Lung Cancer Metastasis (eBook)

Lung Cancer Metastasis 1
Preface 4
Contents 5
Contributors 7
Lung Cancer: Overview 12
Introduction 12
Epidemiology 13
Etiologic Factors 14
Smoking 14
Other Causes 15
Pathology 17
Pathogenesis 18
Chemoprevention 19
Screening 21
Clinical Presentation 22
Symptoms of Local Disease 22
Symptoms of Locally Advanced Disease 23
Symptoms of Metastatic Disease 24
Constitutional Symptoms 25
Paraneoplastic Syndromes 25
Staging 25
Staging Procedures 28
Prognostic Factors 29
Management of Lung Cancer 30
Management of NSCLC 30
NSCLC Confined to the Lung 30
Mediastinal Involvement Without Distant Metastases 31
Distant Metastases 32
Management of SCLC 32
References 33
Hallmarks of Metastasis 39
Introduction 39
The Metastatic Process 40
Theories of Metastasis 42
Dissemination from the Primary Tumor 43
Vascular Transport of Metastatic Cells 46
Proliferative Ability at Site of Metastasis 48
Genes Involved in Metastasis 49
Techniques for Monitoring Metastasis 50
Therapeutics and Future Directions 51
References 53
Tumor Stem Cells and Metastasis 57
Introduction 57
Cancer Stem Cells 58
Side Population Phenotype 60
Origin of Cancer Stem Cells 63
Cancer Stem Cells and Metastasis 64
Implications for Treatments 65
References 68
Epithelial-Mesenchymal Transition as a Mechanism of Metastasis 74
General and Embryonic Aspects of EMT 75
EMT Induces Mesoderm Formation During Gastrulation 76
EMT Induces Formation of Neural Crest Cells 77
EMT in Palate Formation 78
EMT in Heart Morphogenesis 78
Epithelial and Mesenchymal Reciprocal Interactions in Embryonic Lung Morphogenesis 79
Factors Secreted by the Mesenchyme 79
Factors Secreted by the Epithelium 79
Factors Secreted by the Mesenchyme and the Epithelium 80
EMT in the Context of Cancer Progression 81
Receptor Tyrosine Kinase Signaling in the Establishment of EMT 81
TGFbeta as a Central Regulator of EMT 83
A Transcriptional Program Governing EMT 85
EMT and Lung Cancer 86
EMT and Tumor-Stromal Interactions 88
EMT and Cancer Stem Cell Biology 90
How Relevant Is EMT to Cancer Progression and Metastasis? 91
Conclusions 92
References 92
Mechanisms of Tumor Cell Migration and Invasion in Lung Cancer Metastasis 102
Introduction 102
Basement Membrane 103
Tumor Extracellular Matrix 103
Matrix Metalloproteinases 104
Integrins 105
E-Cadherins and Connexins 107
Rho GTPases 108
Actin-Binding Proteins 110
Methods to Study Cancer Cell Invasion and Metastasis 111
Conclusions and Clinical Perspective 111
References 112
Immunologic Mechanisms in Lung Carcinogenesis and Metastasis 119
Introduction 119
Cancer Immunosurveillance 120
Cancer Immunoediting 121
Complicity of Host Cellular Networks in Lung Tumorigenesis 122
Tumor-Mediated Immunosuppression 123
COX-2 125
COX-2 and Lung Cancer 126
COX-2 Downstream Signaling: Prostanoid Receptors 127
Reversal of Epithelial-Mesenchymal Transition 128
Interaction Between COX-2 and EGFR Signaling 129
COX-2 Clinical Trials 130
Targeted Prevention 131
Conclusion 133
References 134
Angiogenesis and Angiogenic Diversity in Lung Cancer Metastasis 143
Introduction 143
The Sequence of Events in Physiologic Angiogenesis 144
Factors Which Regulate Angiogenesis 147
Clinical Implications of Angiogenic Diversity and Angiogenesis Inhibition in Lung Cancer Metastasis 152
Summary 154
References 154
Chemokines in Lung Cancer Metastasis 163
Introduction 163
Angiogenic Chemokines: The CXCR2 Ligands 163
Angiostatic Chemokines: CXCR2-Independent Effects 166
Angiostatic Chemokines: The CXCR3 Ligands 167
CXCR3-Mediated ‘‘Immunoangiostasis’’: Combined Tumor-Mediated and Anti-tumor Th1 Immunity 170
Angiostatic Chemokines: CXCR3-Independent Effects 170
Chemokine-Mediated Metastasis 171
Conclusion 173
References 173
Molecular Control of Lymphatic Metastasis in Lung Cancer 181
Introduction 181
Tumor Lymphangiogenesis in Lung Cancer 182
Invasion of Lymphatic Vasculature in Lung Cancer 188
Modulation of Tumor Lymphangiogenesis and Lymphatic Invasion by Integrins and Proteoglycans 190
References 195
Carcinoma-Associated Fibroblasts in Lung Cancer 200
Introduction 200
Cancer Stroma 202
Markers of Fibroblasts and CAFs 202
Gene Expression Changes in Carcinoma or Senescent-Associated Fibroblasts 205
CAFs Contribution to Carcinogenesis 208
Contributions of CAFs in Metastasis 211
Factors Expressed by CAF in Lung Cancer 212
Integrin alpha11 as a Stromal Factor in NSCLC 213
Clinical Implication of CAFs in Targeted Therapy 213
Conclusion 215
References 215
The Role of Tumor-Associated Macrophages and Other Innate Immune Cells in Metastatic Progression of Lung Cancer 223
Introduction 223
Tumor-Associated Innate Immune Cells 224
Neutrophils (PMNs) 226
Natural Killer (NK) Cells 227
Mast Cells 227
How Could Tumor-Associated Innate Immune Cells Affect the Metastatic Process? 228
Epithelial to Mesenchymal Transformation-Augmented Migratory Ability 229
Disruption of Basement Membranes and Matrix 229
Movement of Tumor Cells to the Bloodstream and Lymph Nodes (Intravasation) 230
Angiogenesis 230
Immunosuppression 231
Killing of Circulating Metastatic Cells 232
Extravasation 232
Distant Growth 233
Association Between Tumor-Associated Leukocytes and Lung Cancer Metastasis 233
Animal Studies 233
Human Studies 237
Conclusions 238
References 238
Experimental Animal Models for Studying Lung Cancer 246
Introduction 246
General Principles 247
Chemical-Induced Lung Cancer Models 248
Transgenic Lung Cancer Models 250
Human Lung Tumor Xenografts 255
Orthotopic Lung Cancer Models 255
Useful Models for the Study of Lung Cancer Metastasis 259
Lung Cancer Models in Preclinical Cancer Drug Development 260
Lung Cancer Model for Studying Adjuvant Modalities 264
Summary 264
References 265
Molecular Imaging in Lung Cancer Metastases 271
Introduction 271
Molecular Probes 272
Imaging Modalities for Clinical Metastases 273
Magnetic Resonance Imaging 274
Nuclear Imaging (SPECT and PET) 274
Molecular Imaging for Experimental Metastasis 275
Bioluminescent Optical Imaging 275
Fluorescent Optical Imaging 276
Applications of Bioluminescent and Fluorescent Optical Imaging 277
Imaging Kinases 279
Imaging Proteases 282
Imaging Protein-Protein Interaction 282
Molecular Imaging Modality in Monitoring Therapeutic Response 283
Molecular Imaging in Drug Discovery and Development 284
Concluding Remarks 285
References 285
Biomarker Discovery for Metastatic Disease 292
Introduction 292
Analyses of Gene Expression in Primary Tumors and Metastases 295
The Oncomine Resource for Microarray Gene Expression Data Sets 296
Special Analysis for Metastatic Lung Cancer Phenotypes Using Oncomine 298
miRNAs as New Biomarkers for Lung Cancers 302
Discovery of Protein Biomarkers Using Proteomics 303
Proteomic Analyses of Lung Cancers and Biofluids 304
Proteomics Analyses of Serum from Patients with Lung Cancers 306
Serum Protein Profiles Associated with Lung Cancers Involving Detection of Abundant Proteins with Antibody Microarrays 307
Using the Immune System’s Production of Autoantibodies as a Form of Biological Amplification 308
Proteomics Analysis of the Epithelial-Mesenchymal Transition (EMT) in Lung Adenocarcinoma Cells, an In Vitro Model for Metastasis 309
Use of Genetically Engineered Mouse Models of Specific Human Cancers 310
Conclusion 311
References 312
Current Clinical Management of Metastatic Lung Cancer 319
Introduction 319
Non-small Cell Lung Cancer 320
Systemic Chemotherapy 320
Customized Chemotherapy Based on Tumor Characteristics 322
Salvage Chemotherapy for Progressive Disease 323
EGFR Inhibitors 324
Molecular Predictive Markers for EGFR Inhibition 326
Antiangiogenic Agents 328
Proteosome Inhibition 330
Histone Deacetylase (HDAC) Inhibitors 331
mTOR Pathway Inhibitors 331
Other Novel Approaches 332
Small Cell Lung Cancer 332
Current Standard of Care 333
Multidrug Combinations 334
Alternating Noncross-Resistant Chemotherapy Regimens 335
Dose Intensification 336
Autologous Stem Cell Transplantation 337
Duration of Chemotherapy 338
Other Cytotoxic Agents 339
Targeted Therapy 340
Antiangiogenic Therapy 340
Other Tyrosine Kinase Inhibitors 341
Bcl-2 Inhibition 342
Vaccine Therapy 342
Summary 343
References 343
Site-Directed Therapy for Lung Cancer Metastases 353
Introduction 353
Brain 354
Multiple Brain Metastases 354
Limited Brain Metastases 355
Prophylactic Cranial Irradiation 358
Adrenal Gland 358
Liver 359
Surgical Resection 359
Radiofrequency Ablation 360
Stereotactic Body Radiation Therapy 362
Lung 363
Pulmonary Metastasectomy 363
Radiofrequency Ablation 365
Stereotactic Body Radiation Therapy 369
Thoracic Irradiation in Extensive-Stage SCLC 370
Bone 371
Uncomplicated Bone Metastases 371
Complicated Bone Metastases 372
Stereotactic Body Radiation Therapy 372
Conclusion 373
References 374
Systems Approach for Understanding Metastasis 384
Introduction 384
Data Sources for Systems Biology 386
Modeling Tools for Systems Biology 387
Ordinary Differential Equations (Deterministic, Linear or Nonlinear, Dynamic, Continuous) 388
Stochastic Differential Equations (Stochastic, Nonlinear, Dynamic, Continuous) 389
Bayesian Networks (Stochastic, Nonlinear, Static, Discrete) 389
Bayesian Network Cancer Diagnosis Classifiers 390
Bayesian Networks for Cancer Mechanism Inference 392
Dynamic Bayesian Networks (Stochastic, Nonlinear, Dynamic, Discrete) 393
Conclusions 393
References 394
Subject Index 396