Liver Metastasis: Biology and Clinical Management (eBook)
XIV, 446 Seiten
Springer Netherlands (Verlag)
978-94-007-0292-9 (ISBN)
Liver metastases are a frequent and often fatal occurrence in cancer patients, particularly those with malignancies of the gastrointestinal (GI) tract. While recent improvements in surgical techniques and a more aggressive approach to resection of liver metastases have improved long term survival for some patients, most patients with hepatic metastases still succumb to their disease. To improve these dismal statistics, a better understanding of the biology of liver metastasis, particularly the early stages that can be targeted for prevention, is essential.
Once cancer cells enter the liver, several different scenarios may occur. The cancer cells may be immediately destroyed by local defence mechanisms, they may enter a state of dormancy as solitary cells and never produce a metastasis, initiate a short-lived process of proliferation that is aborted before a metastasis is established or actively proliferate to form macrometastases. The chapters in Part I of this book provide insight into the cellular/molecular mechanisms that determine which of these scenarios prevails. Written by experts researchers in the filed of metastasis, these chapters provide state-of-the art reviews on the cellular and molecular processes that impact the early stages of the metastatic process. The unique microenvironment of the liver, its various anatomical, cellular and molecular features and the impact they have on metastasis are highlighted. In addition, the role of inflammation (pre-existing and tumor-induced), host innate and adaptive immune responses, cytokines, chemokines, growth factors and the unique molecular signatures of metastatic tumor cells are reviewed with an underscoring of the translational implications of the current state of knowledge.
Against this background, the chapters in Part II of the book provide critical reviews on major aspects of the clinical management of hepatic metastases. These include imaging strategies, surgical and chemotherapeutic treatment approaches and the use of targeted biological therapeutics such as anti-angiogenic drugs as treatment modalities.
By combining information on biological and clinical aspects of liver metastasis, this volume will serve as an excellent resource for scientists, clinicians, clinician/ scientists and trainees in the domains of oncology, surgical oncology, hepatobiliary physiology and radiology.
Liver metastases are a frequent and often fatal occurrence in cancer patients, particularly those with malignancies of the gastrointestinal (GI) tract. While recent improvements in surgical techniques and a more aggressive approach to resection of liver metastases have improved long term survival for some patients, most patients with hepatic metastases still succumb to their disease. To improve these dismal statistics, a better understanding of the biology of liver metastasis, particularly the early stages that can be targeted for prevention, is essential. Once cancer cells enter the liver, several different scenarios may occur. The cancer cells may be immediately destroyed by local defence mechanisms, they may enter a state of dormancy as solitary cells and never produce a metastasis, initiate a short-lived process of proliferation that is aborted before a metastasis is established or actively proliferate to form macrometastases. The chapters in Part I of this book provide insight into the cellular/molecular mechanisms that determine which of these scenarios prevails. Written by experts researchers in the filed of metastasis, these chapters provide state-of-the art reviews on the cellular and molecular processes that impact the early stages of the metastatic process. The unique microenvironment of the liver, its various anatomical, cellular and molecular features and the impact they have on metastasis are highlighted. In addition, the role of inflammation (pre-existing and tumor-induced), host innate and adaptive immune responses, cytokines, chemokines, growth factors and the unique molecular signatures of metastatic tumor cells are reviewed with an underscoring of thetranslational implications of the current state of knowledge. Against this background, the chapters in Part II of the book provide critical reviews on major aspects of the clinical management of hepatic metastases. These include imaging strategies, surgical and chemotherapeutic treatment approaches and the use of targeted biological therapeutics such as anti-angiogenic drugs as treatment modalities. By combining information on biological and clinical aspects of liver metastasis, this volume will serve as an excellent resource for scientists, clinicians, clinician/ scientists and trainees in the domains of oncology, surgical oncology, hepatobiliary physiology and radiology.
Acknowledgement 7
Contents 8
Contributors 10
1 Introduction 13
References 16
Part I Biology 18
2 Architectural and Functional Aspects of the Liver with Implications for Cancer Metastasis 19
2.1 Introduction 21
2.2 Tissue Architecture and Heterogeneity of the Hepatic Lobules 24
2.3 The Hepatic Microcirculation 26
2.4 Liver Parenchymal Cells 28
2.4.1 The Hepatocytes 28
2.4.2 The Cholangiocytes 30
2.4.3 The Oval Cells 31
2.4.4 Liver Parenchymal Cell Renewal and Tissue Regeneration 31
2.5 The Non-parenchymal Cells of the Liver 32
2.5.1 Hepatic Endothelial Cells 33
2.5.2 The Hepatic Macrophages 37
2.5.3 Liver-Associated Lymphocytes and Hepatic Immunity 38
2.5.3.1 Subtypes of Hepatic Lymphocytes 38
2.5.3.2 The Dendritic Cells of the Liver 39
2.5.3.3 Portal Tract-Associated Lymphoid Tissue 39
2.5.3.4 Hepatic Immune Tolerance 40
2.5.4 Hepatic Connective Tissue Cells and Hepatic Fibrogenesis 41
2.5.4.1 The Portal Tract Fibroblasts 41
2.5.4.2 The Perisinusoidal Stellate Cells 43
2.6 Conclusion 44
References 45
3 The Tumor Microenvironment at Different Stages of Hepatic Metastasis 53
3.1 Introduction 55
3.2 Phases of the Hepatic Metastasis Process 56
3.3 The Tumor Microenvironment During the Microvascular Phase of Liver-Infiltrating Cancer Cells 58
3.3.1 Microvascular Entrapment and Death of Liver-Infiltrating Cancer Cells 58
3.3.2 The Inflammatory Response of the Tumor-Activated Hepatic Microcirculation 58
3.3.2.1 Microvascular Adhesion of Liver-Infiltrating Cancer Cells: Critical Role of IL-18-Induced Endothelial Cell Adhesion Molecules 59
3.3.2.2 Activation of Mannose Receptor-Mediated Endocytosis: Implications for Anti-tumor Immune Suppression 63
3.3.2.3 The Prometastatic Effects of Hepatic ICAM-1 65
3.3.3 Microvascular Survival Mechanisms of Liver-Infiltrating Cancer Cells 66
3.3.4 Myofibroblast Transdifferentiation of Perisinusoidal Stellate Cells at Sites of Microvascular Cancer Cell Arrest 66
3.4 The Microenvironment of the Intralobular Micrometastasis 67
3.4.1 Cancer Cell Growth at Liver Metastatic Niches 68
3.4.1.1 The Intra-sinusoidal Metastatic Niche 68
3.4.1.2 The Perisinusoidal Metastatic Niche 70
3.4.1.3 The Periportal Metastatic Niche 70
3.4.2 Stromal Cell Recruitment into Avascular Micrometastases 71
3.4.2.1 Hepatic Stellate Cell-Derived Myofibroblasts 71
3.4.2.2 Portal Tract Fibroblast-Derived Myofibroblasts 72
3.4.2.3 Hepatocyte-Derived Myofibroblasts 73
3.4.3 Targeting Myofibroblasts in Hepatic Micrometastases 73
3.4.4 Contribution of Hepatic-Derived Nerve Growth Factor to the Microenvironment of Intralobular Hepatic Micrometastases 75
3.5 The Tumor Microenvironment During the Angiogenic Phase of Hepatic Metastasis 76
3.5.1 Angiogenic Patterns of Hepatic Metastases 76
3.5.1.1 Sinusoidal-Type Angiogenesis 76
3.5.1.2 Portal-Type Angiogenesis 76
3.5.2 Role of Endogenous, Liver-Derived Antiangiogenic Factors in Metastasis 77
3.6 The Tumor Microenvironment at the Lobar Stage of the Hepatic Metastasis Process 79
3.6.1 Regulation of ''Hepatic Metastasis'' Gene Expression by the Microenvironment 80
3.6.1.1 Hepatic Metastasis Genes Not Expressed in Tumor-Unaffected Liver 80
3.6.1.2 Genes Co-expressed in Hepatic Metastases and Tumor-Unaffected Liver Tissue 80
3.6.1.3 Genes of Tumor-Unaffected Liver Tissue Not Expressed in Hepatic Metastases 81
3.7 Altered Hepatic Microenvironments and Metastasis 83
3.7.1 The Regenerating Liver and Metastasis Development 83
3.7.2 The Fibrotic Microenvironment of the Liver and Metastasis 84
3.7.2.1 Cirrhosis and Hepatic Metastasis 85
3.7.2.2 Discoidin Domain Receptor-2 Deficiency and Hepatic Metastasis Predisposition 85
3.8 Conclusions 86
3.8.1 Hepatic Metastasis Stage I 87
3.8.2 Hepatic Metastasis Stage II 87
3.8.3 Hepatic Metastasis Stage III 90
References 91
4 The Colorectal Cancer Initiating Cell: Markers and Their Role in Liver Metastasis 98
4.1 Colorectal Cancer and Metastasis 100
4.2 Liver Metastases in Colorectal Cancer 101
4.3 Molecular Features of Metastasis Formation: Cancer Initiating Cell Markers 103
4.3.1 Definition of Cancer Initiating Cells (CIC) 103
4.3.2 Colorectal CIC markers 104
4.3.2.1 The CoCIC Marker EpCAM and Claudin-7 105
4.3.2.2 The Contribution of CD44 to the Metastatic Process 107
4.4 Exosomes and Metastasis 115
4.4.1 The Exosomes – Origin, Properties and Function 115
4.4.2 The Exosomes – Role in Angiogenesis and the Premetastatic Niche Formation 117
4.5 Concluding Remarks 120
References 120
5 Role of CXC Chemokines and Receptors in Liver Metastasis – Impact on Liver Resection-Induced Engraftment and Tumor Growth 137
5.1 Liver and Extrahepatic Metastasis of Colorectal Cancer 138
5.2 Tumor Growth and Angiogenesis – Role of Chemokines 139
5.3 CXC Receptor Expression in Colorectal Cancer Metastasis 140
5.4 Interleukin-8/Macrophage Inflammatory Protein-2 and Colorectal Cancer 142
5.5 Stromal Cell-Derived Factor-1 and Colorectal Cancer 147
5.6 Liver Resection-Induced Tumor Growth 149
5.7 Role of MIP-2 in Hepatectomy-Associated Metastatic Growth in the Remnant Liver 150
5.8 MIP-2 and Growth of Extrahepatic Metastases After Liver Resection 151
5.9 Balance Between Pro- and Anti-angiogenic Chemokine Signaling Regulates Angiogenesis and Tumor Growth 152
5.10 Summary 154
References 155
6 Role of Inflammation in the Early Stages of Liver Metastasis 163
6.1 Introduction 165
6.2 Inflammation and the Liver 168
6.2.1 Cellular Mediators of Inflammation 168
6.2.2 Soluble Mediators of Inflammation 171
6.2.3 Chronic Inflammation and Termination of Inflammation 172
6.3 Tumor Cell Arrest and Inflammation 173
6.3.1 Cytokines and the Circulating Tumor Cell 173
6.3.2 Inflammation-Inducible Cell-Adhesion Molecules 177
6.3.3 Circulating Inflammatory Cells 179
6.4 Beyond Adhesion 185
6.5 Conclusion 186
References 186
7 Signal Transduction in Tumor-Endothelial Cell Communication 194
7.1 Introduction 196
7.2 The Integrins 197
7.2.1 Structure and Cell Biology of Integrins 197
7.2.2 Integrin Signaling During Cancer Progression and Invasion 199
7.3 The Cadherins 200
7.3.1 Structure and Cell Biology of Cadherins 200
7.3.2 Cadherin Signaling During Cancer Progression and Invasion 201
7.4 The Immunoglobulin Superfamily of Cell Adhesion Molecules (IgSFCAMs) 202
7.4.1 Structure and Cell Biology of IgSFCAMs 202
7.4.2 IgSFCAMs Signaling During Cancer Progression and Invasion 204
7.5 The Selectins 204
7.5.1 Structure and Function of Selectins 204
7.5.2 Selectin Signaling During Cancer Progression and Invasion 205
7.5.2.1 E-Selectin Induces Forward Signaling in Endothelial Cells 206
7.5.2.2 Reverse Signaling Induced in Cancer Cells Bound to E-Selectin 206
7.6 Extravasation 209
7.6.1 Adhesion to Endothelial Cells and the Homing Concept of Metastasis 209
7.6.2 The Passage Across the Endothelium and the Colonization of Secondary Sites 212
7.7 Concluding Remarks and Therapeutic Perspectives 213
References 213
8 Tumor Dormancy in Liver Metastasis: Clinical and Experimental Evidence and Implications for Treatment 220
8.1 The Process of Metastasis 221
8.1.1 Liver Metastasis 222
8.1.2 Treatment Failure and Recurrence 223
8.2 Metastatic Dormancy in Experimental Models – Solitary Cells and Micrometastases 224
8.2.1 The Liver as a Model for Metastatic Dormancy 225
8.2.2 Micrometastasis Dormancy 226
8.2.3 Models of Solitary Metastatic Cell Dormancy 226
8.2.4 Imaging and Mechanisms of Solitary Metastatic Cell Dormancy 227
8.3 Clinical Dormancy and Recurrence 228
8.3.1 Patterns of Recurrence 229
8.3.2 Circulating and Disseminated Tumor Cells 229
8.4 Therapeutic Implications 230
8.4.1 Direct Treatment Limitations Imposed by Size 230
8.4.2 Systemic Therapy 231
8.4.3 Treatment Delivery and Combinations 232
8.5 Conclusion 233
References 233
9 Role of the IGF-Axis in Liver Metastasis: Experimental and Clinical Evidence 240
9.1 Introduction 242
9.1.1 The IGF Axis and Its Role in Normal Physiology 242
9.1.1.1 The Ligands 243
9.1.2 The Receptors 243
9.1.3 The IGF Binding Proteins 245
9.2 Role of the IGF System in Physiology and Disease 245
9.3 IGF Signaling 246
9.4 Role of the IGF Axis in Metastasis 246
9.4.1 Step 1 – Tumor Cell Detachment and Migration 247
9.4.2 Step 2 – Tissue Remodeling and Invasion 248
9.4.2.1 Step 2a – Angiogenesis 250
9.4.3 Step 3 – Extravasation and Activation of the Host Stroma in the Target Organ 253
9.4.4 Step 4 – Survival and Growth in the Target Organ 254
9.5 Gene and Protein Expression Profiling Identify IGF Axis Proteins as Potential Biomarkers 256
9.6 Targeting the IGF-I Axis in Cancer Therapy: the Experience to Date 257
9.6.1 Strategies That Are in Development or Have Advanced from the Bench to the Bedside 257
9.6.1.1 Antibodies Against the IGF-IR 258
9.6.1.2 Blockade of the IGF-IR Kinase Activity 259
9.6.1.3 Somatostatin Analogues 260
9.6.1.4 GH Releasing Hormone and GH Antagonists 261
9.6.1.5 Use of Soluble Forms of the IGF-IR 261
9.6.1.6 IGFBP-3 Based Therapy 263
9.6.2 Combination Therapy – Evidence from Experimental Models 265
9.7 Conclusion 266
References 266
10 Breast Cancer Liver Metastasis 279
10.1 Introduction 280
10.1.1 Classification of Breast Cancer 281
10.1.2 Towards a Molecular Classification of Breast Cancer 281
10.1.3 The Clinical Promise of Molecular Profiling in Breast Cancer 283
10.1.4 Breast Cancer Metastasis 283
10.2 Breast Cancer Metastasis to the Liver 285
10.2.1 Treatment of Breast Cancer Liver Metastases 285
10.2.2 The Liver as a Metastatic Site 286
10.2.3 Architectural Features of the Liver 287
10.3 Mediators of Breast Cancer Liver Metastasis 289
10.3.1 Studies Using Xenograft Models 290
10.3.2 Studies Using Syngeneic Models 292
10.4 A Role for Tight Junctional Proteins in Breast Cancer Liver Metastasis 294
10.5 Emerging Areas of Interest 297
10.5.1 The Pre-metastatic Niche 297
10.5.2 Recruitment of Myeloid Cells 298
10.5.3 Factors that Mobilize Bone Marrow Cells 298
10.6 Conclusion 300
References 300
Part II Clinical Management 310
11 Imaging of Hepatic Metastases 311
11.1 Introduction 313
11.1.1 The Anatomy of the Liver 313
11.1.2 Descriptive Anatomy 313
11.1.3 Functional and Radiological Anatomy 313
11.2 Imaging of Liver Metastases 314
11.2.1 Background 314
11.2.2 Imaging modalities for Liver Metastases 315
11.2.2.1 Sonography of Liver Metastasis 316
11.2.3 Imaging of Liver Metastasis by Computed Tomography 321
11.2.3.1 General Background 321
11.2.3.2 Technical Aspects of CT 321
11.2.3.3 Appearance of Liver Metastasis in CT Imaging 322
11.2.4 Imaging Liver Metastases by MRI 332
11.2.4.1 General Background 332
11.2.4.2 Technical Aspects of MRI Imaging 332
11.2.4.3 Appearance of Liver Metastases in MR Imaging 335
11.2.4.4 Pitfalls of MR Imaging 337
11.2.4.5 Recent Developments in MR Imaging 337
11.2.5 Technical Aspects of PET and PET CT Imaging of Liver Metastasis 344
11.2.5.1 General Background 344
11.2.5.2 Technical Aspects of PET CT Imaging 345
11.2.5.3 Appearance of Liver Metastasis in PET and PET/CT Imaging 346
11.3 Summary: Challenges and Future Directions 347
References 348
12 Colorectal Carcinoma Liver Metastasis: Surgical Clinical Perspective 356
12.1 Introduction 358
12.1.1 Justification for Liver Resection as a Therapeutic Option 358
12.1.2 The Patient Referral 359
12.1.3 Unexpected Presentation on the Operating Table 359
12.2 Preoperative Evaluation 360
12.2.1 Multidisciplinary Cancer Conference (MCC) 360
12.2.2 Fitness for Major Surgery 360
12.3 Required Investigations 361
12.3.1 Imaging 361
12.3.2 Tumour Markers/Other Biochemistry 361
12.3.2.1 Endoscopy 361
12.4 Special Investigations 361
12.4.1 Liver Functional Reserve Assessment 361
12.4.1.1 Hepatic Steatosis 362
12.4.2 Laparoscopic Staging 363
12.4.3 PET Scanning 364
12.4.4 Portal Vein Embolization (PVE) 365
12.5 Defining Resectability 365
12.5.1 Extra-Hepatic Disease 366
12.5.1.1 Pulmonary Metastases 367
12.5.1.2 Hepatic Pedicle Nodal Metastases 367
12.5.1.3 Peritoneal Metastases 367
12.6 When to Operate When to Use Neoadjuvant Chemotherapy
12.7 Downstaging 369
12.8 The "Ghost" Lesion 369
12.9 Intraoperative Techniques 371
12.9.1 Resection Margins 372
12.9.2 Hanging Maneuver 372
12.9.3 Hepatic Inflow Control 373
12.9.4 Intraoperative Ultrasound 373
12.10 Two-Stage Hepatectomy 373
12.10.1 First-Stage 374
12.10.2 Second-Stage Hepatectomy 374
12.11 Follow Up After Liver Resection 374
12.11.1 Re-resection for Recurrence 374
12.12 Chemotherapy 375
12.12.1 5-Fluorouracil (5-FU) 375
12.12.2 Irinotecan 376
12.12.3 Oxaliplatin 376
12.12.4 Bevacizumab 376
12.12.5 Cetuximab 376
12.12.6 Chemotherapy Induced Hepatic Injury 377
12.13 Ablative Therapy 377
12.14 Questions, Controversies and Future Developments 378
12.15 Conclusion 378
References 379
13 Evaluation and Management of Liver Metastases from Non-gastrointestinal Cancer 384
13.1 Introduction 385
13.2 Pathophysiology of Liver Metastasis 386
13.3 A Surgical Approach to Liver Metastases 388
13.3.1 Breast Cancer 390
13.3.2 Renal Cell Cancer 392
13.3.3 Gynecological Cancer 394
13.3.4 Melanoma 396
13.3.5 Bronchopulmonary Neuroendocrine Tumors 398
13.3.6 Testicular Cancer 399
13.4 Conclusions 400
References 400
14 Proteomic Profiling of Hepatic Metastases: Paving the Way to Individualized Therapy 403
14.1 Introduction 404
14.2 Proteomic Analysis in Clinical Practice: The Present and the Future 407
14.3 Novel Tools for Proteomics Investigation 408
14.4 Sample Preparation and Proteome Stability 411
14.5 Proteomics in Neoplastic Progression, What Are We Learning from Clinical Experience and Where Are We Going? 412
14.6 Conclusions and Future Directions 415
References 416
15 Targeting Angiogenesis in the Treatment of Hepatic Metastasis 419
15.1 Introduction 420
15.2 Angiogenesis and Tumor Metastasis 421
15.2.1 Angiogenic Factors 422
15.2.1.1 VEGF 422
15.2.1.2 Other Angiogenesis Factors 423
15.3 Angiogenesis Inhibitors 423
15.4 Clinical Studies 424
15.4.1 Bevacizumab for Liver Metastatic Colorectal Cancer 424
15.4.2 Bevacizumab for Neuroendocrine Tumors 426
15.5 Hepatic Toxicity 427
15.6 Conclusion 429
References 429
16 Uveal Melanoma – A Paradigm of Site-Specific Liver Metastasis 433
16.1 Introduction 434
16.2 Liver Metastasis 435
16.3 Systemic Disease 436
16.4 Molecular Mediators of UM Progression and Metastasis 437
16.4.1 HGF/SF and C-Met 438
16.4.2 IGF-1 and IGF-1R 438
16.4.3 CXCR4 and CXCL12 439
16.4.4 KISS1 440
16.5 Future Directions 441
References 441
Index 446
| Erscheint lt. Verlag | 1.3.2011 |
|---|---|
| Reihe/Serie | Cancer Metastasis - Biology and Treatment |
| Zusatzinfo | XIV, 446 p. |
| Verlagsort | Dordrecht |
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Medizinische Fachgebiete ► Chirurgie |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Radiologie / Bildgebende Verfahren | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Studium ► Querschnittsbereiche ► Infektiologie / Immunologie | |
| Schlagworte | Breast Cancer • Cancer and inflammation • Colon Cancer • Liver metastasis • Liver microenvironment • surgical oncology |
| ISBN-10 | 94-007-0292-2 / 9400702922 |
| ISBN-13 | 978-94-007-0292-9 / 9789400702929 |
| Haben Sie eine Frage zum Produkt? |
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