Liver Regeneration and Carcinogenesis (eBook)

Front Cover 1
Liver Regeneration and Carcinogenesis: Molecular and Cellular Mechanisms 4
Copyright Page 5
Contents 8
Contributors 18
Preface 22
Chapter 1. Liver Regeneration Then and Now 26
I. Landmarks 26
II. Normal Adult Rat Liver 27
III. Liver Regeneration 28
IV. Hepatocyte Priming 30
V. Regeneration Signals 32
VI. Conclusions 44
References 44
Chapter 2. Hepatocyte Growth Factor (HGF) and Its Receptor (Met) in Liver Regeneration, Neoplasia, and Disease 52
I. Introduction 52
II. Structural and Functional Aspects of HGF and the HGF Receptor 53
III. HGF Localization 55
IV. Liver and the Processing of HGF 57
V. HGF and the Early Proteolytic Events Following Partial Hepatectomy 62
VI. HGF Localization 65
VII. Summary 68
References 69
Chapter 3. Structure and Functions of the HGF Receptor (c-Met) 76
I. Hepatocyte Growth Factor and Scatter Factor 76
II. HGF Receptor 78
III. Regulation of c-met Expression 85
IV. Role of HGF in Tissue Regeneration and Embryogenesis 86
V. Role of c-met in Carcinogenesis 87
References 88
Chapter 4. Expression and Function of Growth-Induced Genes during Liver Regeneration 96
I. Liver Regeneration: The Important Questions 96
II. Immediate-Early Gene Expression in Hepatic Cells 97
III. Modification of Preexisting Transcription Factors Immediately Following Partial Hepatectomy Turns on Immediate-Early Genes 101
IV. Induction Patterns of 70 Genes Following Partial Hepatectomy Define the Temporal Course of Liver Regeneration 103
V. Transcription Factors Induced in the Regenerating Liver 105
VI. Immediate-Early Genes Involved in Signal Transduction 109
VII. Immediate-Early Genes That Are Secreted Proteins 111
VIII. Liver-Specific Immediate-Early Genes: Relationship to the Maintenance of Hepatocyte Differentiation and Metabolism 112
IX. Immediate-Early Genes in H35 Cells That Are Expressed as Delayed-Early Genes in Regenerating Liver 114
X. Conclusions 116
References 118
Chapter 5. Stem Cells and Hepatocarcinogenesis 124
I. Introduction 124
II. Cellular Biology of the Hepatic Stem Cell Compartment 126
III. Neoplastic Development in the Liver 129
IV. Conclusions 133
References 134
Chapter 6. Contributions of Hepadnavirus Research to Our Understanding of Hepatocarcinogenesis 138
I. General Overview of Hepadnavirus Animal Models and Hepatocarcinogenesis 138
II. Hepatitis B Virus Envelope Protein (HBsAg) Transgenic Mice 142
III. Woodchuck Hepatitis Virus (WHV) Model of Hepatocarcinogenesis 147
IV. Hepadnavirus X Gene Encodes an Oncogenic Transcriptional Transactivator 154
V. Conclusions 159
References 159
Chapter 7. Apoptosis and Hepatocarcinogenesis 166
I. Apoptosis and Other Types of Active Cell Death 166
II. Active Cell Death in the Liver 170
III. Biochemical and Molecular Aspects of Apoptosis 177
IV. Active Cell Death in the Stages of Hepatocarcinogenesis 183
V. Conclusions 191
References 192
Chapter 8. Liver Tumor Promotion and the Suppression of p53-Dependent Cell Cycle Checkpoint Function 204
I. Introduction 12
II. Mechanisms of Cell Cycle Control 205
III. Cell Cycle Checkpoints, Lifespan Extension, and Genetic Instability 206
IV. Isolation of EL/EGV Hepatocytes and Promotion of Hepatocarcinogenesis in Vitro 208
V. Immortal Rat Hepatocytes Require PB for Clonal Expansion 211
VI. Mechanisms of Promotion of Hepatocarcinogenesis by Phenobarbital 216
VII. Conclusions 218
References 219
Chapter 9. Mechanisms of Liver Tumor Promotion 224
I. Introduction 224
II. Stages of Liver Carcinogenesis 226
III. Cell Cycle Regulation and Liver Carcinogenesis 229
IV. TGFß and Liver Carcinogenesis 233
V. Apoptosis and Liver Carcinogenesis 241
VI. Summary 242
References 243
Chapter 10. Hypomethylation of DNA: An Epigenetic Mechanism That Can Facilitate the Aberrant Oncogene Expression Involved in Liver Carcinogenesis 252
I. Introduction 252
II. Epigenetics 255
III. DNA Methylation 255
IV. Working Hypothesis and Experimental Model 260
V. Liver Tumor Promotion: A Role for Hypomethylation of DNA 261
VI. Methyl Deficient Diets 263
VII. DNA Damage and Altered DNA Methylation 265
VIII. DNA Methylation and Chemoprevention 266
IX. Differences in DNA Methylation between Rodents and Humans 268
X. Conclusions 270
XI. Summary 271
References 272
Chapter 11. Transgenic Models of Hepatic Growth Regulation and Hepatocarcinogenesis 282
I. Transgene-Based Strategies for Studying Liver Growth, Development, and Cancer 282
II. Oncogenic Transgenes and Hepatic Neoplasia 284
III. Growth Factor Transgenes and Hepatic Neoplasia 293
IV. Hepatotoxic Transgenes and Liver Neoplasia 296
V. Transgenes and Multistage Carcinogenesis 301
VI. Transgenes and Hepatic Growth Regulation 307
VII. Assessment and Future Directions 314
References 315
Chapter 12. Genetic Susceptibility to Liver Cancer 326
I. Introduction 326
II. Genetics of Human Liver Cancer 327
III. Genetics of Experimental Liver Cancer 330
IV. Conclusion 339
References 340
Chapter 13. Surgical Treatment of Hepatic Tumors and Its Molecular Basis 348
I. Introduction 348
II. Diagnosis of Surgical Liver Tumors 349
III. Indications for Surgical Treatment 351
IV. Surgical Anatomy 361
V. Hepatic Regeneration after Resection and Transplantation: Current Clinical Concepts 367
References 370
Chapter 14. Gene Therapy for the Treatment of Inherited and Acquired Diseases of the Liver 376
I. Human Gene Therapy—A Definition 376
II. Strategies for Liver-Directed Gene Therapy 377
III. Gene Transfer Techniques for Liver-Directed Gene Therapy 386
IV. Clinical Applications of Gene Therapy Directed to the Hepatic Compartment 394
V. Conclusions 402
References 403
Index 410