Advances in Cancer Research (eBook)

Cover 1
Contents 6
Contributors to Volume 97 10
Dedication 14
George Vande Woude 14
Klas Wiman 15
Olle Ringdeacuten 15
Carl-Henrik Heldin and Arne Oumlstman 15
Alan R. Fersht 16
Peter H. Krammer 16
Kenneth Nilsson 16
Marie Henriksson 17
Chapter 1: Structural Biology of the Tumor Suppressor p53 and Cancer-Associated Mutants 19
Abbreviations 19
I. Introduction 20
II. The Domain Structure of Human p53 20
III. The Structure of the DNA-Binding Domain 22
A. p53C Has Evolved to Be Unstable 25
B. Design of a Superstable Variant of p53C 25
C. From Core Domain to the Full-Length Protein 26
IV. Effects of Common Cancer Mutations 26
A. Structural Effects of Oncogenic Mutations 29
V. Rescuing Mutant p53 33
A. Lessons from Second-Site Suppressor Mutations 34
B. p53C as a Drug Target 34
VI. Concluding Remarks 37
References 37
Chapter 2: Immunotherapy by Allogeneic Stem Cell Transplantation 43
I. Introduction 44
II. Graft-Versus-Host Disease 45
A. Mechanisms 45
B. Acute GVHD 46
C. Chronic GVHD 47
D. Prevention and Treatment of GVHD 47
III. The Graft-Versus-Leukemia Effect 48
A. Preliminary Studies 48
B. Tumor Burden 49
C. Enhancement of Graft-Versus-Leukemia 49
D. Cytotoxic T Cells 51
E. Pathophysiology of Graft-Versus-Leukemia 52
IV. NK Cells 52
V. Early Detection of Relapse 53
A. Minimal Residual Disease 53
B. Mixed Chimerism 53
C. Molecular Detection of CML 54
D. Immunoglobulin and T Cell Receptor Gene Rearrangement 54
VI. The Graft-Versus-Cancer Effect 55
A. Immunotherapy Against Cancer 55
B. Reduced Intensity Conditioning and Allogeneic Stem Cell Transplantation 56
C. Reduced Intensity Conditioning and Stem Cell Transplantation for Renal Carcinoma 56
D. Reduced Intensity Conditioning and Stem Cell Transplantation for Various Solid Tumors 57
E. Combined Liver Transplantation and Stem Cell Transplantation for Liver Cancer 58
F. Future of Stem Cell Transplantation for Solid Cancers 59
VII. Mesenchymal Stem Cells 59
A. Surface Markers and Homing 59
B. Immunity and Safety of MSCs 60
C. Immunomodulation by MSC 60
D. Immunosuppressive Mechanisms by MSCs 61
VIII. Future Directions 62
Acknowledgments 65
References 65
Chapter 3: Mnt Takes Control as Key Regulator of the Myc/Max/Mxd Network 79
I. Myc: The Most Frequently Deregulated Oncogene in Human Tumors 80
A. Myc in Control of Cell Fate 80
B. Deregulation of Myc in Tumor Development 82
C. Myc as a Therapeutic Target for Human Cancer 83
II. Mnt: The Key Transcriptional Regulator of the Myc/Max/Mxd Network 84
A. Discovery and Characterization of Mnt 84
B. Mnt, the Major Myc Antagonist 85
C. Effects of Mnt Deficiency 86
D. Relief of Mnt-Mediated Repression: The Critical Event for Myc Target Gene Activation 87
E. Mnt to Be or Not to Be a Tumor Suppressor 91
III. Concluding Remarks 93
Acknowledgments 93
References 94
Chapter 4: Lytic Cycle Switches of Oncogenic Human Gammaherpesviruses 99
I. Two Life Cycles of EBV and KSHV: Latency and Lytic Replication 100
II. Virally Encoded Lytic Cycle Activator Genes 102
A. Upstream and Downstream Events in Lytic Cycle Activation 103
B. Agents That Induce the Lytic Cycle 107
C. Role of Phosphorylation in the Downstream Functions of the EBV ZEBRA Protein 115
III. Conclusions: Some Unsolved Mysteries About Lytic Cycle Switches of Oncogenic Human Gammaherpesviruses 121
Acknowledgments 123
References 123
Chapter 5: No Life Without Death 129
I. Introduction 129
II. Apoptosis in Life and Disease 130
III. The Apoptotic Machinery 131
A. Mitochondria and Cell Death: The Intrinsic Pathway 131
B. DR-Induced Apoptosis: The Extrinsic Pathway 133
IV. The CD95/CD95L System 134
A. Regulation of CD95L Expression in Activation-Induced Cell Death 136
B. Transcriptional Regulation of CD95L Expression in T Cells 138
C. Regulation of CD95L Expression by Oxidative Signals 141
V. HIV and Apoptosis 144
A. The Genetic Structure of HIV 145
B. HIV Proteins and Apoptosis 145
Acknowledgments 147
References 147
Chapter 6: Control of Apoptosis in Human Multiple Myeloma by Insulin-like Growth Factor I (IGF-I) 157
I. Selected Biological Properties of Human Multiple Myeloma 158
II. Human MM Models In Vitro and In Vivo 160
III. Targeting Anti-apoptosis and Proliferative Signals in Human MM 161
A. Anti-apoptotic Events in Human MM 161
B. The IGF-I Signaling Pathways 164
C. IGF-I as a Growth and Survival Factor in MM 166
D. IGF-I as a Target for Therapy 167
IV. The Effect of Combinational Treatment with PPP on Human MM Cells Is Additive and Synergistic 172
Acknowledgments 177
References 177
Chapter 7: c-MYC Impairs Immunogenicity of Human B Cells 185
I. Introduction 186
II. Personal Perspective by G.W.B. 186
III. Taking Over the Work from Eva and George... 190
A. Growth Pattern and Cell Surface Phenotype of Burkitt's Lymphoma Cells Can Be Recapitulated by c-myc Overexpression in Primary Human B Cells Conditionally Immortalized by EBV 190
B. Conditional B Cells Driven into Proliferation by c-myc Overexpression Loose Their Ability to Stimulate Allogeneic T Cells and Become Invisible to Cytotoxic T Cells 192
C. c-MYC Down-Regulates NF-kappaB and Interferon Response Genes 195
D. c-MYC Impairs the Interferon Response at Different Levels: At the Level of Induction as Well as at the Level of Action of Type I Interferons 198
IV. Discussions 198
Acknowledgments 201
References 202
Chapter 8: Cancer Dormancy: Lessons from a B Cell Lymphoma and Adenocarcinoma of the Prostate 207
I. Introduction 208
II. Scope of the Present Discussion 208
III. Clinical Studies 210
IV. Experimental Dormancy of B Cell Lymphoma 211
V. The Prostate Adenocarcinoma Model 213
VI. Concluding Remarks 215
Acknowledgments 216
References 216
Chapter 9: Therapeutic Targets of Multiple Angiogenic Factors for the Treatment of Cancer and Metastasis 221
I. Introduction 222
II. Tumor Angiogenesis 223
A. Tumor Blood Vessels 223
B. Tumor-Produced Angiogenic Factors 224
C. VEGF Family and VEGF Receptors 225
D. VEGF-A-Induced Angiogenesis and Permeability 226
E. Non-VEGF Angiogenic Factors 228
III. Angiogenesis Inhibitors 228
A. Growth Factor Antagonists 229
B. VEGF-A Antagonists 229
C. Antagonists for Non-VEGF Factors 230
D. Broad-Spectrum Endogenous Inhibitors 230
E. Oral Angiogenesis Inhibitors 231
IV. Lymphangiogenesis and Lymphatic Metastasis 233
V. Clinical Development of Antiangiogenic Drugs 234
VI. Conclusions and Perspectives 235
Acknowledgments 236
References 237
Chapter 10: Novel Three-Dimensional Organotypic Liver Bioreactor to Directly Visualize Early Events in Metastatic Progression 243
I. Introduction 244
A. Metastasis 244
B. Models to Study Metastasis 246
II. Bioreactors 248
A. Liver Bioreactor 250
III. Tumor Growth in the Bioreactor 251
IV. Tumor-Hepatocyte Juxtapositioning 254
V. Future Studies 257
Acknowledgments 259
References 260
Chapter 11: PDGF Receptors as Targets in Tumor Treatment 265
I. Molecular Biology of PDGF 266
A. PDGF Isoforms and PDGF Receptors 267
B. Signaling via PDGF Receptors 267
II. Physiological Roles of PDGF 269
III. Roles of PDGF Receptors in Tumors 270
A. PDGF Stimulation of Malignant Cells 270
B. Tumor Angiogenesis and PDGF Receptor Signaling 275
C. PDGF and Recruitment of Tumor Fibroblasts 277
D. Regulation of Tumor Drug Uptake and IFP by PDGF Receptors 278
E. Implications of Roles for PDGF Receptor Signaling in Metastasis 279
IV. Clinical Studies 281
A. PDGF Antagonists 281
B. Clinical Effects Ascribed to PDGF Receptor Inhibition 282
V. Future Perspectives 284
Acknowledgments 285
References 285
Chapter 12: Extracellular Matrix, Nuclear and Chromatin Structure, and Gene Expression in Normal Tissues and Malignant Tumors: A Work in Progress 293
I. Introduction 294
II. The ECM 295
III. ECM-Response DNA Elements 296
IV. Potential Mechanisms for the Transcriptional Activation of ECM-Response DNA Elements 298
A. Exposure to ECM Influences the Nuclear Translocation and DNA-Binding Properties of SpecificTranscription Factors That Bind to ECM-Response Elements 298
B. Exposure to ECM May Initiate Mechanical Signals That Alter the Organization of Nuclear Factors in a Manner That Promotes Activation of ECM-Response Elements 299
C. ECM-Induced Activation of DNA-Response Elements Involves Mechanisms That Invoke Changes in Chromatin Structure 300
V. Potential Mechanisms Through Which ECM Influences the General Organization of Nuclear Factors and Overall Transcriptional Activity 302
A. Of Mouse and Women: Application to Human Breast Epithelial Cells 302
B. ECM-Induced Differentiation May Involve the Selective Activation of Particular Tissue-Specific Genes, But an Overall Decrease in Gene Activity 303
C. ECM-Induced Changes in Overall Chromatin Structure May Have Profound Implications on Nuclear Organization and Gene Expression 304
VI. Advancing Toward a Deeper Understanding of the Malignant Phenotype 305
VII. A 3D Reconstruction for the Future of Cancer Research 307
Acknowledgments 307
References 307
Chapter 13: Targeted Cancer Therapy: Promise and Reality 313
I. What Is Signal Transduction Therapy? 313
II. Types of Signaling Inhibitors 314
A. Protein Kinases 315
B. Targeting Cellular Proliferation 315
C. Targeting Cell Survival 316
D. Targeting Angiogenesis 316
E. Targeting Nuclear Factors 316
III. Signaling Networks 317
IV. Target and Drug Evaluation Using Preclinical Tumor Models 318
A. In Vitro Screens 318
B. In Vivo Models: Xenografts 319
C. Transgenic Models 320
D. Clinical Trials 321
V. How Successful Is Signal Transduction Therapy in the Clinic? 321
A. CML and Gleevec 322
B. Inhibiting the EGFR Family 325
VI. Using PK Receptors as Homing Molecules for Cancer Therapy 328
VII. Conclusions 329
References 330
Chapter 14: Restoration of Wild-Type p53 Function in Human Tumors: Strategies for Efficient Cancer Therapy 339
I. The Emergence of p53 as a Key Tumor Suppressor 339
II. P53 Biological Activity and Binding to DNA 340
A. p53 Responds to Cellular Stress and Induces Cell Cycle Arrest and Apoptosis 340
B. p53 DNA Binding and Regulation of Transcription of Downstream Target Genes 342
III. Reactivation of Mutant p53 344
A. A Mutant p53-Targeting Peptide 344
B. Second-Site Mutations 344
C. Screening for Mutant p53-Targeting Small Molecules 345
IV. Virus-Based Therapeutic Strategies for Mutant p53-Carrying Tumors 348
A. Adp53 Gene Therapy 348
B. ONYX-015: A Replication-Deficient Adenovirus 348
V. Concluding Remarks 349
Acknowledgments 351
References 351
Index 357