osteosarcoma 44
2.15 RECQL4 and Genomic Stability 45
2.16 Role of Chromosomal Instability and Telomere Maintenance in Osteosarcoma 45
2.17 Comparative Genomic Hybridization 46
2.18 Microarray Analysis of Osteosarcoma 47
2.19 Summary 48
2.20 Acknowledgments 48
3 Multiple Myeloma and Other Hematological Malignanciesof Bone 61
3.1 Multiple Myeloma and Bone Disease 61
3.2 Pathophysiology of Bone Disease in Multiple Myeloma 61
3.3 Osteoclast Activation/Stimulation 61
3.4 RANKL 62
3.5 MIP-1 62
3.6 Parathyroid Hormone Related Peptide (PTHrP) 63
3.7 IL-6 63
3.8 Osteoblast Inhibition in Myeloma 63
3.9 IL-7 and IL-3 64
3.10 DKK1 64
3.11 Clinical Manifestations of Myeloma 65
3.12 Bone Destruction 65
3.13 Hypercalcemia 65
3.14 Neurologic Symptoms 65
3.15 Other Systemic Complications 65
3.16 Diagnosis 66
3.17 Evaluation of Bone Involvement 66
3.18 Prognosis 66
3.19 Treatment of Myeloma Bone Disease 67
3.20 Bone Involvement in Hodgkins Disease 68
3.21 Bone Involvement in Non-Hodgkins Lymphoma (NHL) 68
3.22 Adult T Cell Leukemia/Lymphoma (ATL) Bone Disease 69
3.23 Hypercalcemia Associated with ATL 69
3.24 Pathophysiology of ATL Bone Disease 70
3.25 Treatment of ATL Bone Disease 70
4 Mechanism of Metastasis to Bone: The Role of BoneMarrow Endothelium 75
4.1 Introduction 75
4.2 The Clinical Sequelae of Bone Metastasis 75
4.3 Natural History 76
4.4 Prognosis and Clinical Course 76
4.5 Hypercalcemia 77
4.6 Pathologic Fracture 77
4.7 Bone Pain 78
4.8 Spinal Cord Compression 78
4.9 Costs of Treatment 78
4.10 Endothelial Cells: A Brief Overview 78
4.11 Bone Marrow Endothelial Cells and Bone Physiology 80
4.12 Bone-Marrow Endothelial Cells in Tumor Angiogenesis 80
4.13 Bone-Marrow Endothelial Cells as an Adhesive Substrate for Circulating Cancer Cells 81
4.14 Rho GTPases: A Brief Background 82
4.15 Rho GTPases and Angiogenesis 83
4.16 Rho-Mediated Endothelial Cell Motility 84
4.17 Closing Comments and an Emerging Concept 85
5 Lysophosphatidic Acid: Role in Bone and Bone Cancer 90
5.1 List of Abbreviations 90
5.1 Lysophosphatidic Acid 90
5.2 In vivo Sources of LPA 91
5.3 Biological Activities of LPA 92
5.4 LPA Receptors 92
5.5 Expression of LPA Receptors in Skeletal Cells 93
5.6 Rapid Effects of LPA on Bone and Cartilage Cells 94
5.6.1 Ca 2+ Signaling 94
5.6.2 MAP Kinase Activation 94
5.6.3 Cytoskeletal Rearrangements 95
5.7 Long-Term Effects of LPA on Skeletal Cells 95
5.7.1 Cell Proliferation, Survival, and Differentiation 95
5.7.2 Cytoskeletal Changes, Adhesion, and Migration 96
5.7.3 Gene Expression 97
5.8 Potential Regulatory Roles of LPA in Bone 97
5.8.1 Fracture Healing 97
5.8.2 Regulation of Mechanotransduction 98
5.8.3 The Pathology of Arthritis 98
5.8.4 Regulation of Bone Mass by Leptin 99
5.9 LPA and Cancers That Metastasize to Bone 99
5.9.1 LPA and Thyroid Cancer 99
5.9.2 LPA and Prostate Cancer 99
5.9.3 LPA and Breast Cancer 99
5.10 LPA and Bone Metastasis 99
6 Role of Bone Microenvironment/Metastatic Nichein Cancer Progression 106
6.1 Introduction 106
6.2 Tumor-Derived Growth Factors, Cytokines, and Chemokines Mediate Early Changes in the Bone and Tumor Microenvironment 106
6.2.1 Angiogenic Growth Factors -- The VEGF Family Proteins 107
6.2.2 Other Growth Factors 108
6.2.3 Pharmacological Inhibition of the Soluble Factors that Promote Metastasis 108
6.3 Within the Bone NicheNiche Interactions Promote Tumor Progression 108
6.3.1 Stem Cell and Tumor Cell Migratory Pathways 109
6.4 Bone Marrow-Derived Cells Are Recruited to Primary Tumor, Promoting Invasion, Migration, and Dissemination 109
6.5 Accessory Bone Marrow-Derived Cells Support Tumor Cell Survival and Dissemination 110
6.6 Bone Marrow-Derived Cells Are Recruited to Sites of Future Metastasis, Forming the Pre-metastatic Niche 111
6.6.1 Early Stromal Changes at Sites of Future Metastasis 111
6.6.2 Tumor-Secreted Factors Preparing Distant Sites for Future Metastasis 111
6.6.3 Stem Cell Niche Dynamics at Pre-metastatic Sites 112
6.6.4 Pre-metastatic Lymph Nodes 112
6.6.5 Therapeutic Inhibition of the Pre-metastatic Niche 112
6.7 Metastatic Cancer Stem Cells Home Back to Bone 113
6.8 Genetic Regulation of Metastasis 113
6.8.1 Tumor Suppressor Genes 114
6.8.2 Metastasis Suppressor Genes 114
6.8.3 Genetic Targeting 114
6.9 Therapeutic Implications 115
7 Detection and Characterization of Disseminated Tumor Cells present in Bone Marrow of Cancer Patients 119
7.1 Summary 119
7.2 Background: Clinical Relevance of DTC Detection in BM 119
7.3 Potential and Limitations of DTC Enrichment and Detection Methods 120
7.3.1 Enrichment Methods 120
7.3.2 Detection Methods 121
7.3.3 Immunocytochemical Techniques 121
7.3.3.0 Advantages 122
7.3.3.1 Disadvantages 122
7.3.4 Polymerase Chain Reaction Based Assays 122
7.3.4.0 Advantages 123
7.3.4.1 Disadvantages 123
7.3.5 Enzyme-Linked Immunospot (ELISPOT) Technology 123
7.3.5.0 Advantages 123
7.3.5.1 Disadvantages 123
7.4 Characterization of DTCs 124
7.4.1 Phenotypic and Molecular Characterization of DTCs 124
7.4.2 Features Enabling Homing, Dormancy, and Re-growth of DTCs 125
7.4.3 Stem Cell-Like Phenotypes of DTCs 126
7.4.4 Identification of Therapeutic Targets for DTCs 127
8 Molecular Imaging of Cancer Cells Growing in Bone 134
8.1 Introduction and Background 134
8.2 Molecular Imaging Strategies 134
8.2.1 Biomarker Imaging 134
8.2.2 Direct Molecular Imaging 135
8.2.3 Indirect (Reporter Gene) Molecular Imaging 136
8.2.3.0 Radiotracer Reporter Gene Imaging 137
8.2.3.1 Optical Imaging Genes 140
8.3 Imaging of Cancer Cells Growing in Bone 141
8.3.1 Clinical Application 141
8.3.1.0 Scintigraphy 142
8.3.1.1 Computed Tomography 143
8.3.1.2 Magnetic Resonance Imaging (MRI) 143
8.3.1.3 Positron Emission Tomography (PET) 143
8.3.2 The Applications of Imaging Technologies in Mouse Models 144
8.3.2.0 Bioluminescence and Fluorescence Imaging in the Detection of Bone Metastasis Coupled with Other Imaging Techniques 145
8.4 Issues for the Future 150
9 Inflammatory Cytokines and Their Role in BoneMetastasis and Osteolysis 156
9.1 Introduction 156
9.2 The Link Between Inflammation and Cancer Progression 156
9.3 The Inflammatory Bone Microenvironment in Cancer Progression 157
9.4 Mediators of the Inflammatory Response 157
9.5 TNF- 158
9.6 TGF- 159
9.7 Interleukin-6 160
9.8 CXCL12/CXCR4 161
9.9 Interleukin-8 162
9.10 Interleukin-10 163
9.11 Interleukin-12 and -23 163
9.11.1 Interleukin-12 164
9.11.2 Interleukin-23 164
9.12 Summary 165
9.13 Acknowledgments 165
10 Prostate Cancer Bone Colonization: Osteomimicryin the Bone Niche 171
10.1 Abbreviations 171
10.1 Introduction and Chapter Overview 171
10.2 Phenotypic Alterations in Prostate Cancer Cells Growing in Bone: A New Signaling Triad 172
10.3 The Plasticity of PCa Cells. Potential Evolutionary Significance 174
10.4 The Functional Role of Cancer Derived RANKL in Osteoclastogenesis 176
10.5 Perlecan Supports Signal Amplification Leading to Osteomimicry and PCa Disease Progression 177
10.6 Acknowledgments 177
11 Bone Pain Associated with Cancer Metastasis 181
11.1 Bone Cancer Pain 181
11.2 Treatment of Bone Cancer Pain 182
11.3 Animal Models Used to Study Bone Cancer 183
11.4 Therapeutics and Skeletal Remodeling 187
12 Small Animal Models for the Study of Cancer in Bone 194
12.1 Introduction 194
12.2 Breast Cancer 195
12.2.1 Models for the Study of Breast Cancer Metastasis to Bone 195
12.2.1.0 Spontaneous 195
12.2.1.1 Syngeneic 195
12.2.1.2 Xenografts 196
12.2.1.3 Transgenic 197
12.3 Lung Cancer 197
12.3.1 Models for the Study of Lung Cancer Metastasis to Bone 198
12.3.1.0 Spontaneous 198
12.3.1.1 Syngeneic 198
12.3.1.2 Xenograft 198
12.3.1.3 Transgenic 200
12.4 Prostate Cancer 200
12.4.1 Models for the Study of Prostate Cancer Metastasis to Bone 200
12.4.1.0 Spontaneous 200
12.4.1.1 Syngeneic 201
12.4.1.2 Xenograft 201
12.4.1.3 Transgenic 204
12.5 Renal Cancer 204
12.5.1 Models for the Study of Renal Cell Cancer Metastasis to Bone 205
12.5.1.0 Spontaneous 205
12.5.1.1 Xenograft 205
12.6 Multiple Myeloma 206
12.6.1 Models for the Study of MM Metastasis to Bone 206
12.6.1.0 Spontaneous 206
12.6.1.1 Syngeneic 206
12.6.1.2 Xenograft 206
12.6.1.3 Transgenic 207
12.7 Melanoma 207
12.7.1 Models for the Study of Melanoma Metastasis to Bone 207
12.7.1.0 Spontaneous 207
12.7.1.1 Syngeneic 208
12.7.1.2 Xenograft 208
12.8 Concluding Remarks 210
13 Hormonal therapies in Breast and Prostate Cancer: Effects on Bone and the Role of Bisphosphonates 217
13.1 Introduction 217
13.2 Hormonal Therapies in Breast and Prostate Cancer 217
13.2.1 Prostate Cancer 217
13.2.1.0 Use of Gonadotropin-Releasing Hormone Agonists (GnRH-Agonists) in Prostate Cancer 218
13.2.1.1 Neoadjuvant and Adjuvant Therapy with GnRH-Agonists for Prostate Cancer 218
13.2.1.2 Locally Advanced Disease 218
13.2.1.3 Metastatic Disease in PCa 218
13.2.1.4 Consequences of GnRH-Agonist Treatment 218
13.2.1.5 Loss of Bone Density 219
13.2.1.6 Estrogen Loss Due to GnRH-Agonist Treatment 219
13.2.1.7 Fractures and GnRH-Agonists 219
13.2.2 Breast Cancer (BCa) 219
13.2.2.0 Tamoxifen and Bone 220
13.2.2.1 AIs and Bone 220
13.3 Efficacy of AIs 220
13.3.1 Studies of Healthy Women on AIs -- Effects on Bone Markers 220
13.3.2 Data on Premenopausal Women 221
13.4 AIs as First-Line Treatment for BCa Effect on Bone Loss and Fractures 221
13.4.1 AIs Compared to Tamoxifen 221
13.4.1.0 Anastrozole 221
13.4.1.1 Letrozole 222
13.4.1.2 Exemestane 222
13.4.2 AIs After 2--3 Yrs of Tamoxifen Versus Tamoxifen Alone 222
13.4.2.0 Anastrozole 222
13.4.2.1 Letrozole 222
13.4.2.2 Exemestane 222
13.4.3 AIs Versus Placebo After Tamoxifen for 5 Yrs 223
13.4.3.0 Letrozole 223
13.5 Role of Bisphosphonates in Prostate and Breast Cancer 223
13.5.1 Prevention and Treatment of Bone Metastases 223
13.5.2 Prostate Cancer 223
13.5.3 Breast Cancer 224
13.6 Prevention of Bone Loss in Prostate and BCa 224
13.6.1 Prostate Cancer 224
13.6.2 Prevention of Bone Loss with Bisphosphonates 224
13.6.3 Use of Estrogen to Prevent Bone Loss in PCa 225
13.6.4 Prevention and Treatment of Bone Loss in Breast Cancer 225
13.7 Osteoporosis Prevention and Treatment in Breast and Prostate Cancer Patients 226
13.7.1 Clinical Monitoring 226
14 Therapeutic Approaches to Metastatic Bone Cancer II:Targeted and Non-targeted Systemic Agents 231
14.1 Introduction 231
14.2 Renal Cell Carcinoma 232
14.3 Thyroid Cancer 233
14.3.1 Well-Differentiated Carcinoma of the Thyroid 233
14.3.2 Medullary Thyroid Carcinoma 233
14.3.3 Anaplastic Thyroid Carcinoma 234
14.4 Prostate Cancer 234
14.5 Breast Cancer 236
14.6 Lung Cancer 236
14.7 Radiopharmaceuticals 237
14.8 Conclusion 237
15 The Role of Allogeneic Bone Marrow Transplantin Cancer Treatment 240
15.1 Introduction and Historical Perspectives 240
15.2 Principles and Technical Aspects of Stem Cell Transplantation 241
15.3 Current Indications for Allogeneic Stem Cell Transplantation in Cancer Patients 242
15.3.1 Acute Myeloid Leukemia (AML) 242
15.3.2 Acute Lymphoblastic Leukemia (ALL) 243
15.3.3 Chronic Myeloid Leukemia (CML) 243
15.3.4 Myelodysplastic Syndromes (MDSs) 243
15.3.5 Lymphoid Malignancies (Non-Hodgkin's Lymphoma Hodgkin's Lymphoma, Multiple Myeloma and Chronic Lymphocytic Leukemia)
15.4 Transplant-Related Complications 245
15.5 The Future of SCT 246
16 The Role of Radiosurgery in the Treatment of BoneLocalized Cancers 251
16.1 Introduction 251
16.2 Historical Background 251
16.2.1 Discovery and Implementation of External Beam Radiation Therapy 251
16.2.2 Evolution of Radiosurgery 252
16.3 Radiobiological Considerations 253
16.4 Current Applications 254
16.4.1 Clinical Evaluation and Dosing for External Beam Radiation Therapy 254
16.4.2 Clinical Evaluation and Dosing for Stereotactic Radiosurgery 256
16.5 Conclusion/Future Directions 259
Index 262