Polyploidization and Cancer (eBook)

Randy Y.C. Poon is a professor of Biochemistry at the Hong Kong University of Science and Technology. He was educated at Tonbridge School and received his Master of Arts degree from St. Catharine’s College at the University of Cambridge. He then studied for a Doctor of Philosophy degree at the University of Cambridge and Cancer Research UK with Tim Hunt, FR S. Dr. Poon conducted postdoctoral training at the Salk Institute with Tony Hunter, FR S. Dr. Poon is a member of Editorial Board of numerous international journals, including the Biochemical Journal and Cancer Biology and Therapy. His research interests focus on understanding the molecular basis of cell cycle control in normal and cancer cells.

Title Page 3
Copyright Page 4
DEDICATION 5
PREFACE 6
ABOUT THE EDITOR... 7
PARTICIPANTS 8
Table of Contents 10
Chapter 1. POLYPLOIDY, ANEUPLOIDY AND THE EVOLUTION OF CANCER 13
Introduction 13
The Tetraploidy to Aneuploidy Progression in Carcinogenesis 13
Tetraploidy and Aneuploidy in Barrett’s Esophagus 14
p16 15
p53 15
Tetraploidy 15
Aneuploidy 15
Not All Aneuploids Are Equal 16
Why Do Cancer Cells Survive with Such Massive Alterations to Their Genome? 17
Aneuploidy in Development 18
Polyploidy in the Evolution of Species 19
Why Is Aneuploidy Common in Neoplastic Progression? 19
A Competitive Advantage of Aneuploidy 19
Aneuploidy May Generate Advantageous Lesions 20
Aneuploidy May Be an Evolutionarily Neutral By-Product of Carcinogenesis 21
DNA Damage Sensing by Linkage 22
Ancient and Recent Cancer Genes 22
Conclusion 22
Acknowledgements 23
References 23
Chapter 2. MOLECULAR MECHANISMS AND FUNCTION OF THE SPINDLE CHECKPOINT, A GUARDIAN OF THE CHROMOSOME STABILITY 26
Introduction 26
Bipolar Attachment and Chromosome Congression 27
Molecular Basis of the Spindle Checkpoint 28
Activation of the Spindle Checkpoint Signaling 30
Mad2 Template Model 31
Phosphorylation and Spindle Checkpoint Function 32
Silencing the Spindle Checkpoint 33
Additional Surveillance System 33
A Trigger of Tumorigenesis 35
Conclusion 35
References 36
Chapter 3. UNDERSTANDING CYTOKINESIS FAILURE 38
Cytokinesis Occurs in Multiple Stages 38
Stage I. Positioning the Division Plane and Initiating Cytokinesis 39
The Importance of Microtubules 39
The RhoA Pathway Plays an Essential Role in Furrow Initiation 39
Failure of Cytokinesis During Stage I 41
Stage II. Ingression of the Cleavage Furrow 41
Stimulation of Actin Filament Assembly 41
Localization and Activation of Myosin 42
Organization of Actin and Myosin in the Furrow 43
Scaffolding Proteins in the Furrow 44
Anillin 44
Septins 44
Stage III. Formation of the Midbody 45
Stage IV. Abscission 46
Membrane Trafficking and Cytokinesis 46
The Role of the Secretory Pathway 46
The Role of Endocytosis and the Recycling Endosome Pathway 48
Membrane Fusion During Abscission 48
Role of the ESCRT Machinery 48
Regulation of Cytokinesis 49
Regulation of Cytokinesis by Protein Kinases 49
Regulation of Cytokinesis by CDK Activity 49
Regulation by Polo Kinase 50
Regulation by Aurora B and the Chromosome Passenger Complex 51
Regulation of Cytokinesis by Tyrosine Kinases 52
Regulation of Cytokinesis by Lipids 52
Coupling of Cytokinesis to Other Cellular Pathways 53
Cytokinesis and Protein Synthesis 53
Cytokinesis and DNA Replication 53
Cytokinesis and DNA Damage 53
Conclusion 54
Acknowledgements 55
References 55
Chapter 4. DNA DAMAGE AND POLYPLOIDIZATION 67
Polyploidization and Cancer 67
Mechanisms of Polyploidization 68
The DNA Damage Checkpoints 70
Polyploidization Induced by DNA Damage 72
The Sensitivity of Polyploid Cells to DNA Damage 74
Polyploidization and Cancer Therapies 74
Conclusion 75
Acknowledgements 76
References 76
Chapter 5. ROLE OF THE p53 FAMILY IN STABILIZING THE GENOME AND PREVENTING POLYPLOIDIZATION 82
p53—Tumor Suppressor 82
p53 and Genomic Stability 83
p53 and Cell Cycle Checkpoints 83
G1/S Checkpoint 83
p53 Model 83
Intra-S Phase Checkpoint 83
p53 Model 83
G2/M Checkpoint 84
p53 Model 84
Mitotic Checkpoint or Spindle Assembly Checkpoint 84
The p53 Model Is Controversial 84
p53 in DNA Repair 84
Mechanisms of Polyploidization 85
Disadvantages of Polyploidy 85
Tetraploidy Checkpoint Theory 86
Agonists and Antagonists of p53 Function in Genome Stability 87
Introduction to p73 87
p73 Functions 88
The Role of p73 in Genomic Stability 89
Combined Loss of p53 and p73 Leads to Excess Polyploidy and Aneuploidy 89
The Ploidy Defect Is Not Due to a Mitotic Defect but a Failure of Premitotic Mechanisms 89
Excess Failure of the G2/M DNA Damage Checkpoint and Constitutive Deregulation of Cyclin-Cdk and p27/Kip1 Fuel Aberrant Ploidy upon p73 Loss 90
Conclusion 95
References 95
Chapter 6. CENTROSOMES, POLYPLOIDY AND CANCER 101
Introduction 101
The Centrosome Duplication Cycle 102
Aberrant Centrosome Numbers in Cancer Cells 102
Multiple Pathways Can Lead to Aberrant Centrosome Numbers: Studies Using Human Papillomavirus (HPV) Oncoproteins 103
Mechanisms of Centrosome Amplification in Tumor Cells 104
Primary Centrosome Overduplication 104
Permanent Centrosome Accumulation 105
Transient Centrosome Accumulation 107
Aberrant Centrosome Numbers as a Consequence of Polyploidy—Implications for Genomic Instability in Cancer 107
Endoreduplication 107
Abortive Mitoses 107
Cell Fusion 108
DNA Rereplication 108
Aberrant Centrosome Numbers as a Cause of Polyploidy 108
Conclusion 109
Acknowledgements 109
References 109
Chapter 7. POLYPLOIDY: MECHANISMS AND CANCER PROMOTION IN HEMATOPOIETIC AND OTHER CELLS 112
Overview: Characteristics of Polyploidy and Its Induction Under Different Conditions 112
Prevalence of Polyploidy/Aneuploidy in Different Cancers 114
Cancer Theories: Potential Involvement of Aneuploidy in Cancer Promotion 115
The Somatic Gene Mutation Theory 115
The Mutator Phenotype Hypothesis 115
The Genomic Instability Theory 116
The Aneuploidy Theory of Cancer 116
Regulators of Mitosis and Mechanisms Leading to Aneuploidy 116
Stem Cells and Cancer Development 117
Chromosome Passenger Proteins and Their Role in Ploidy Promotion 118
INCENP (Properties and Effects of Its Deregulated Expression on the Cell Cycle) 118
Borealin (Properties and Effects of Its Deregulated Expression on the Cell Cycle) 119
Survivin (Properties and Effects of Its Deregulated Expression on the Cell Cycle) 119
Aurora-B (Properties and Effects of Its Deregulated Expression on the Cell Cycle) 121
Chromosome Passenger Proteins and Cancer (Emphasis on the Role of Aurora-B) 122
Conclusion 123
Acknowledegments 123
References 123
Chapter 8. POLYPLOIDIZATION OF LIVER CELLS 130
Introduction 130
Polyploidization During Normal (Developmental) Liver Growth 131
Mechanism of Binucleation and Polyploidization 133
Polyploidy in Regenerating Liver and During Pathological States 137
Conclusion 139
Acknowledgements 139
References 139
Chapter 9. ANALYSIS OF CELLULAR DNA CONTENT BY FLOW AND LASER SCANNING CYTOMETRY 143
Introduction 143
Supravital Cell Staining 146
DNA Staining after Disruption of Plasma Membrane 147
DNA Staining in Fixed Cells 148
Concurrent Analysis of Cell Surface Antigen and DNA Content 149
Accuracy of DNA Content Measurement 150
Accessibility of DNA in Chromatin to Fluorochromes 150
Fluorochrome Binding to DNA—Mass Action Law 151
Assessment of DNA Ploidy 151
Conclusion 152
Acknowledgement 153
References 153
INDEX 154