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The Biology of Gastric Cancers (eBook)

Timothy Wang, James Fox, Andy Giraud (Herausgeber)

eBook Download: PDF

2009 | 2009
XX, 332 Seiten
Springer New York (Verlag)
978-0-387-69182-4 (ISBN)

Lese- und Medienproben

Ebook-Leseprobe (PDF)

As someone who has spent nearly half his life wondering about the relationship between Helicobacter and gastric cancer, I find this textbook on the subject exciting and timely. In fact, I am not aware of any other volume that has been able to distil so much new knowledge into such a comprehensive account of a poorly understood field. Taking my own view, as a scientist placed in the middle of the spectrum between basic science and clinical medicine, I can see that the editors, Jim Fox, Andy Giraud, and Timothy Wang, provide a broad mix of expertise, which ensures that the subject is treated with the right balance. From clinicopathologic observations in humans, to epidemiology, through animal models, to molecular and cell biology, this team has hit the mark for most readers. Fox is a well-known leader in animal models with broad expertise. He pioneered the field with observations on Helicobacter species in animals, from the time when only one spiral gastric bac- rium was known, 'Campylobacter pyloridis. ' Fox partners with Wang, whose team recently announced a dramatic advance in the field of carcinogenesis-the obser- tion that bone marrow-derived stem cells participate in the changes that become cancer. To this nice mix has been added Andy Giraud from my own country, who brings to the table some remarkable genetic models of gastric cancer based on alterations in the gp130/stat3-signaling pathway.

As someone who has spent nearly half his life wondering about the relationship between Helicobacter and gastric cancer, I find this textbook on the subject exciting and timely. In fact, I am not aware of any other volume that has been able to distil so much new knowledge into such a comprehensive account of a poorly understood field. Taking my own view, as a scientist placed in the middle of the spectrum between basic science and clinical medicine, I can see that the editors, Jim Fox, Andy Giraud, and Timothy Wang, provide a broad mix of expertise, which ensures that the subject is treated with the right balance. From clinicopathologic observations in humans, to epidemiology, through animal models, to molecular and cell biology, this team has hit the mark for most readers. Fox is a well-known leader in animal models with broad expertise. He pioneered the field with observations on Helicobacter species in animals, from the time when only one spiral gastric bac- rium was known, "e;Campylobacter pyloridis. "e; Fox partners with Wang, whose team recently announced a dramatic advance in the field of carcinogenesis-the obser- tion that bone marrow-derived stem cells participate in the changes that become cancer. To this nice mix has been added Andy Giraud from my own country, who brings to the table some remarkable genetic models of gastric cancer based on alterations in the gp130/stat3-signaling pathway.

Foreword 5
Preface 8
Contents 10
Contributors 13
Editors’ Biographies 17
Overview and Pathology of Gastric Cancer 21
Overview 21
Epidemiology 22
The Etiology of Gastric Cancer 23
The Bacterial Agent 25
Host Susceptibility 25
External Environment 26
Models of Gastric Carcinogenesis 28
Pathology 29
Intestinal-Type Adenocarcinomas 30
Diffuse-Type Adenocarcinomas 30
Precancerous Lesions 31
Cancer Control 35
References 38
Epidemiology of Gastric Cancer and Helicobacter pylori 45
Introduction 45
Gastric Cancer Epidemiology 45
Classifications of Adenocarcinomas of the Stomach 46
Incidence of Gastric Cancer 46
Geographical Distribution 47
Trends Over Time 47
Differences in Epidemiology of Various Tumor Types 48
Mortality and Case Fatality 48
Risk Factors for Gastric Cancer, Excluding Helicobacter pylori 49
Genetic Factors 50
Environmental Factors 50
Epstein-Barr Virus–Related Tumors 52
Helicobacter pylori Epidemiology 52
Prevalence and Incidence by Region 53
Risk Factors for Infection 54
Mechanisms of Transmission 55
Links Between Helicobacter pylori and Cancer 57
Effect Modifiers for Helicobacter pylori and Malignancy 59
Genetic Factors 59
Bacterial Factors 59
Environmental Factors 60
Unanswered Epidemiologic Questions 61
Why Do Males Have Higher Risk for Cancer? 61
Is There an African Enigma? 61
Can Treatment of Helicobacter pylori Prevent Cancer? 62
What Is the Best Approach to Helicobacter pylori Prevention? 63
References 64
Diet and Gastric Cancer 78
Introduction 78
Fruits and Vegetables 78
Vitamins and Minerals 80
Carotenoids 80
Observational Epidemiologic Studies 80
Randomized Trials 83
Experimental Studies 84
Vitamin C 86
Observational Epidemiologic Studies 86
Randomized Trials 86
Experimental Studies 87
Vitamin E 88
Observational Epidemiologic Studies 88
Randomized Trials 88
Experimental Studies 89
Selenium 89
Observational Epidemiologic Studies and Randomized Trials 90
Nitrate, Nitrite, and Nitrosamines 93
Alcohol 95
Salt 96
Body Weight 97
Summary 98
References 98
MALT Lymphoma: Clinicopathologic Features and Molecular Pathogenesis 109
Introduction 109
Histologic and Immunophenotypic Features of MALT Lymphoma 110
The Role of H. pylori Infection in MALT Lymphomagenesis 113
Clinical Aspects: Diagnosis and Treatment 114
Clinical Presentation, Diagnosis, and Staging of MALT Lymphoma 114
Treatment Options for MALT Lymphoma 118
Treatment of Early, H. pylori–Associated Gastric MALT Lymphoma 119
Treatment of Helicobacter pylori–Negative, Advanced, or Relapsed Gastric MALT Lymphoma 121
Treatment of High-Grade Gastric Lymphoma 122
Susceptibility to MALT Lymphoma: Genetics of the Host and Pathogen 123
Host Genetic Susceptibility to Gastric MALT Lymphoma 123
Characteristics of Helicobacter pylori Strains Associated with MALT Lymphoma 124
Pathogenesis of Early, Helicobacter pylori–Dependent MALT Lymphoma: Role of T-Cell–Derived Costimulatory Signals 125
Specificity of MALT Lymphoma–Derived Immunoglobulin 128
Pathogenesis of Late, Helicobacter pylori–Independent MALT Lymphoma: Effect of Chromosomal Translocations 129
Molecular Mechanisms of High-Grade Transformation 133
Animal Models of MALT Lymphoma 138
Models of Infection-Induced MALT Lymphoma 138
Transgenic Mouse Models of MALT Lymphoma 142
References 145
Gastrointestinal Stromal Tumors of Gastric Origin 152
Introduction 152
Histologic and Molecular Classification 152
Histology 153
KIT Receptor Tyrosine Kinase Mutations 153
Immunohistochemistry 155
Additional Molecular Factors Relevant to Diagnosis and Treatment 155
Epidemiology 157
Incidence 157
Familial Gastrointestinal Stromal Tumors 158
Clinical Presentation 159
Diagnostic Studies 161
Endoscopy, Fine-Needle Aspiration, and Biopsy 161
Radiographic Studies 162
Prognostic Factors 163
Risk Stratification 163
KIT Mutations 165
Treatment 166
Surgery 167
Chemotherapy and Radiation Therapy 168
Targeted Molecular Therapy 169
Imatinib Mesylate 169
Impact of Tyrosine Kinase Mutations 170
Detection of Response to Imatinib 171
Resistance to Imatinib 172
Sunitinib Malate for Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors 173
Multimodality Treatment of Advanced Disease 173
Surveillance 174
Conclusions 175
References 175
Human Gastric Neuroendocrine Neoplasia: Current Pathologic Status 181
Introduction 181
The Gastric Endocrine Cells 181
Nonneoplastic Lesions 181
Corpus-Fundus 183
Enterochromaffin-Like Cell Hyperplasia 184
Enterochromaffin-Like Cell Dysplasia 184
Mechanisms 185
Antrum 185
Tumors 186
Histology and Grading 189
Clinicopathologic Typing and Prognosis 190
arcinoids 190
Poorly Differentiated Endocrine Carcinomas 192
Tumor-Node-Metastasis Staging 193
Frequency of Enterochromaffin-Like Changes and Carcinoids 194
Technical Notes 194
Final Remarks 194
References 195
Gastric Neuroendocrine Neoplasia 201
Introduction 201
Animal Models of Enterochromaffin-Like Cell Neoplasia 204
Mastomys 204
Gastrin 204
AP-1 and Menin 205
Histamine 1 Receptor 206
CCN2/Connective Tissue Growth Factor 206
Cotton Rat 206
Genetically Engineered Models 208
H2 Receptor Knockouts 208
CCK2 Receptor Knockouts 208
MEN1 Transgenic Mouse 209
SV40 Transgenic Mouse 209
Reg Transgenic Mouse 209
Helicobacter pylori Models 209
Low Acid States/Hypergastrinemia 210
Human Gastric Neuroendocrine Tumors 210
Prevalence 210
Gastric Neuroendocrine Tumors Incidence: Surveillance, Epidemiology, and End Results Database Evaluation 211
General Clinical Presentation 213
Gastrin-Sensitive (Type I/II) Neuroendocrine Tumors 213
Gastrin-Autonomous (Type III) Neuroendocrine Tumors 213
Biologic Relationships 214
Low Acid States 214
Immune Disease 214
Pathology and Pathobiology 214
Histopathology and Histopathogenesis 214
General Pathologic Classification 215
Type I Neuroendocrine Tumors 215
Type II Neuroendocrine Tumors 217
Type III Neuroendocrine Tumors 217
The World Health Organization Pathologic Classification 218
Relationship to Multiple Endocrine Neoplasia Mutations 218
Molecular Biologic Classification 219
Malignant Signatures and Candidate Genes 219
Management Strategy 220
Diagnosis 220
Plasma and Urine Markers 221
Therapy 221
Medical Therapy 221
Endoscopic Therapy 223
Surgical Therapy 223
Type I and II Neuroendocrine Tumors 224
Type III Neuroendocrine Tumors 224
Neuroendocrine Carcinomas 224
Follow-Up Studies 224
Prognostic Features and Outcome Data 224
Type I Neuroendocrine Tumors 225
Type II Neuroendocrine Tumors 225
Type III Neuroendocrine Tumors 225
Neuroendocrine Carcinomas 226
Summary 226
Conclusion 226
References 227
Epstein-Barr Virus and Gastric Cancer 233
Introduction 233
Virology 234
Detection Methods 236
Epidemiology 237
Pathogenesis 239
Clinicopathologic Features of Epstein-Barr–Associated Gastric Cancer 242
Clinical Implications 242
Conclusions and Future Prospects 244
References 244
Role of Host Genetic Susceptibility in the Pathogenesis of Gastric Cancer 250
Introduction 250
Gastric Cancer and Helicobacter pylori Infection 250
Helicobacter pylori and Chronic Gastric Inflammation 251
Helicobacter pylori Infection and the Gastric Cancer Versus Duodenal Ulcer Phenotypes 252
Genetic Polymorphisms in the Interleukin-1 Gene Cluster Increase the Risk of Gastric Cancer and Its Precursors 253
Role of Other Cytokine Gene Polymorphisms 255
Role of Polymorphisms in the Innate Immune Response Genes 257
Overall Contribution of a Host Proinflammatory Genetic Makeup to Pathogenesis of Gastric Cancer 259
Role of Human Leukocyte Antigen Polymorphisms in Gastric Cancer 259
Role of Environmental Factors in Gastric Carcinogenesis 261
Conclusion 261
References 262
Chapter 10Cancer Genetics of Human Gastric Adenocarcinoma 266
Introduction 266
Inherited Susceptibility 266
Familial Clustering 266
Hereditary Diffuse Gastric Cancer 267
E-Cadherin Mutations 267
Idiopathic cases 268
Hereditary Nonpolyposis Colorectal Cancer 268
Li-Fraumeni and Peutz-Jeghers Syndromes 270
Adenomatous Polyposis Syndromes 270
Other Syndromes 270
Host and Environment Observations 271
Host Genotypes Associated with Gastric Adenocarcinoma 271
Molecular Alterations 272
Cytogenetic Studies 272
Chromosomal Instability 273
Microsatellite Instability 274
Molecular Profiling of Human Gastric Adenocarcinomas 275
Specific Somatic Alterations 275
Trefoil Factor Family 1 Loss 275
E-cadherin Mutations and Loss 276
p53 Mutations 277
Kinases/Phosphatases 277
FHIT Mutations 278
c-MET Overexpression 278
Methylation Silencing Alterations 279
Wnt Signaling 279
Growth Factor Alterations 280
Apoptosis Alterations 281
Angiogenesis Alterations 281
Other Alterations 282
Potential Biomarkers 283
Prognostic Markers 283
Chemosensitizati/on Markers 283
Serum Markers 284
Potential Targets for Treatment and Intervention 284
References 285
Genomic and Proteomic Advances in Gastric Cancer 299
Introduction 299
Genomics 300
A Summary of Available Genomic Technologies 300
Design of Genomic Experiments 302
Bioinformatic Analysis of Genomic Data 304
Limitations of DNA Microarray Experiments 305
Genomic Advancements in Clinical and Molecular Correlations in Gastric Cancer 306
Distinguishing Cancer from Noncancer 306
Distinguishing Classes of Gastric Cancer 308
Making Clinical and Molecular Associations in Gastric Cancer 309
Advancements of Gastric Cancer Biology Using Genomics 310
Investigating Metastasis Using Genomics 311
Using Genomics to Understand Pathogenesis of Helicobacter pylori 312
Using Genomics to Understand Host Pathogenesis from Helicobacter pylori Colonization 312
Introducing Genomics-Based Systems Biology to Gastric Cancer 313
Conclusion 314
Proteomics 314
Proteomics: A Brief Overview 314
Technical Challenges in Proteomics 315
Lack of High-Throughput Detection 315
Lack of Amplification Techniques 316
Increased Population Complexity and Dynamic Range 316
Proteomic Platforms 317
Two-Dimensional Polyacrylamide Gel Electrophoresis/Mass Spectroscopy 317
Liquid Chromatography/Tandem Mass Spectrometry 318
Surface-Enhanced Laser Desorption Ionization–Time-of-Flight Platform 319
Antibody Arrays 320
Proteomic Applications in Gastric Cancer 320
Protein Alterations Associated with Helicobacter pylori Infection 320
Protein Alterations Between Nonmalignant and Malignant Gastric Tissues 322
Comparisons Between Metastatic and Nonmetastatic Gastric Cancers 325
Proteomic Differences Between Nonmalignant and Malignant Gastric Juice 326
Comparing Serum from Cancer and Noncancer Patients 327
Concluding Remarks 329
Conclusion 329
References 330
Animal Models of Gastric Carcinoma 336
Introduction 336
Animal Model Basics: Comparative Medicine and Genetics 336
Rodent Stomach Morphology 337
Genetics and Gender 337
Helicobacter-Induced Gastric Carcinogenesis 338
Pathology of Helicobacter-Induced Gastric Carcinoma in Rodents 339
Helicobacter-Induced Gastric Carcinogenesis in Wild-Type Mice 340
Helicobacter felis in Wild-Type Mice 340
Helicobacter pylori in Wild-Type Mice 341
Helicobacter-Induced Gastric Carcinogenesis in Genetically Engineered Mice 341
Helicobacter-Induced Gastric Carcinogenesis in INS-GAS Transgenic Mice 342
Helicobacter-Induced Gastric Carcinogenesis in p27(kip1) / Mice 343
Helicobacter-Induced Gastric Carcinogenesis in Tff2 / Mice 343
Paradoxical Tumor Protection in p53 Haploinsufficient Mice 344
Mixed Results in Apc Haploinsufficient Mice 344
Helicobacter-Induced Gastric Carcinogenesis in Mongolian Gerbils 345
Helicobacter mustelae in Ferrets 347
Gastric Helicobacter spp. in Domestic Cats 348
Gastric Helicobacter spp. in Nonhuman Primates 349
Chemoprophylaxis of Helicobacter-Induced Gastric Carcinogenesis in Rodent Models 349
Chemical Gastric Carcinogenesis 350
N-Nitroso Compounds 350
N-Methyl-N'-nitro-N-nitrosoguanidine in Rats 351
N-Methyl-N'-nitro-N-nitrosoguanidine in Mice 352
N-Methyl-N-nitrosourea in Mice 352
N-Methyl-N'-nitro-N-nitrosoguanidine/N-Methyl-N-nitrosoureain Mongolian Gerbils and Hamsters 353
N-Methyl-N'-nitro-N-nitrosoguanidine in Ferrets 353
N-Methyl-N'-nitro-N-nitrosoguanidine and N-Ethyl-N'-nitro-N-nitrosoguanidinein Dogs 354
N-Methyl-N'-nitro-N-nitrosoguanidine and N-Ethyl-N'-nitro-N-nitrosoguanidine in Nonhuman Primates 354
Duodenogastric Reflux 355
Cigarette Smoke and Tobacco Products 355
High Salt Intake and Gastric Cancer: Risk Factor or Red Herring? 356
High Salt Intake Alone Does Not Induce Gastric Cancer 357
High-salt Variably Promotes Chemical Gastric Carcinogenesis 357
High Salt Does Not Promote Helicobacter-Induced Gastric Carcinogenesis 358
Combined Chemical and Infectious Gastric Carcinogenesis 358
Naturally Occurring Gastric Carcinoma in Animals 359
Naturally Occurring Gastric Carcinoma in Rodents 359
Naturally Occurring Gastric Carcinoma in Dogs and Cats 360
Naturally Occurring Gastric Carcinoma in Nonhuman Primates 360
Conclusions 361
References 361
Insights into the Development of Preneoplastic Metaplasia: Spasmolytic Polypeptide-Expressing Metaplasia and Oxyntic Atrophy 373
Introduction 373
Human Gastric Cancer Pathogenesis 373
Mouse Models of Oxyntic Atrophy and Metaplasia 376
Oxyntic Atrophy and Metaplasia After Chronic Helicobacter felis Infection 377
Oxyntic Atrophy, Hyperplasia, and Metaplasia After Genetic Manipulation 379
Insights into the Origin of Spasmolytic Polypeptide-Expressing Metaplasia After Acute Oxyntic Atrophy 381
Toward a Unified Hypothesis for the Origin of Gastric Metaplasias 383
References 384
Deregulation of E-Cadherin in Precancerous Lesions and Gastric Cancer 388
Introduction 388
E-Cadherin and Cancer: Not Only the Adhesive Glue 388
The Role of E-Cadherin in Metastasis 389
The Role of E-Cadherin in Carcinogenesis 389
Mechanism of Inactivation of E-Cadherin 390
Genetic Inactivation 390
Inactivation by Hypermethylation 391
Transcriptional Regulation 391
Posttranslational Modification 392
Changes of E-Cadherin in Gastric Cancer and Precursors 392
Expression of E-Cadherin 392
Mutation of E-Cadherin Gene 393
CpG Island Methylation of E-Cadherin Gene 393
Soluble E-Cadherin 394
Marker for Prognosis and Evaluation 395
Conclusion 395
References 396
Role of CagA in Helicobacter pylori Infection and Pathology 400
Introduction 400
Type IV Secretion System of Helicobacter pylori 400
Helicobacter pylori CagA Is Translocated From the Bacteria to Gastric Epithelial Cells and Receives Tyrosine Phosphorylation 401
Intracellular Host Cell Targets of Helicobacter pylori CagA Protein 402
Biologic Activities of CagA 403
Diversity of CagA 404
The Distribution of CagA Protein Diversity and Association Between the CagA Protein Diversity and Gastric Cancer 406
The Distribution of CagA Protein Diversity in the World 407
Conclusions 409
References 410
The Role of Helicobacter pylori Virulence Factors in Rodent and Primate Models of Disease 413
Introduction 413
Gastric Peristalsis 414
Motility 414
Adherence 417
Acid Resistance 418
Resistance to Oxidative Stress 419
Prevention of Damage 419
Repair of Damage 421
Immune Evasion/Modulation 423
Bacterial Diversity/Recombination 424
Virulence Factors Associated with Carcinogenesis 425
CagA 425
VacA 427
Conclusion 427
References 428
Host Immunity in the Development of Gastric Preneoplasia 434
Introduction 434
Initiation of the Host Response to Helicobacter pylori 434
Activation of the Adaptive Response 437
Th cells That Control Gastrointestinal Inflammation 439
The Role of Adenosine in Th Cell Function 440
The Selection of Th Cell Response During Helicobacter pylori Infection 441
The Implications of Treg Development and Persistence 442
How Does the Gastric Immune/Inflammatory Response Lead to Neoplasia? 442
Epithelial Responses 443
Regulation of Cellular Responses by Redox: AP Endonuclease-1/Redox Factor-1 444
Regulation of Epithelial Cell Proliferation and Apoptosis by Helicobacter pylori Infection 446
Redox-Sensitive Pathways That Control Apoptosis 447
Redox-Dependent Activities of AP Endonuclease -1Redox factor-1 447
Direct Effects of the Host Response That Predispose to Neoplasia 448
Summary 448
References 449
Atrophy and Altered Mesenchymal–Epithelial Signaling Preceding Gastric Cancer 457
Introduction 457
Causes of Gastric Atrophy 457
The Correa Paradigm 458
Causes of Parietal Cell Atrophy 461
Hypochlorhydria—Cause or Effect? 462
Inflammatory Cytokines 463
Mouse Models of Gastric Atrophy 464
Bacterial Infection 464
Genetic Manipulation 466
Chemical Ablation of Parietal Cells 467
Autoimmune G astritis 467
Zymogenic (Chief) Cell Atrophy 467
Signaling Networks Regulated During Gastric Atrophy 468
Epidermal Growth Factor Receptor Signaling 469
Notch Signaling 470
Wnt Signaling 471
Hedgehog Signaling Pathways 472
Hedgehog Signaling 474
Sonic Hedgehog in the Stomach 475
Regulation of Sonic Hedgehog by Inflammation and Interferon-Gamma 477
Sonic Hedgehog in Gastric Cancer 478
Regional Differences in Hedgehog Signaling and Response 478
References 480
Genetic Models of Gastric Cancer in the Mouse 491
Introduction 491
Trefoil Factor 1 / Mutant 492
The gp130757F757F Knockin Mutant 496
Cdx1 and 2 Transgenic 500
Gastrin Mutants 500
Insulin-Gastrin Transgenic 500
Actin-Gastrin Transgenic 501
Gastrin Knockout 501
Parietal Cell Mutants 502
H+, K+-ATPase Knockout 502
Na+/H+ Exchanger Knockout 503
Potassium Channel Knockouts 503
Histamine (H2) Receptor Knockout 503
IQGAP1 Knockout 504
MTH1 Knockout 504
K19-C2mE Transgenic and Variants 505
Thrombospondin 1 Knockout 505
Transforming Growth Factor alpha Transgenic 505
Dioxin/Aryl Hydrocarbon Receptor Transgenic 506
Klf4 / Knockout 506
p27kip1 / Knockout 507
APCmin/+ and Wnt Signaling Pathway Mutants 507
Major Histocompatibility Complex Class II Knockout 508
Carbonic Anhydrase IX Knockout 508
p53 Hemizygous Knockout 508
SV40 T Antigen Transgenics 509
Carcinoembryonic Antigen SV40 T Antigen Transgenic 509
H+, K+-ATPase beta Subunit SV40 T Antigen Transgenic 509
TGFbeta, TGFbeta Receptor, and Signaling Mutants 510
TGFbeta1 Knockout 510
TGFbeta Type II Receptor Dominant-Negative Transgenic 511
SMAD4 Hemizygous Knockout 511
Elf and SMAD4 Compound Hemizygous Knockouts 512
Runx3 Knockout 512
Forkhead Homolog 6 Knockout 513
Sonic Hedgehog Knockout 513
Occludin Knockout 514
CCR7 Knockout 514
NFkappaB2 Knockout 514
Conclusion 515
References 515
Prostaglandin and Transforming Growth Factor Beta Signaling in Gastric Cancer 521
Introduction 521
Cyclooxygenae-2 in Gastric Cancer 521
Cyclooxygenases and Prostanoids in Tumor Development 521
Arachidonic Acid Cascade and Cyclooxygenase-2 521
Suppression of Intestinal Polyposis by Inhibition of Cyclooxygenae-2 Pathway 522
Expression of Cyclooxygenae-2 and Microsomal Prostaglandin E Synthase-1 in Gastric Cancer 523
Cyclooxygenae-2 Expression in Gastric Tumorigenesis 523
Cyclooxygenae-2 Induction by Helicobacter pylori Infection 523
Induction of Microsomal Prostaglandin E Synthase-1 Expression and Production of Prostaglandin E2 in Gastric Cancer 524
Suppression of Intestinal-Type Gastric Cancer by Cyclooxygenae-2 Inhibition 525
Suppression of Gastric Cancer Development by Nonsteroidal Anti-inflammatory Drugs 525
Suppression of Gastric Cancer by Cyclooxygenae-2 Inhibition in Animal Models 525
Induction Mechanism and Outcome Effects of Cyclooxygenae-2 Pathway in Gastric Cancer 526
Molecular Mechanisms of Cyclooxygenae-2 Induction in Gastric Cancer 526
Angiogenesis Mediated by the Cyclooxygenae-2 Pathway in Gastric Cancer 526
Other Effects Regulated by Cyclooxygenae-2 Pathway in Gastric Cancer 527
Inflammation-Associated Hyperplasia and Metaplasia by Induction of Cyclooxygenae-2 and Microsomal Prostaglandin E Synthase-1 in Mouse Stomach 527
Hyperplasia and Mucous Metaplasia by Activation of Prostaglandin E2 Pathway 527
Inflammatory Response by Infectious Stimulation and Prostaglandin E2 Induction 528
Inflammatory Responses in Helicobacter pylori–Associated Gastric Cancer 529
Wnt and Prostaglandin Signaling in Gastric Cancer 529
Activation of Wnt Signaling in Gastric Cancer Cells 529
Canonical Wnt Pathway in Tumorigenesis 529
Accumulation and Mutation of Beta-Catenin in Gastric Cancer Cells 530
Possible Mechanisms for Wnt Activation in Gastric Cancer 531
Gastric Adenocarcinoma by Cooperation of Wnt Signaling and Prostaglandin E2 Pathway 532
Preneoplastic Lesions by Wnt Activation in Gastric Mucosa 532
Gastric Adenocarcinoma by Cooperation of Wnt and Prostaglandin E2 Pathways 532
Transforming Growth Factor Beta Signaling in Gastric Cancer 534
Suppression of Transforming Growth Factor Beta Signaling in Gastric Cancer 534
Growth Inhibition of Epithelial Cells by Transforming Growth Factor Beta Pathway 534
Mutations in Transforming Growth Factor BetaRII in Gastric Cancer 535
Suppression of TGF-Beta Receptor Type I and Smad Expression in Gastric Cancer 536
Prognosis and Predisposition of Gastric Cancer by Altered Transforming Growth Factor Beta Pathway 536
Gastric Tumorigenesis by Suppression of TGF-Beta in Mice 537
Transforming Growth Factor Beta1 and Smad4 Knockout Mice and Gastrointestinal Tumors 537
Other Mouse Models for Gastric Tumors 537
Activation of TGF-Beta Pathway in Gastric Cancer Progression 538
Transforming Growth Factor Beta as a Promoter of Tumor Progression 538
Effects of Transforming Growth Factor Beta Signaling in Gastrointestinal Cancer 538
Suppression of RUNX3 in Gastric Cancer 539
RUNX3 in Transforming Growth Factor Beta Pathway 539
Suppression of RUNX3 in Mice and Human 539
Suppression of Bone Morphogenetic Protein Signaling in Gastric Cancer 540
Suppression of Bone Morphogenetic Protein in Gastrointestinal Tumors 540
Suppression of Bone Morphogenetic Protein by Noggin in Mouse Stomach 540
Conclusion 541
References 541
REG Proteins and Other Growth Factors in Gastric Cancer 549
Introduction 549
REG Proteins 549
Molecular Structure of the Reg Protein Family 550
REG Protein–Producing Cells and Their Physiologic Role 551
REG Proteins in the Gastritis–Gastric Cancer Sequence After Helicobacter pylori Infection 554
Expression of REG Proteins in Helicobacter pylori Gastritis 554
Mechanism for REG Protein Expression in Gastritis 555
Roles of REG Proteins in Gastric Carcinogenesis 556
Other Growth Factors in Gastric Cancer 559
Epidermal Growth Factor Receptor Family and Its Ligands 560
Vascular Endothelial Growth Factor and Its Receptor 560
Fibroblast Growth Factor Receptor Family, Platelet-Derived Growth Factor, Hepatocyte Growth Factor, and Their Receptors 561
Growth Factors Including REG Proteins as Therapeutic Targets 562
References 563
Role of Bone Marrow–Derived Cells in Gastric Adenocarcinoma 569
Cancer Stem Cell Hypothesis 569
Gastric Cancer Arises from Gastritis Through a Series of Pathologic Stages 571
The Gastric Stem Cell as a Potential Origin of Gastric Cancer Stem Cells 572
Different Types of Adult Stem Cells 574
Overview 574
Adult Stem Cells 575
The Changing Paradigm of Adult Stem Cells 575
Additional Adult Stem Cell Types Recognized 575
Stems Cells: A Continuum of Potential? 576
Bone Marrow–Derived Cells and Cancer 576
Methods to Track Bone Marrow Cells in Murine Studies 578
Cytoplasmic Markers 578
Beta-Galactosidase 578
Green Fluorescent Protein, or Enhanced Green Fluorescent Protein 579
Nuclear Markers 579
Preparing Mice for Transplants 579
The Role of Bone Marrow–Derived Cells During Acute Injury and Tissue Repair 580
Bone Marrow–Derived Cells Engraft with Chronic Inflammation and Give Rise to Metaplasia and Dysplasia 582
Fusion 583
Which Bone Marrow–Derived Cell Gives Rise to Dysplasia? 584
Human Studies and Bone Marrow–Derived Cells in Cancer 585
Summary and Future Directions 588
References 590
Stromal Cells and Tumor Microenvironment 595
Introduction 595
Composition of Stroma 597
Cells Comprising the Vasculature 597
Inflammatory Cells 599
Fibroblasts 599
Myofibroblasts 599
Interactions Within the Stroma 601
Interactions Between Cancer Cells and Their Microenvironment 602
New Therapeutic Tools in Targeting Stromal Cells 602
References 604
Future Prospects for Helicobacter pylori Vaccination 609
Current Therapies of Helicobacter Infection 609
Helicobacter pylori Subverts the Mechanisms of Defense 610
Acidic pH of the Stomach: Role of Urease 610
Helicobacter pylori Is a Flagellated Bacterium Living in the Stomach Lumen 610
Acute Helicobacter pylori Infection Leads to the Development of Innate and Adaptive Immune Responses 611
Chronic Helicobacter pylori Infection Is Characterized by the Presence of a Systemic and Local Anti-Helicobacterpylori Immune Response 611
Preclinical Development of Vaccines Directed Against Helicobacter pylori 612
Animal Models of Helicobacter pylori Infection 612
Curative and Therapeutic Vaccines 613
Source of Helicobacter pylori–Derived Antigens 613
Whole-Cell Vaccines 613
Antigen-Based Vaccines 613
Vaccine Formulations 614
Mechanisms of Action of the Vaccine-Induced Helicobacter Clearance 616
Human Clinical Trials of Anti-Helicobacter pylori Vaccine 616
Urease-Based Vaccine 616
Live Vector Vaccines 617
Inactivated Whole Killed Cells 618
Bottleneck of Vaccine Development 618
Lack of Major Investments 618
Oral Tolerance 618
Helicobacter Immune Escape and/or Helicobacter Immune Control? 619
The Adjuvants 620
Immune Correlates 621
Future of Vaccine Development 621
References 622
Index 629

Erscheint lt. Verlag	25.2.2009
Zusatzinfo	XX, 332 p. 45 illus., 8 illus. in color.
Verlagsort	New York
Sprache	englisch
Themenwelt	Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
	Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
	Naturwissenschaften ► Biologie
	Technik
Schlagworte	Biology • carcinoma • cytokines • Gastric cancer • Genetics • Helicobacter pylori • polymorphisms
ISBN-10	0-387-69182-0 / 0387691820
ISBN-13	978-0-387-69182-4 / 9780387691824

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Print-Ausgabe

Buch | Hardcover

149,79 €