Mechanisms of Oncogenesis (eBook)

Preface 5
Contents 7
Contributors 9
1 Cytokines and Stressors: Implications for Cancer Immunotherapy 13
1.1 Introduction 13
1.2 Stressor Effects on Neurochemical Processes 14
1.2.1 Hypothalamic-Pituitary-Adrenal Effects of Stressors 14
1.2.2 Central Neurochemical Effects of Stressors 15
1.3 Cytokine Contribution to the Stress Response and Mood States 16
1.3.1 Neurochemical Consequences of Cytokine Treatment 16
1.3.2 Behavioral Effects of Cytokines 17
1.3.3 Cytokines and Mood States 17
1.4 Immunological Consequences of Stressor Exposure 18
1.5 Stress and Cytokine Production 19
1.5.1 Stressors Influence Th1 and Th2 Derived Cytokines 19
1.5.1.1 Impact on Interferon- 19
1.5.1.2 Impact on Interleukin-4 19
1.5.1.3 Impact on Interleukin-10 and Interleukin-2 20
1.5.1.4 Impact on Interleukin-5 21
1.5.1.5 Impact on Interleukin-6 21
1.5.1.6 Impact on Interleukin-1 and Tumor Necrosis Factor- 22
1.6 Cytokines and Depression 23
1.7 Conclusion 24
References 24
2 The Role of Oncogene Activation in Tumor Progression 31
2.1 Introduction 31
2.2 The Epidermal Growth Factor Receptor Family 31
2.3 Mechanisms of EGFR Dysregulation 32
2.4 The EGFR Receptor Signal Pathway 32
2.5 EGFR-Targeted Therapy in Human Cancers 33
2.6 Role of the EGFR Family Member ErbB2/HER2 in Breast Cancer 33
2.7 The c-Met Receptor 34
2.8 The c-MET-HGF/SF Signal Pathway: Role in Malignant Progression 35
2.9 The Ras Oncogene 36
2.10 Mechanisms of Ras Dysregulation 36
2.11 Ras Mediated Signaling Cascade: Implications in Malignant Progression 37
2.12 Ras in Human Cancers and Targeted Ras Therapies 37
2.13 The Src Kinase Family 38
2.14 Src Dysregulation 38
2.15 The Src Signaling PathwayImplications in Malignant Progression 39
2.16 The c-Myc Oncogene 40
2.17 Mechanisms of c-Myc Dysregulation 40
2.18 The Role of c-myc in Oncogenesis and Malignant Transformation 40
2.19 Conclusion 41
References 41
3 Carcinogenic Effects of Ionising Radiation 54
3.1 Introduction 54
3.2 Historical Highlights 55
3.2.1 Early Radiologists 55
3.2.2 Radium Dial Painters 55
3.2.3 Underground Hard-Rock Miners 55
3.2.4 Medically Irradiated Patients 55
3.2.5 Marshall Islanders Exposed to Radioactive Fallout 56
3.2.6 Experimental Radiation Carcinogenesis 56
3.3 Sources, and Levels of Ionising Radiation in the Environment 56
3.4 Carcinogenic Effects on Specific Tissues 58
3.4.1 Skin 58
3.4.2 Hematopoietic and Lymphoid Tissues 58
3.4.3 Thyroid Gland 59
3.4.4 Other Endocrine Glands 59
3.4.5 Breast 60
3.4.6 Respiratory Tract 60
3.4.7 Gastrointestinal Tract 61
3.4.8 Skeleton 62
3.4.9 Genital Organs 63
3.4.10 Kidney and Urinary Bladder 63
3.4.11 Central Nervous System 64
3.4.12 Cancers, All Sites Combined 64
3.5 Mechanisms and DoseIncidence Relationships 64
3.5.1 Effects of Radiation at the Cellular and Subcellular Levels 64
3.5.2 In Vitro Neoplastic Transformation 65
3.5.3 Carcinogenesis In Vivo 66
3.6 Modifying Effects of Other Physical and Chemical Agents 67
3.7 Assessment of the Carcinogenic Risks of Low-Level Irradiation 67
References 69
4 Chemical Carcinogenesis Role of Chloroform 0 Further Studies 73
4.1 Introduction 73
4.2 Short-Term Studies 73
4.3 Carcinogenicity Studies 74
4.4 Mechanistic and Interactive Effects 74
4.5 Risk 75
4.6 Conclusion 75
4.7 Addendum 75
References 76
5 Use of Organ Explant and Cell Culture in Cancer Research 80
5.1 Introduction to Tissue Culture and References 80
5.2 Standard Definitions and Uses of Tissue Culture 81
5.3 Gene-Expression Profiling 83
5.4 Laser Capture Microdissection 83
5.5 Molecular Imaging 84
5.5.1 In Vitro Mouse Models 85
5.5.2 Magnetic Resonance Imaging 85
5.5.3 Fluorescence Imaging 85
5.5.4 Intravital Microscopy 86
5.5.5 Other Imaging Methods 86
5.5.6 Met-HGF/SF: A System Studied Through Molecular Imaging 87
5.6 Quantitative Analysis 88
5.6.1 Advantages of Quantitative Analysis 88
5.6.2 Methods of Quantitative Analysis 89
5.7 Conclusion 91
References 92
6 Chromosomal Abnormalities in Selected Hematopoietic Malignancies Detected by Conventional and Molecular Cytogenetics: Diagnostic and Prognostic Significance 97
6.1 Introduction 97
6.2 Technological Advances in Cancer Cytogenetics 97
6.2.1 Harvesting of Cells for Cancer Cytogenetics 98
6.2.2 Conventional Cytogenetic Banding Techniques in Cancer Cytogenetics 98
6.2.3 Molecular Cytogenetic Techniques in Cancer Cytogenetics 98
6.3 Numerical and Structural Chromosomal Abnormalities 99
6.4 The Classification of Hematopoietic Malignancies 100
6.5 Cytogenetic Abnormalities in Selected Hematopoietic Malignancies 100
6.5.1 The Philadelphia Chromosome in Chronic Myelocytic Leukemia 100
6.5.2 Chromosomal Abnormalities in Chronic Lymphocytic Leukemia (CLL) 103
6.5.3 T(8 14) in Burkitt Lymphoma/Leukemia
6.5.4 Recurrent Cytogenetic Abnormalities in Acute Myeloid Leukemia (AML) 105
6.5.4.1 AML with t(8 21)(q22
6.5.4.2 AML with t(15 17)(q22
6.5.4.3 AML with inv(16)(p13.1q22) or t(16 16)(p13.1
6.5.4.4 AML with 11q23 (MLL) Abnormalities 106
6.5.5 Recurrent Cytogenetic Abnormalities in Acute Lymphoblastic Leukemia (ALL) 107
6.5.6 Structural Changes in ALL 107
6.5.6.1 t(12 21)(p13.3
6.5.6.2 CBFA2 (AML1/RUNX1) Amplification 108
6.5.6.3 11q23/MLL Gene Rearrangement and t(4 11) in ALL
6.5.6.4 T(1 19)(q23
6.5.6.5 t(17 19)(q22
6.5.7 Numerical Chromosomal Abnormalities in ALL 111
6.5.7.1 Near-Tetraploidy and Near-Triploidy in ALL 111
6.5.7.2 Hyperdiploidy (> 50 Chromosomes)
6.5.7.3 Hyperdiploidy (47--50 Chromosomes) 111
6.5.7.4 Hypodiploidy and Near-Haploidy 111
6.5.8 Selected Recurrent Cytogenetic Abnormalities in Myelodysplastic Syndrome (MDS) 112
6.5.8.1 Cytogenetic Features and Classification Criteria 112
6.5.8.2 Chromosome 5 Abnormality 113
6.5.8.3 Chromosome 7 Abnormality 113
6.5.8.4 Therapy-Related MDS (t-MDS) 114
6.5.9 Myeloproliferative Diseases 114
6.5.9.1 MPDs Other than CML 114
6.6 Conclusion 115
References 116
7 Mechanisms of Cancer Growth and Progression in Lymphoma 122
7.1 Introduction 122
7.2 B Cell Development 122
7.2.1 Early B Cell Maturation: Production of B Cell Receptor (BCR) 123
7.2.2 Late B Cell Maturation: Production of High Affinity Immunoglobulin 123
7.3 Cellular Origin of B Cell Lymphomas 124
7.3.1 Naïve (Circulating) B Cells 126
7.3.2 Germinal Center B Cells 126
7.3.3 Memory B Cells (Post-germinal Center Cells) 127
7.3.4 Molecular Profiling Supports Differentiation Stages for Neoplastic B Cells 127
7.4 Transforming Events in Lymphomagenesis 128
7.4.1 Genomic DNA Modification: Point Mutations and Translocations 128
7.4.2 Transforming Viruses 130
7.5 Role of Antigen Receptor, Microenvironment and Antigenic Stimulation in B-Cell Lymphomas 131
7.5.1 Chronic Infection and Lymphoma 131
7.5.2 Lymphoma and Immunologic Disorders 131
7.6 Functional Consequences of Genetic Lesions in Lymphomagenesis 132
7.6.1 Blocking Apoptosis 132
7.6.2 Enhancing Cell Growth and Proliferation 132
7.6.3 Blocking Differentiation 132
7.7 Conclusion 133
References 133
8 Pediatric Cancer Mechanisms of Cancer Growth and Progression 136
8.1 Introduction 136
8.2 Teratomas 137
8.3 Malignant Tumors 137
8.4 Incidence 137
8.5 Etiology 137
8.6 Environmental Factors 137
8.7 Mechanisms in Carcinogenesis 138
8.8 Chromosme Translocations 138
8.9 Genomic Imprinting 139
8.10 Proto-oncogenes and Oncogenes 139
8.11 Anti-oncogenes 139
8.12 Controlling Gene Expression 140
8.13 DNA Methylation 141
8.14 Zinc-Fingers 142
8.15 Proteomics 142
8.16 Differentiation (Epigenetic Control of Gene Expression) 142
8.17 Loss of Imprinting and Cancer 142
8.18 Cell Proliferation: Proto-oncogenes and Anti-oncogenes 143
8.19 Intercellular Signaling in Development: Sonic Hedgehog (SHH) 143
8.20 Examples: Sequential Gene Expression in Growth and Neoplasia 144
8.20.1 Wilms Tumor 144
8.20.2 Beckwith-Wiedemann Syndrome 145
8.20.2.1 IGF2 145
8.20.2.2 H19 147
8.20.2.3 CDKN1C 147
8.20.2.4 KCNQ1 147
8.20.2.5 KCNQ1OT1 147
8.20.2.6 Other Imprinted Genes 147
8.21 Defects of Differentiation and CNS Tumor Syndromes 147
8.21.1 Neurofibromatosis Type 1 (NF1) 147
8.21.2 Neurofibromatosis Type 2 (NF2) 147
8.21.3 Tuberous Sclerosis (TS) 148
8.21.4 Von Hippel-Lindau Disease (VHL) 148
8.21.5 Turcot Syndrome 148
8.21.6 Gorlin Syndrome (Nevoid Basal Cell Carcinoma Syndrome -- NBCC) 148
8.21.7 Cowden Syndrome 148
8.21.8 Li-Fraumeni Syndrome (LFS) 148
8.22 Similarities Between the Embryo and Cancer 149
References 150
9 Carcinogenetic Pathway of Malignant Melanoma 155
9.1 Introduction 155
9.2 The Role of Photocarcinogenesis in Melanoma 156
9.3 Tumorigenesis of Melanoma 157
9.3.1 p16 (INK4A) 157
9.3.2 p53 (TP53) 158
9.3.3 c-KIT 158
9.3.4 EGFR 159
9.3.5 Cyclin D1 159
9.3.6 Telomerase 160
9.3.7 RAS 160
9.4 Conclusion 161
References 161
10 Ewing Sarcoma: Molecular Characterization and Potential Molecular Therapeutic Targets 164
10.1 Introduction 164
10.2 Etiology and Pathogenesis 164
10.3 Tissue Diagnosis 165
10.4 Prognostic Factors 166
10.5 Treatment and Clinical Outcomes 166
10.6 Approaches to Identify Molecular Targets 167
10.7 Other Therapeutic Alternatives 168
10.7.1 Dendritic Cell Immunotherapy 168
10.7.2 siRNA Targets Against the EWS-FLI1 Oncogene 168
10.8 Future Directions 169
References 169
11 Molecular Mechanisms of Central Nervous System Metastasis 172
11.1 Introduction 172
11.2 The Metastatic Process 172
11.3 Molecular Mechanisms 173
11.4 Hedgehog Signaling Pathway 173
11.5 Transforming Growth Factor- 174
11.6 Angiopoietin Pathway 174
11.7 Matrix Interactions 175
11.8 VEGF Pathway 175
11.9 Other Molecular Pathways 176
11.10 Endogenous Inhibitors 177
11.11 Conclusions 177
References 177
12 Carcinogenesis of Human Papillomavirus in Head and Neck Squamous Cell Carcinoma 183
12.1 Introduction 183
12.2 Squamous Cell Carcinoma 183
12.3 Squamous Epithelium 183
12.4 Carcinogeneis of Head and Neck Squamous Cell Carcinoma 184
12.4.1 Human Papillomavirus (HPV) 184
12.4.2 Role of HPV in Head and Neck Squamous Cell Carcinoma Carcinogenesis 184
12.4.2.1 Epidemiology Analysis 185
12.4.2.2 Laboratory Analysis 185
12.4.2.3 Clinical Analysis 185
12.5 HPV Testing Methods 187
12.6 Conclusion 188
References 188
13 Postmenopausal Hormone Replacement Therapy and Breast Cancer 0 Clinicopathologic Associations and Molecular Mechanisms 191
13.1 Introduction 191
13.2 Endogenous Sex Steroid Hormones and Breast Carcinogenesis 191
13.3 Long Term Use of Postmenopausal Combined Hormone Replacement Therapy (HRT) Is Associated with an Increased Risk of Breast Cancer 192
13.4 Association of HRT Use with Histologic Features and Prognosis of Breast Cancers 194
13.5 Initiation of New Breast Cancers Versus Promotion of Pre-existing Tumors 196
13.6 The Effect of HRT on the Proliferation of Breast Cancers 197
13.7 Effect of HRT on Hormone Receptor and Gene Expression Profile in Breast Cancers 199
13.8 Chemo-/Hormonal Prevention 200
References 200
14 Carcinogenesis of Lung Cancer 207
14.1 Incidence and Epidemiology 207
14.2 Cancer Risk in Smoking 207
14.3 Etiology and Pathogenesis 208
14.4 Histology of Lung Adenocarcinoma, Pneumocyte Hyperplasia and Emphysema 209
14.5 Cytology of Lung Adenocarcinoma 211
14.6 Molecular Pathways 211
14.6.1 Chromosomal Changes 212
14.6.2 Tumor Suppressor Oncogenes 212
14.6.3 Proliferation Markers 214
14.7 Conclusion 215
References 215
15 Genesis of Barrett0s Neoplasia: Current Concepts 217
15.1 Introduction 217
15.2 Etiology and Pathogenesis 217
15.3 Cancer Risk in Barretts Esophagus 217
15.4 Pathology of Barretts Esophagus and of Barretts Esophagus Associated Neoplasia 218
15.5 Differential Diagnosis of Barretts Esophagus 220
15.6 Cytology and Barretts-Associated Neoplasia 221
15.7 Molecular Pathways of Neoplastic Progression 221
15.8 Cell Cycle and DNA Ploidy 221
15.9 Proliferation Markers and Adhesion Molecules 221
15.10 Tumor Suppressor Genes 222
15.11 Death-Inducing Signaling Molecules 222
15.12 Angiogenic Markers 223
15.13 Other Molecular Markers 223
15.14 Omics of Barretts Neoplasia 224
15.15 Conclusion 225
References 225
16 Genesis of Pancreatic Ductal Neoplasia 229
16.1 Introduction 229
16.2 Epidemiology and Etiology 230
16.3 Hereditary Pancreatic Carcinoma 230
16.4 Pancreatic Ductal Adenocarcinoma Precursor Lesions 230
16.5 Genetic and Molecular Alterations in Pancreatic Carcinoma 232
16.5.1 Telomeres 232
16.5.2 Tumor Suppressor Genes 232
16.5.3 Oncogenes 232
16.5.4 BRCA 2 and Fanconi Anemia Pathway Genes: Caretaker Genes 233
16.5.5 Gene Overexpression 233
16.6 Epigenetic Changes 233
16.7 Alterations in Core Signaling Pathways 233
16.7.1 Developmental Signaling Pathways 234
16.8 Altered Protein Expression 234
16.8.1 Cyclooxygenase 2 (COX-2) 234
16.8.2 Matrix Metalloproteinase 7 (MMP-7, Matrilysin) 234
16.8.3 Mucins 235
16.8.4 Cell Cycle Regulation Proteins 235
16.9 Gene Expression Profiling 235
16.10 miRNA Analysis 235
16.11 Progression Pathway in PanINs 235
16.12 Mouse Models of Pancreatic Cancer 236
16.13 Pancreatic Cancer Cell of Origin 237
16.14 Conclusion 237
References 237
17 Recent Advances in the Pathogenesis of Pancreatic Endocrine Neoplasms 241
17.1 Introduction 241
17.2 Categorization and Classification 242
17.3 Composition and Development of the Normal Pancreas 243
17.4 Formation and Regulation of Endocrine Cell Mass 243
17.4.1 Beta-Cell Neogenesis 243
17.4.2 Beta-Cell Replication 245
17.4.3 Beta-Cell Hypertrophy 245
17.4.4 Apoptosis in Beta Cells 245
17.5 Regulators of Pancreatic Endocrine Cell Mass 246
17.6 Pathways of Pathogenesis in Multiple Endocrine Neoplasia Syndromes 248
17.7 Multiple Endocrine Neoplasia Type 1 248
17.7.1 MEN1 Gene 249
17.7.2 MEN-1 Tumorigenesis: A Two-Step Inactivation 249
17.7.3 First Step 249
17.7.4 Second Step 250
17.7.5 Loss of Heterozygosity at 11q13 250
17.7.6 Events Following Inactivation of MEN1 Gene 250
17.8 Von Hippel-Lindau Syndrome 251
17.9 Neurofibromatosis Type 1 251
17.10 Tuberous Sclerosis 251
17.11 Findings of Molecular Genetic Analyses 252
17.11.1 Comparative Genomic Hybridization 254
17.11.2 Specific Chromosomal Aberrations 254
17.11.3 Cell Cycle Regulators 258
17.11.4 Gene Expression Profiling 260
17.12 Additional Evidence in Support of Pancreatic Endocrine Tumorigenesis 260
17.13 Summary 262
References 263
18 Mechanisms of Carcinogenesis in Colorectal Cancer 273
18.1 Introduction 273
18.2 Chromosomal Instability and Microsatellite Instability Pathways 274
18.3 APC and -Catenin 274
18.4 K-ras and p53 274
18.5 DCC 275
18.6 DNA Mismatch Repair (MMR) Genes 275
18.7 TGF Pathway 276
18.8 MicroRNAs 277
18.9 Conclusion Remarks 277
References 278
19 Carcinogenetic Pathway of Superficial Low-Grade Urothelial Carcinoma 282
19.1 Introduction 282
19.2 Chromosomal Aberrations 283
19.3 Activation of Tyrosine Kinase Receptor and Pathway 283
19.3.1 Fibroblastic Growth Factor Receptor 3 (FGFR3) 284
19.3.2 Phosphatidylinositol 3 Kinase p110 (PI3KCA) 284
19.3.3 Ras 284
19.3.4 Other Tyrosine Kinase Receptors 285
19.4 Conclusion 285
References 285
20 Carcinogenetic Pathway of Urothelial Carcinoma 288
20.1 Introduction 288
20.2 p53 Cell Cycle Regulation Pathway 289
20.3 Ras-MAPK Signal Transduction Pathway 291
20.4 Retinoblastoma Pathway 291
20.5 Combined Effects of p53, p21 and Rb 293
20.6 Angiogenesis 293
20.7 DNA Methylation 294
20.8 Conclusion 294
References 294
21 Mechanisms of Carcinogenesis in Prostate Cancer 297
21.1 Introduction 297
21.1.1 Prostate Cancer Subtypes 297
21.1.1.1 Hereditary (Genetic Material Damage): Familial, Racial 297
21.1.1.2 Sporadic (Genetic Material Damage): Diet, Age, Occupation 298
21.2 Genetics 298
21.2.1 RNASEL 298
21.2.2 MSR1 298
21.3 Inflammation and Prostate Cancer 299
21.3.1 Proliferative Inflammatory Atrophy (PIA) 299
21.3.2 GSTP1 (p Class Gluthatione S-Transferase Gene) 299
21.3.3 NKX3.1 300
21.3.4 Additional Genes 300
21.3.4.1 OOG1 300
21.3.4.2 CHECK2 300
21.3.4.3 BRCA2 300
21.4 Cyclooxygenase 2(COX-2) Pathway and Pc Relation 300
21.5 Hormonal Related Theories of Prostate Carcinogenesis 301
21.5.1 Androgen Receptor Gene (AR) 301
21.5.2 Cytochrome P-450c17 (CYP17) Gene 301
21.5.3 5-Alpha-Reductase Type II (SRD5A2) Gene 302
21.5.4 Estrogens and Prostate Cancer 302
21.6 Conclusion 303
References 303
22 HPV in Cervical Carcinoma 307
22.1 Introduction 307
22.2 Human Papillomavirus (HPV) 307
22.3 Detection of HPV and Cervical Lesions 308
22.3.1 Papanicolaou (PAP) Smear 308
22.3.2 Immunohistochemistry 308
22.3.3 In Situ Hybridization (ISH) Assays 309
22.4 Dysplasia and the Progression to Carcinoma 310
22.5 Prevention and Therapy 311
References 311
Index 313