Metastasis of Colorectal Cancer (eBook)

Contents 7
Contributors 9
Introduction 12
1 The Metastatic Process: An Overview 16
1.1 Introduction 17
1.2 Models of Metastasis 18
1.2.1 The Progression Models 18
1.2.2 The Transient Compartment Model 20
1.2.3 The Early Oncogenesis Model 20
1.2.4 The Fusion Model 20
1.2.5 The Gene Transfer Models 21
1.2.6 The Genetic Predisposition Model 21
1.3 Metastatic Steps 22
1.3.1 Development of the Primary Colorectal Neoplasm 24
1.3.1.1 Initiation of the Primary Colorectal Neoplasm 24
1.3.1.2 Influence of Stromal Cells 25
1.3.1.3 Influence of the Extracellular Matrix 26
1.3.1.4 Epithelial-Mesenchymal Transition 27
1.3.1.5 Angiogenesis and Lymphangiogenesis 29
1.3.2 Intravasation 30
1.3.3 Circulation of Cancer Cells 31
1.3.4 Extravasation 33
1.3.4.1 The Adhesion to Endothelial Cells and the Homing Concept of Metastasis 34
1.3.4.2 The Passage Across the Endothelium 37
1.3.5 Colonization of the Secondary Sites 37
1.4 Concluding Remarks 38
References 40
2 Physiopathology of Colorectal Metastasis 47
2.1 Mechanisms of Metastatic Spread 47
2.1.1 Circulatory Spread 47
2.1.1.1 Lymphatic Spread 48
2.1.1.2 Hematogenous Spread 52
2.1.2 Local Spread 55
2.1.3 Tumour Dormancy 56
2.2 Sites of Metastasis and Consequences of Spread 57
2.2.1 Liver 57
2.2.1.1 Steps in Liver Invasion 58
2.2.1.2 Development of Liver Failure 61
2.2.2 Lungs 62
2.2.3 Peritoneum 62
2.2.4 Bone and Bone Marrow 63
2.2.5 Brain Metastasis 64
2.3 Factors Contributing to Metastatic Spread 64
2.3.1 Tumour Factors 64
2.3.1.1 Tissue Factor 64
2.3.1.2 EGFR 65
2.3.2 Host Factors 66
2.3.2.1 Immunity 66
2.3.2.2 Diet, Exercise and Liver Disease 67
2.3.3 Iatrogenic Factors 68
2.4 Conclusion 70
References 71
3 The Genetics of Colorectal Cancer 79
3.1 Introduction 80
3.2 The Adenoma-to-Carcinoma Sequence 80
3.3 Mechanisms of Genomic Instability 81
3.3.1 Overview 81
3.3.2 Chromosome Instability 82
3.3.3 DNA Mismatch Repair Inactivation and Microsatellite Instability 83
3.3.4 Base Excision Repair Defects/MYH 86
3.4 Common Deregulated Signalling Pathways 87
3.4.1 The Wingless/Wnt Signalling Pathway 87
3.4.1.1 APC 87
3.4.1.2 0 ß-Catenin (CTNNB1) 89
3.4.2 K-RAS, B-RAF and RAS-RAF-MAPK Signalling Pathway 90
3.4.2.1 K-RAS 90
3.4.2.2 B-RAF 90
3.4.3 p53 (TP53) 91
3.4.4 The Phosphatidyl Inositol 3-Kinase (PI3K) Pathway 92
3.4.5 TGF-ß Signalling Pathways 93
3.4.5.1 TGFBR2 94
3.4.5.2 The SMAD Genes 95
3.4.5.3 TGF-ß Superfamily Receptors: ACVR2 and BMPR1A 97
3.5 Genome-Wide Analyses of Colorectal Cancer Genes 98
3.6 Metastasis Genes 99
3.7 Conclusions 103
References 105
4 Epigenetics of Colorectal Cancer 115
4.1 Introduction 115
4.2 DNA Methylation Defects in Colorectal Cancer 118
4.2.1 Hypomethylation of DNA 118
4.3 Inactivation of Tumour Suppressor Genes by CpG Island Hypermethylation 122
4.4 Epigenetic Regulation of microRNA in Cancer 125
4.5 microRNAS as Metastasis Switches 126
4.6 Histone Modification Defects in Colon Cancer 127
4.7 Epigenetic Contribution to Colorectal Cancer Metastasis 129
4.8 Epigenetic Biomarkers and Therapies 130
References 132
5 Cancer-Initiating Cells in Colorectal Cancer 140
5.1 Introduction 141
5.2 The Cell Surface Phenotype of Colon Cancer-Initiating Cells 143
5.3 Colon Cancer-Initiating Cells and Chemoresistance 147
5.4 The Role of Cancer-Initiating Cells in Metastases 148
5.5 Cancer-Initiating Cells as Biomarkers 151
5.6 Cancer-Initiating Cells and Clinical Trials 152
5.7 Cell of Origin and C-ICs 153
5.8 Controversies in the Cancer Stem Cell Field 154
5.9 Conclusions 155
References 157
6 Epithelial-Mesenchymal Transition in Colorectal Cancer 160
6.1 Introduction 160
6.2 Tumour Budding as a Prognostic Factor in CRC 162
6.3 WNT Signalling and Nuclear -Catenin in CRC 163
6.4 Intratumoural Distribution of Nuclear -Catenin 164
6.5 WNT Targets in CRC 166
6.5.1 Proliferation-Associated WNT Targets 166
6.5.2 Stemness-Associated WNT Targets 167
6.5.3 Invasion- and Neoangiogenesis-Associated WNT Targets 168
6.6 Inducers of Nuclear ß-Catenin Localization 169
6.7 Regulation of E-Cadherin Expression in CRC 171
6.8 Snail1 and Snail2 173
6.9 ZEB1, ZEB2 and Twist 173
6.10 Conclusion 175
References 176
7 Cell Adhesion Molecules in Colon Cancer Metastasis 186
7.1 Introduction 186
7.2 Integrins 187
7.2.1 Integrin a-Subunits of VLA Subfamily a2, a3, a5 and a6 Chains
7.2.2 av Integrin Subfamily 189
7.2.3 Integrin ß-Subunits ß1, ß4 and ß6 Chains
7.3 E-Cadherin 192
7.4 CD44 and Its Variant Isoforms 195
7.5 Selectins 196
7.5.1 P-Selectin 198
7.5.2 L-Selectin 200
7.5.3 E-Selectin 200
7.6 Immunoglobulin (IG) Superfamily 202
7.6.1 Intercellular Adhesion Molecule-1 (ICAM-1) 202
7.6.2 Carcinoembryonic Antigen (CEA) 203
7.7 Conclusion 206
References 207
8 Epithelial Cell Signalling in Colorectal Cancer Metastasis 217
8.1 Receptor Tyrosine Kinase Signalling in Colorectal Cancer Metastases 218
8.1.1 Receptor Tyrosine Kinase Structure and Mechanisms of Activation 218
8.1.2 Deregulation of Receptor Tyrosine Kinase, a Common Feature in Colon Metastases 220
8.1.2.1 EGFR 220
8.1.2.2 Met/HGF Receptor 222
8.1.2.3 Receptor Tyrosine Kinase-Targeted Therapy 223
8.1.3 The Role of RTK-Proximal Signalling Effectors: Road Maps to the Activation of RAS/MAPK and PI3K/AKT 223
8.1.3.1 The Role of Grb2, Shc, and Gab1 Adaptor Proteins in Colorectal Cancer: An Open Question 225
8.2 The K-RAS Oncogene and Its Downstream Signalling 226
8.2.1 The ERK MAPK Signalling Pathway 227
8.2.2 The PI3K Signalling Pathway 228
8.2.3 Oncogenic K-RAS Signalling Inhibits Epithelial Cell Polarity 230
8.2.4 Oncogenic K-RAS Signalling Promotes Cell Invasion, Migration and Intravasation 232
8.2.5 Oncogenic K-RAS Signalling Prevents Anoikis 235
8.2.6 Oncogenic K-RAS Signalling in Extravasation, Proliferation and Angiogenesis 236
8.3 Conclusions 239
References 241
9 Angiogenesis and Lymphangiogenesis in Colon Cancer Metastasis 254
9.1 Introduction: Tumour-Vascular Interface in Progression and Metastasis of Colorectal Cancer 254
9.2 Mechanisms of Vascular and Lymphatic Growth 256
9.2.1 Formation of Microvascular Networks 256
9.2.2 Lymphangiogenesis and Molecular Mediators of Lymphatic Development 263
9.3 Oncogenic and Microenvironmental Inducers of Tumour Angiogenesis in Colon Cancer 265
9.3.1 Aberrations of Vascular Growth in Cancer 265
9.3.2 Genesis of the Pro-angiogenic Phenotype in Colorectal Cancer 265
9.3.3 Cellular, Molecular and Systemic Triggers of Tumour Angiogenesis 270
9.3.4 Tumour Angiogenesis Metastasis and the Haemostatic System 272
9.4 Effectors of Angiogenesis and Lymphangiogenesis in Primary and Metastatic Colorectal Tumours 274
9.4.1 Angiogenesis in Primary CRC 275
9.4.2 Angiogenesis and Metastasis in CRC 276
9.4.3 Tumour-Associated Lymphatic Circulation in CRC 278
9.5 Targeting Vascular Processes in Metastatic Colorectal Disease 280
9.5.1 Anti-angiogenesis in CRC 280
9.5.2 Anti-lymphangiogenesis 281
9.5.3 Future Directions in Targeting Tumour-Vascular Interface in Metastatic CRC 281
References 285
10 Role of the Host Inflammatory Response in Colon Carcinoma Initiation, Progression and Liver Metastasis 299
10.1 General Introduction 299
10.2 Role of Inflammation in Cancer Progression: Focus on CRC 300
10.2.1 Role of Tumour-Infiltrating Macrophages in Tumour Progression and in CRC 302
10.2.2 Review of Macrophage-Derived Cytokines that Play a Role in CRC and Liver Metastasis 304
10.2.2.1 Role of IL-6 305
10.2.2.2 Role of TNF- and the TNF Receptors 306
10.2.2.3 Role of IL-1 307
10.2.2.4 Role of IL-23 309
10.3 Role of Inflammatory Cytokines and Chemokines in Colon Cancer Cell Invasion and Migration 309
10.4 Tumour Cells Entering the Liver Can Elicit a Rapid Host Inflammatory Response that Promotes Metastasis 311
10.4.1 Pre-extravasation Events 311
10.4.2 Post-extravasation Events 318
10.5 Summary and Future Directions 319
References 321
11 Molecular Prognostic Markers in Colon Cancer 330
11.1 Introduction 331
11.2 Pathologic Prognostic Markers 332
11.3 Genomic Instability 333
11.3.1 Loss of Heterozygosity of 17p and 18q (LOH) 333
11.3.2 DNA -- Ploidy 335
11.3.3 Microsatellite Instability (MSI) 335
11.4 Genetic Markers 336
11.4.1 Metabolic Genes 336
11.4.1.1 Thymidylate Synthase (TS) 336
11.4.1.2 Dihydropyrimidine Dehydrogenase (DPD) 338
11.4.1.3 Methylenetetrahydrofolate Reductase (MTHFR) 339
11.4.2 EGFR Pathway and Potential Markers 339
11.4.2.1 K-Ras 339
11.4.2.2 B-Raf 340
11.4.2.3 Germline Polymorphisms Within the EGFR Signalling Pathway 340
11.4.3 Angiogenesis 341
11.4.3.1 VEGF-Dependent Regulation of Angiogenesis 341
11.4.3.2 VEGF-Independent Regulation of Angiogenesis 342
11.5 Epigenetic Markers 342
11.5.1 CpG Island Methylator Phenotype (CIMP) 342
11.6 Ongoing Trials 343
11.6.1 E5202 343
11.6.2 CALGB-C80405 343
11.6.3 PETACC-8 344
11.7 Conclusions 344
References 347
12 The Sentinel Lymph Node and Staging of Colorectal Cancer 351
12.1 Introduction 352
12.2 Feasibility of Sentinel Lymph Node Mapping 353
12.3 Techniques of Sentinel Lymph Node Diagnosis 353
12.4 Comparaison Between Sentinel Lymph Node Mapping and Standard Methods 360
12.5 Prognostic Relevance of Occult Tumour Cells in Lymph Nodes 361
12.6 Perspectives 363
12.7 Conclusion 363
References 364
13 Treatment of Colorectal Cancer 367
13.1 Surgical Anatomy 367
13.2 Surgical Options 369
13.2.1 Colon Cancer 369
13.2.2 Rectal Cancer 371
13.3 Neo-Adjuvant and Adjuvant Therapy 374
13.3.1 Fluoropyrimidines 374
13.3.2 Oxaliplatin 376
13.3.3 Monoclonal Antibodies 376
13.3.4 Other Agents 376
13.3.5 Radiotherapy 377
13.3.6 Summary of Recommendations for Colon Cancer 378
13.3.7 Summary of Recommendations for Rectal Cancer 379
13.4 Surveillance 379
13.5 Management of Metastatic Disease 380
13.5.1 Resectable Metastases 380
13.5.2 Un-resectable Metastases 383
13.5.3 Resistance to Chemotherapy 383
13.6 Palliative Therapy 384
13.7 Overall Conclusion 384
References 385
14 Diagnosis and Treatment of Rectal Cancer 397
14.1 Introduction 398
14.2 Diagnosis and Staging of Rectal Cancer 399
14.3 The Role of Radiotherapy in the Treatment of Rectal Cancer 401
14.3.1 External Beam Radiation Therapy in Combination with Surgery 401
14.3.1.1 To Prevent Local Recurrence 401
14.3.1.2 To Promote Tumour Down-Staging 401
14.3.1.3 To Facilitate Sphincter Preservation Surgery 401
14.3.1.4 To Provide Local Control Either with Curative or Palliative Intent 403
14.3.2 Timing of Radiation Therapy 405
14.3.3 Radiation Therapy Alone or with Chemotherapy? 407
14.3.4 Dose Fractionation 407
14.3.5 Immediate or Delayed Surgery 408
14.4 Surgery for Rectal Cancer 408
14.4.1 Laparoscopy 410
14.4.2 Local Treatment for Early Rectal Cancer 410
14.5 Adjuvant Chemotherapy 411
14.5.1 Before the Era of TME Surgery 411
14.5.2 Neo-Adjuvant Chemo-Radiation Therapy and TME Era 411
14.6 Conclusion 412
References 413
15 Future Directions 416
References 418
Index 419