Bagley The Tumor Microenvironment

1. Auflage 2010
ISBN: 978-1-4419-6615-5
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 770 Seiten

Reihe: Cancer Drug Discovery and Development

The fact that tumors are composed of both tumor cells and host cells has long been known. These tumor-associated cells include vascular endothelial cells and pe- cytes, as well as inflammatory cells such as neutrophils, monocytes, macrophages, mast cells and eosinophils, and lymphocytes. The tumor cells also interact with stromal cells and with elements of the tissue extracellular matrix. What has been less appreciated is the role that these cells could have in modulating the growth, invasion, and metastasis of the tumor. Early on, the elements of what we now call the tumor microenvironment were considered to be more or less innocent bysta- ers to the role of the tumor cells as they grew and invaded local sites. Today, there is an increased understanding of the critical role of the tumor microenvironment as dramatically influencing the course of tumor development and dissemination. This volume represents a superb compilation of the latest thoughts and data regarding the role of each essential component of the tumor microenvironment in cancer development and progression. Perhaps, the earliest recognition of the role of nonmalignant cells as cancer re- lators was the recognition that lymphocytes can participate in what was termed “immune surveillance” in the 1960s. Our understanding of tumor immunity has improved markedly since then, and there are now successful clinical studies sh- ing the potential use of immune-based therapies in cancer treatment.

Autoren/Hrsg.

Bagley, Rebecca G.

Inhaltsverzeichnis

1;The Tumor Microenvironment;3
1.1;Preface;5
1.2;Contents;7
1.3;Contributors;11
1.4;Part I Physiological Parameters;19
1.4.1;Chapter 1: Combination Strategies Targeting Hypoxia Inducible Factor 1 (HIF-1) for Cancer Therapy;20
1.4.1.1;Introduction;20
1.4.1.2;Small Molecule Inhibitors of HIF-1;22
1.4.1.3;Targeting HIF-1: Single Agent or Combination?;25
1.4.1.3.1;Molecularly Targeted Agents and HIF-1 Inhibition;26
1.4.1.3.2;Hypoxic Cells Are More Resistant to Chemotherapy and Radiation Therapy;27
1.4.1.3.2.1;Combination of HIF-1 Inhibitors with Chemotherapy;27
1.4.1.3.2.2;Combination of HIF-1 Inhibitors with Radiation Therapy;28
1.4.1.3.3;Intratumor Hypoxia as a Potential Mechanism of Resistance to Anti-angiogenic Therapies;29
1.4.1.3.3.1;Combination of Anti-angiogenic Therapies and HIF-1 Inhibitors;30
1.4.1.3.4;Cancer Cell Metabolism and the Hypoxic Tumor Microenvironment;31
1.4.1.3.4.1;HIF-1 Inhibitors in Combination Strategies Targeting Tumor Metabolism;31
1.4.1.4;Conclusion;32
1.4.1.5;References;32
1.4.2;Chapter 2: The Tumor Microenvironment: New Insights into Regulation of Tumor pH by Carbonic Anhydrases;39
1.4.2.1;Biological Importance of pH;39
1.4.2.2;Sources of Cellular Acid;41
1.4.2.2.1;Cellular Respiration;41
1.4.2.2.2;The Warburg Effect;42
1.4.2.3;Transport of Acid Across the Surface Membrane;44
1.4.2.3.1;Intracellular and Extracellular pH in Tumors;44
1.4.2.3.2;Regulation of Tumor pH by Membrane Transport;44
1.4.2.3.3;Efflux of Metabolic Acid;45
1.4.2.3.4;Buffering of H+ Ions;46
1.4.2.3.5;Extrusion of H+ Ions;46
1.4.2.3.6;Regulation of pH Using Nonrespiratory Sources of H+ Ions;47
1.4.2.4;Role of Carbonic Anhydrase in Acid-Equivalent Transport;48
1.4.2.4.1;Intracellular and Extracellular Carbonic Anhydrase Isoforms;48
1.4.2.4.2;Facilitated CO2 Diffusion;48
1.4.2.4.3;Facilitated H+ Diffusion;50
1.4.2.4.4;The Transport Metabolon;50
1.4.2.4.5;The Dominant Role for Carbonic Anhydrase in Tumors;51
1.4.2.5;Future Directions and Outlook for Therapy;51
1.4.2.6;References;53
1.4.3;Chapter 3: Hypoxia, Gene Expression, and Metastasis;58
1.4.3.1;The Link Between Hypoxia and Metastasis;59
1.4.3.2;Causes and Consequences of Tumor Hypoxia;60
1.4.3.3;HIF Regulation by Oxygen;61
1.4.3.4;HIF Regulation by Genetic Alterations of Upstream Regulators;62
1.4.3.5;HIF Target Genes Involved in the Metastatic Process;64
1.4.3.6;Hypoxia, Cancer Stem Cells, and Metastasis;66
1.4.3.7;Conclusion;68
1.4.3.8;References;68
1.4.4;Chapter 4: Molecular Mechanisms Regulating Expression and Function of Cancer-Associated Carbonic Anhydrase IX;74
1.4.4.1;Abstract;74
1.4.4.2;Carbonic Anhydrases;74
1.4.4.3;Molecular Features of CA IX;77
1.4.4.4;CA IX Tissue Distribution;79
1.4.4.5;Regulation of CA IX Expression;80
1.4.4.6;Role of CA IX in Cancer;83
1.4.4.7;Clinical Value of CA IX;87
1.4.4.8;CA IX Targeting Strategies;90
1.4.4.9;Conclusion;95
1.4.4.10;References;95
1.4.5;Chapter 5: Glycolytic Pathway as a Target for Tumor Inhibition;106
1.4.5.1;Introduction;106
1.4.5.2;Alterations of Glucose Metabolism in Cancer;109
1.4.5.2.1;Overexpression of Glycolytic Enzymes in Cancer Favors Aerobic Glycolysis;110
1.4.5.2.1.1;GLUT1;110
1.4.5.2.1.2;HKII;111
1.4.5.2.1.3;PFK1;111
1.4.5.2.1.4;PKM2;112
1.4.5.2.1.5;LDH-A;112
1.4.5.2.1.6;The PPP;113
1.4.5.2.2;Mitochondrial Dysfunction and Increased Glycolysis in Cancer;114
1.4.5.2.3;Tumor Microenvironment and Selection of Highly Glycolytic Cancer Cells;115
1.4.5.2.3.1;HIF-1 and Glycolysis;115
1.4.5.2.3.2;HIF-1 and Mitochondria;116
1.4.5.2.4;Mutations of Tumor Suppressor Genes and Metabolic Alterations;118
1.4.5.2.4.1;p53 Regulation of Glycolysis and Mitochondrial Respiration;118
1.4.5.2.4.2;AMPK and Glycolytic Regulation;119
1.4.5.2.5;Activation of Oncogenes and Increased Glycolysis;119
1.4.5.2.5.1;c-Myc;119
1.4.5.2.5.2;Ras;120
1.4.5.2.5.3;PI3K/Akt Pathway;120
1.4.5.3;Glycolytic Pathway as a Target for Tumor Inhibition;121
1.4.5.3.1;2-Deoxyglucose;122
1.4.5.3.2;3-Bromopyruvate;122
1.4.5.3.3;Lonidamine;123
1.4.5.3.4;Oxythiamine and 6-Aminonicotinamide;124
1.4.5.3.5;Dichloroacetate;124
1.4.5.3.6;Other Metabolic Modulators;125
1.4.5.4;Summary;125
1.4.5.5;References;126
1.5;Part II Malignant Cells;134
1.5.1;Chapter 6: Aberrant DNA Methylation in Cancer Cells;135
1.5.1.1;Introduction;135
1.5.1.2;Characteristics of DNA Methylation;136
1.5.1.2.1;Maintenance of DNA Methylation Statuses;136
1.5.1.2.2;Regulation of Gene Transcription by DNA Methylation;138
1.5.1.2.3;Maintenance and De Novo DNA Methylases;139
1.5.1.3;Methylation Alterations in Cancer Cells;139
1.5.1.3.1;Genome-Overall Hypomethylation;139
1.5.1.3.2;Aberrant DNA Methylation of CpG Islands;140
1.5.1.3.3;Driver Methylation and Passenger Methylation;141
1.5.1.4;Possible Involvement of Altered Methylation in Tumor Microenvironments;141
1.5.1.4.1;Unique Natures of Aberrant DNA Methylation, in Contrast with Mutations;141
1.5.1.4.2;Field for Cancerization and DNA Methylation;142
1.5.1.4.3;Epithelial-Mesenchymal Transition and DNA Methylation;142
1.5.1.4.4;Tumor Microenvironments and DNA Methylation;143
1.5.1.5;Epilogue;144
1.5.1.6;References;144
1.5.2;Chapter 7: DNA Repair and Redox Signaling;147
1.5.2.1;Introduction;150
1.5.2.2;Overview of DNA Repair Pathways;151
1.5.2.2.1;DR;151
1.5.2.2.2;BER;153
1.5.2.2.3;MMR;154
1.5.2.2.4;NER;155
1.5.2.2.5;NHEJ Repair;157
1.5.2.2.6;HR;157
1.5.2.3;Overview of Redox Signaling;158
1.5.2.3.1;The Thioredoxin (Trx) System;159
1.5.2.3.2;The Glutaredoxin/Glutathione (GRX/GSH) System;160
1.5.2.3.3;Roles of Redox Systems;160
1.5.2.4;The Redox Activity of APE1;161
1.5.2.4.1;How APE1 Performs Its Redox Functions;162
1.5.2.4.2;APE1-Regulated Transcription Factors and Their Link to DNA Damage Repair;162
1.5.2.4.3;p53;163
1.5.2.4.4;AP-1;166
1.5.2.4.5;HIF-1a;167
1.5.2.5;Other Global Influences of APE1;168
1.5.2.5.1;Cell Survival;169
1.5.2.5.2;Angiogenesis;170
1.5.2.5.3;Inflammation;171
1.5.2.6;DNA Repair in the Tumor Microenvironment;172
1.5.2.7;Modulating APE1’s Activities as a Cancer Therapeutic Approach;173
1.5.2.8;Conclusions;176
1.5.2.9;References;176
1.5.3;Chapter 8: Cancer Stem Cells and Microenvironment;183
1.5.3.1;Introduction;183
1.5.3.2;ESCs: A Prototype Model of Stem Cell Biology;186
1.5.3.3;Stem Cells and Microenvironment;190
1.5.3.4;CSCs and the Microenvironment;192
1.5.3.5;Concluding Remarks;194
1.5.3.6;References;195
1.5.4;Chapter 9: Epithelial–Mesenchymal Transition in Development and Diseases;200
1.5.4.1;Overview of EMT;200
1.5.4.2;Type 1 EMT in the Formation of Mesoderm and Neural Crest;202
1.5.4.2.1;Mesoderm Formation;203
1.5.4.2.2;Neural Crest Formation;204
1.5.4.2.3;MET;204
1.5.4.3;Type 2 EMT in Tissue and Organ Fibrosis;204
1.5.4.3.1;Implications of EMT in Fibrosis;204
1.5.4.3.2;Re-epithelialization of Wounded Skin;205
1.5.4.4;Type 3 EMT in Cancer Metastasis;206
1.5.4.4.1;EMT Stimuli from Tumor Microenvironment;206
1.5.4.4.2;Molecular Regulation of EMT;209
1.5.4.4.3;Signaling Pathways;210
1.5.4.4.4;Cytokines;212
1.5.4.4.5;Hypoxia;214
1.5.4.4.6;EMT Generates Cancer Stem Cells;215
1.5.4.4.7;Genetic and Epigenetic Control of EMT;215
1.5.4.4.8;Micro RNA for EMT;216
1.5.4.5;Perspective;217
1.5.4.6;References;218
1.5.5;Chapter 10: Invasion and Metastasis;225
1.5.5.1;Tumors as Tissues;225
1.5.5.2;Metastatic Disease;226
1.5.5.3;Metastatic Cascades;226
1.5.5.4;Migration, Invasion, and Metastasis;228
1.5.5.5;Rethinking Metastasis;233
1.5.5.6;Conclusions;236
1.5.5.7;References;237
1.5.6;Chapter 11: Dormancy of Disseminated Tumor Cells: Reciprocal Crosstalk with the Microenvironment;241
1.5.6.1;General Concepts on Tumor Cell Dormancy in the Context of Cancer Progression;241
1.5.6.1.1;Dormancy of Micrometastasis;243
1.5.6.1.1.1;Angiogenic Dormancy;243
1.5.6.1.1.2;Immunity-Driven Dormancy of Micrometastasis;246
1.5.6.1.2;Cellular Dormancy;248
1.5.6.2;Cellular Dormancy and the Microenvironment;250
1.5.6.3;Stroma-Associated Factors and Tumor Cell Dormancy;253
1.5.6.3.1;Collagen Matrix Signaling;253
1.5.6.3.2;Hormone Depletion and Dormancy;254
1.5.6.3.3;TGFb Signaling;255
1.5.6.4;Models to Study Dormancy;257
1.5.6.5;References;260
1.6;Part III Vasculature And Stroma;267
1.6.1;Chapter 12: Impact of Endothelial Progenitor Cells on Tumor Angiogenesis and Outcome of Antiangiogenic Therapy: New Perspecti;268
1.6.1.1;Introduction;268
1.6.1.2;The Identification of EPCs;270
1.6.1.3;The Controversy Surrounding Functions of EPCs;270
1.6.1.4;The Controversy About the Definition of EPCs;273
1.6.1.5;EPCs as a Surrogate Biomarker for Antiangiogenic Therapy;275
1.6.1.6;Therapy-Induced EPC Mobilization and Tumor Vessel Incorporation;276
1.6.1.7;Conclusions;280
1.6.1.8;References;280
1.6.2;Chapter 13: Bone Marrow Derived Mesenchymal Stem/Stromal Cells and Tumor Growth;285
1.6.2.1;Introduction;286
1.6.2.2;Characteristics of CAFs;286
1.6.2.3;Bone Marrow Derived MSCs as Source of CAFs;287
1.6.2.4;Alterations in Tumor Associated Stromal Cells;289
1.6.2.5;Implications of MSCs as a Source of CAFs: A Model to Study Tumor Stroma Interactions;290
1.6.2.6;Activation of BMD MSCs and Growth of Tumors;291
1.6.2.6.1;Speculation on Role of Chemokines on Activation of Circulating MSCs and Effect on Tumor Growth in African American Individuals ;291
1.6.2.6.1.1;Lack of DARC Expression, Circulating Chemokines and Pathological Conditions;292
1.6.2.6.1.2;DARC Expression and Cancer in African American Men;293
1.6.2.7;Activation of Bone Marrow-Derived MSCs and Metastasis;293
1.6.2.8;Conclusion;295
1.6.2.9;References;295
1.6.3;Chapter 14: Integrin Signaling in Lymphangiogenesis;299
1.6.3.1;Introduction;299
1.6.3.2;Lyphangiogenesis;300
1.6.3.2.1;Lymphatic Vasculature;300
1.6.3.2.2;Lymphatic Makers;301
1.6.3.2.3;Induction of Lymphangiogenesis;301
1.6.3.2.4;Lymphangiogenesis and Pathology;303
1.6.3.3;Integrins;304
1.6.3.3.1;Integrin Expression and Function;304
1.6.3.3.2;Role of Integrins in Promoting Endothelial Cells Migration, Proliferation, and Survival;306
1.6.3.3.3;Ligand Specificity of Integrins;306
1.6.3.3.4;Integrin Signaling;307
1.6.3.3.4.1;Fak;307
1.6.3.3.4.2;Shc;309
1.6.3.3.4.3;Rho Family of Small GTPases;310
1.6.3.3.4.4;Talin;310
1.6.3.3.4.5;Vinculin;311
1.6.3.3.4.6;Paxillin;311
1.6.3.4;Intergrins and Lymphangiogenesis;311
1.6.3.4.1;a9ß1 ;311
1.6.3.4.2;a1ß1 and a2ß1;312
1.6.3.4.3;a5ß1;312
1.6.3.4.4;a4ß1 ;312
1.6.3.5;Conclusion;313
1.6.3.6;References;313
1.6.4;Chapter 15: Role of Pericytes in Resistance to Antiangiogenic Therapy;320
1.6.4.1;Introduction;320
1.6.4.2;Biology, Physiology, and Pathology of Pericytes;321
1.6.4.3;Pericytes and Tumor Angiogenesis;322
1.6.4.4;Pericytes and Resistance to Antiangiogenic Therapy;324
1.6.4.4.1;VEGF Pathway and Pericytes in Tumor Angiogenesis;324
1.6.4.4.2;Resistance to Antiangiogenic Therapy;324
1.6.4.4.3;Targeting Pericytes for Antivascular Strategies;326
1.6.4.5;Conclusions;327
1.6.4.6;References;329
1.6.5;Chapter 16: Tumour-Promoting Stromal Myofibroblasts in Human Carcinomas;333
1.6.5.1;Introduction;333
1.6.5.2;Myofibroblasts Involved in Tissue Fibrosis Share Characteristics with Tumour-Associated Myofibroblasts;335
1.6.5.3;Carcinoma-Associated Fibroblast Characterised as Tumour-Promoting Myofibroblasts;336
1.6.5.4;Somatic Genetic and Epigenetic Alterations in Tumour-Associated Stroma;339
1.6.5.5;Heterogeneous Cellular Origins of Carcinoma-Associated Myofibroblasts;341
1.6.5.6;Normal Stroma-Derived Tumour-Suppressive Signalling and Tumour Stroma-Derived Tumour-Promoting Signalling;343
1.6.5.7;Tumour-Associated Stroma Promotes Neoangiogenesis;345
1.6.5.8;Roles of Tumour-Associated Stroma in Promoting Cancer Cell Invasion and Metastasis;348
1.6.5.9;Conclusions/Perspectives;350
1.6.5.10;References;351
1.7;Part IV Immune-Mediated Cells;358
1.7.1;Chapter 17: Mast Cells and Tumor Microenvironment;359
1.7.1.1;Introduction;360
1.7.1.2;Mast Cell Biology;362
1.7.1.3;Mast Cells Could Be Beneficial to the Tumor;363
1.7.1.4;Breast Cancer;365
1.7.1.5;Melanoma and Basal Cell Carcinoma;366
1.7.1.6;Pancreatic Cancer;366
1.7.1.7;Lung Cancer;367
1.7.1.8;Mast Cells Could be Detrimental to the Tumor;368
1.7.1.9;Conclusion;369
1.7.1.10;References;370
1.7.2;Chapter 18: Macrophages in the Tumor Microenvironment;377
1.7.2.1;Pro-tumor Aspects;378
1.7.2.1.1;Immunosuppressive Phenotype;379
1.7.2.1.2;Macrophages and Inflammation;381
1.7.2.1.3;Role in Angiogenesis and Metastasis;382
1.7.2.2;Anti-tumor Potential/.Therapeutic Implications;385
1.7.2.3;References;386
1.7.3;Chapter 19: The Prognostic Significance of Tumor-Infiltrating Lymphocytes;390
1.7.3.1;Introduction;390
1.7.3.2;Antitumor Functions of T Lymphocytes;391
1.7.3.2.1;CD8+ T Cells;392
1.7.3.2.2;CD4+ T Cells;393
1.7.3.2.2.1;CD4+ T Cells Help for Cytotoxic T Lymphocytes Induction;394
1.7.3.2.2.2;CD4+ T Cells for Maintenance of a Cytotoxic T Lymphocytes Response;396
1.7.3.2.2.3;CD4+ T Cells for the Induction and Maintenance of CD8+ T Cell Memory Responses;396
1.7.3.2.2.4;T helper 1 Versus T helper 2 Responses for Antitumor Immunity;397
1.7.3.3;Regulatory CD4+ Cells;398
1.7.3.3.1;Existence of Different Types of CD4+ Regulatory T Cells In Vivo;399
1.7.3.3.2;Markers to Identify CD4+ Regulatory T Cells In Vivo;399
1.7.3.3.3;Tumor-Induced CD4+ Regulatory T Cells;400
1.7.3.3.4;CD4+CD25+ Regulatory T Cells in Mice and Human;401
1.7.3.3.5;Suppression Occurred Inside Tumor Tissues;402
1.7.3.3.6;Origins of Tumor-Induced CD4+ Regulatory T Cells;403
1.7.3.4;Th17 Cells;403
1.7.3.5;Other Aspects That Complicate the Relationship Between the Tumor-Infiltrating Lymphocytes and Prognosis;404
1.7.3.6;Targeted Tumor Tissues to Recruit and Train T Cells;406
1.7.3.7;Concluding Remarks;407
1.7.3.8;References;408
1.7.4;Chapter 20: The Pro-inflammatory Milieu and Its Role in Malignant Epithelial Initiation;413
1.7.4.1;Introduction;414
1.7.4.2;Acute Versus Chronic Inflammation in the Context of the Tumor Microenvironment;415
1.7.4.3;Malignant Epithelial Initiation Within a Pro-inflammatory Milieu;418
1.7.4.4;Tumor Immune Evasion and Progression Within Sustained Chronic Inflammation;419
1.7.4.5;Tumor Progression, Metastatic Potential, and Inflammation;420
1.7.4.6;Soluble Mediators of the Immune Response in the Pro-inflammatory Milieu Responsible for Cancer Development as well as Maintena;421
1.7.4.7;Oxidative Stress Species and Their Functional Significance in Cancer Development;421
1.7.4.8;The Role of Matrix Remodeling Proteases in the Tumor Microenvironment;422
1.7.4.9;Functional Significance of Specific Transcription Factors and Primary Inflammatory Cytokines;423
1.7.4.10;Functional Significance of Myeloid Cell Recruitment Within Tumors;426
1.7.4.11;Relationship of Bone Marrow-Derived Cells and the Tumor Microenvironment;428
1.7.4.12;Conclusion;428
1.7.4.13;References;429
1.7.5;Chapter 21: Natural Killer Cells for Adoptive Immunotherapy;435
1.7.5.1;Introduction;435
1.7.5.2;Immunophenotype;436
1.7.5.2.1;Ontogeny;436
1.7.5.3;Localization and Trafficking;437
1.7.5.4;Activation of NK Cells by Cytokines and Accessory Cells;438
1.7.5.5;Cytokine Secretion;438
1.7.5.6;Cytotoxicity;439
1.7.5.7;Activating and Inhibitory Signals;439
1.7.5.8;Activating Receptors;440
1.7.5.9;Licensing;441
1.7.5.10;NK Cells and Anti-tumor Response;441
1.7.5.11;Tumor Infiltrating Lymphocytes;442
1.7.5.12;NK Cells and Haploidentical Transplantation;442
1.7.5.12.1;Umbilical Cord Transplantation;444
1.7.5.12.2;Non-myeloablative Transplantation;444
1.7.5.13;Killer Cell Immunotherapy;445
1.7.5.13.1;NK Cell Adoptive Therapy;445
1.7.5.13.1.1;Haploidentical NK Cells;445
1.7.5.13.1.2;In Vitro NK Cell Expansion;446
1.7.5.13.1.3;Alternative NK Cell Sources;447
1.7.5.13.1.4;NK Cell Lines;447
1.7.5.13.1.5;Engraftment and In Vivo Expansion of Adoptively Transferred NK Cells;448
1.7.5.13.1.6;Adjunctive Strategies;448
1.7.5.13.1.7;Host Factors;449
1.7.5.14;Summary;449
1.7.5.15;References;450
1.8;Part V Extracellular Matrix;459
1.8.1;Chapter 22: Fibronectin;460
1.8.1.1;The Tumor Stroma;460
1.8.1.2;Fibronectin;461
1.8.1.2.1;Molecular Structure of Fibronectin;461
1.8.1.2.2;Gene Structure and FN-Knock Out;461
1.8.1.2.3;Synthesis and Matrix Assembly;462
1.8.1.2.4;Fibronectin Knock Out Mice and Phenotype;463
1.8.1.3;Fibronectin and Cancer;464
1.8.1.3.1;Fibronectin and Tumor Growth;464
1.8.1.3.2;Tumor Angiogenesis;465
1.8.1.3.3;EDB-FN in Tumor Growth and Angiogenesis;465
1.8.1.3.4;Potential Function of the EDB-Domain;466
1.8.1.3.5;EDA-FN in Tumor Growth and Angiogenesis;466
1.8.1.3.6;EDA/EDB-Double Null Mutants;467
1.8.1.3.7;Cryptic Site Exposure as a Result of EDB Alternative Splicing;467
1.8.1.3.8;FN as a Modulator of Tumor Invasion and Metastasis;468
1.8.1.3.9;Migration-Stimulating Factor;468
1.8.1.4;FN and Tumor Dormancy;469
1.8.1.5;Fibronectin: Beyond Fibrils;470
1.8.1.6;Therapeutic Interventions;470
1.8.1.6.1;Targeted Delivery to FN Isoforms;471
1.8.1.6.2;Anti-a5b1 Integrin Function-Blocking Antibody (Volociximab);472
1.8.1.6.3;Endogenous Inhibitors of Angiogenesis;472
1.8.1.6.3.1;Endostatin and Tumstatin;472
1.8.1.6.3.2;Anastellin (III1-C);473
1.8.1.7;References;473
1.8.2;Chapter 23: Collagen in Cancer;480
1.8.2.1;The Collagen Family of Proteins;480
1.8.2.2;The Extracellular Matrix;482
1.8.2.3;Role of Collagen in Cancer: Overview;484
1.8.2.3.1;Adhesion Receptor Binding to Collagen;486
1.8.2.3.2;Protein–Collagen Interactions;491
1.8.2.3.3;Matrix Metalloproteinases;494
1.8.2.3.4;Collagen Fragments;496
1.8.2.3.5;Fibronectin Fragments;499
1.8.2.4;References;500
1.8.3;Chapter 24: Integrins and Cancer;511
1.8.3.1;Integrin Structure and Function;512
1.8.3.1.1;Background;512
1.8.3.1.2;Focal Adhesion Kinase;512
1.8.3.1.3;Integrin-Linked Kinase;515
1.8.3.2;Integrins, Motility, and Invasion;516
1.8.3.3;Integrins and Epithelial–Mesenchymal Transition;519
1.8.3.4;Integrins, Mechanotransduction, and Cancer;522
1.8.3.5;Integrin Signaling as a Therapeutic Target;523
1.8.3.6;References;525
1.8.4;Chapter 25: Matrix Metalloproteinases and Cancer Cell Invasion/Metastasis;532
1.8.4.1;Introduction;532
1.8.4.2;Classification of Proteases;533
1.8.4.3;MMP Biology;533
1.8.4.4;MMP Chemistry;534
1.8.4.5;Natural Inhibitors of MMPs;536
1.8.4.6;Regulation of MMP Function;536
1.8.4.7;Participation of MMPs in Various Aspects of Cancer;539
1.8.4.7.1;Gene Expression Signatures in Cancer;540
1.8.4.7.2;Anticancer Effects of MMPs;541
1.8.4.8;Stromal Cell Production of MMPs: Contribution to Cancer Progression;542
1.8.4.8.1;MMP Involvement in Tumor Angiogenesis;543
1.8.4.9;Involvement of MMPs in Transition to an Invasive/Metastatic Cancer Phenotype;544
1.8.4.9.1;Cancer Cell Invasion in a Three-Dimensional Matrix;544
1.8.4.9.2;Protease-Independent Cell Invasion: Fact or Fantacy;546
1.8.4.9.3;Epithelial-to-Mesenchymal Transition in Cancer;546
1.8.4.9.4;Premetastatic Niche;547
1.8.4.10;Inflammation and Cancer: Role of MMPs;548
1.8.4.11;MMPs as Therapeutic Targets in Cancer;548
1.8.4.11.1;Exocyte Binding and Alosteric Inhibitors of MMPs;550
1.8.4.11.2;RNA Interference (RNAi) Technology to Target MMPs in Cancer;550
1.8.4.12;References;551
1.8.5;Chapter 26: Tetraspanins and Cancer Metastasis;556
1.8.5.1;Structure, Organization, and Major Functions of Tetraspanins;557
1.8.5.1.1;The Structure of Tetraspanins;557
1.8.5.1.2;The Tetraspanin Web;557
1.8.5.1.3;Major Functional Activities of Tetraspanins: Migration and Membrane Fusion;561
1.8.5.2;Tetraspanins, Metastasis, Angiogenesis, and Thrombosis;563
1.8.5.2.1;Metastasis and Angiogenesis;563
1.8.5.2.2;Tetraspanins and Metastasis Suppression;564
1.8.5.2.2.1;The Metastasis Suppressor Gene CD82/KAI1 and Tumor Cell Migration;564
1.8.5.2.2.2;CD9 Interferes with Distinct Steps of the Metastatic Cascade;567
1.8.5.2.2.3;CD81 and CD63 and Metastasis Suppression;570
1.8.5.2.3;Tetraspanins and Tumor Progression;571
1.8.5.2.3.1;CD151 and Tumor Cell Motility;571
1.8.5.2.3.2;Tspan8 and Metastasis;573
1.8.5.2.4;Tetraspanins, Premetastatic Niche, Angiogenesis, Thrombosis, and Exosomes;574
1.8.5.2.4.1;Tetraspanins and Exosomes;574
1.8.5.2.4.2;Tetraspanins and the Premetastatic Niche;576
1.8.5.2.4.3;Tetraspanins and Angiogenesis;577
1.8.5.3;Tetraspanins and Cancer Therapy;579
1.8.5.3.1;Rescuing the Metastasis Suppressor Gene CD82;579
1.8.5.3.2;Interfering with Metastasis-Promoting Activities of Tetraspanins;580
1.8.5.4;Conclusion;581
1.8.5.5;References;583
1.9;Part VI Secreted Proteins;600
1.9.1;Chapter 27: Chemokines and Metastasis;601
1.9.1.1;Introduction;601
1.9.1.2;Chemokines and Their Receptors;603
1.9.1.3;Chemokines on Leukocyte Recruitment and Activation in Malignant Tumors;608
1.9.1.4;Chemokines in Tumor Angiogenesis;610
1.9.1.5;Chemokines in Tumor Growth and Metastasis;613
1.9.1.6;Chemokines Targeting and Chemotherapy;617
1.9.1.7;Conclusion and Future Perspective;618
1.9.1.8;References;618
1.9.2;Chapter 28: Transforming Growth Factor-b in Lung Cancer, Carcinogenesis, and Metastasis;632
1.9.2.1;Introduction;632
1.9.2.2;Transforming Growth Factor-b Signaling;635
1.9.2.3;Transforming Growth Factor-b Isoforms;637
1.9.2.4;Transforming Growth Factor-b Receptors;639
1.9.2.5;Smads;644
1.9.2.6;Microenvironment;645
1.9.2.7;Epithelial-to-Mesenchymal Transition;648
1.9.2.8;Immune System;652
1.9.2.9;Drugs, Treatments, and Therapies;653
1.9.2.10;Genomics;657
1.9.2.11;Animal Models;659
1.9.2.12;Conclusions;663
1.9.2.13;References;664
1.9.3;Chapter 29: Cooperative Interactions Between Integrins and Growth Factor Signaling in Pathological Angiogenesis;671
1.9.3.1;Introduction;671
1.9.3.2;Blood Vessel Formation;673
1.9.3.2.1;Pathological Angiogenesis;674
1.9.3.3;Integrins and Their ECM Ligands in Angiogenesis;675
1.9.3.4;Modulation of Growth Factor/Growth Factor Receptor Systems within Different Tissue Microenvironments;677
1.9.3.4.1;Integrin–ECM Interactions Regulate Growth Factor Expression and Bio-distribution;677
1.9.3.4.2;Modulation of Growth Factor Signaling by Integrins;679
1.9.3.5;Integrin/Growth Factor Cooperation in Angiogenesis;680
1.9.3.6;Integrin/Growth Factor Receptor Cooperation in Angiogenesis;683
1.9.3.7;Conclusions;686
1.9.3.8;References;687
1.9.4;Chapter 30: The Extracellular Matrix and the Growth and Survival of Tumors;692
1.9.4.1;Introduction;692
1.9.4.2;Mechanical Forces and the ECM in Cancer Progression;693
1.9.4.3;Contact Between ECM and Tumor Cells Regulates Proliferation and Survival;695
1.9.4.3.1;Regulation of Tumor Cell Proliferation by ECM Proteins;695
1.9.4.3.2;Regulation of Apoptosis by ECM Proteins;696
1.9.4.3.3;Stimulation of Apoptosis by ECM Proteins;697
1.9.4.4;Proteolytic Modification of the ECM and Tumor Growth and Survival;698
1.9.4.4.1;Proteolytic Modification of the ECM and Cancer Progression;698
1.9.4.4.2;Proteolytic Modification of the ECM Reveals Cryptic Domains in ECM Proteins (Matricryptins);699
1.9.4.4.3;Proteolytic Modification of the ECM Releases Soluble Active Peptides (Matrikines);699
1.9.4.4.4;Proteolytic Degradation of the ECM Releases Soluble Growth Factors;701
1.9.4.5;Clinical Implications;702
1.9.4.5.1;Broad Inhibitors of ECM Degradation;702
1.9.4.5.2;Integrin Inhibitors;702
1.9.4.5.3;Protease Inhibitors;703
1.9.4.5.4;Angiogenesis Inhibitors;703
1.9.4.6;Conclusion;704
1.9.4.7;References;704
1.9.5;Chapter 31: Secreted Growth Factors as Therapeutic Targets;708
1.9.5.1;Pro-angiogenic and Lymphangiogenic Factors;709
1.9.5.2;Pro-stromal Factors;715
1.9.5.3;Immune System Modulators;718
1.9.5.4;Malignant Cell Growth Factors;719
1.9.5.5;References;725
1.9.6;Chapter 32: Adrenomedullin;730
1.9.6.1;Structure and Function;730
1.9.6.2;Angiogenesis;732
1.9.6.3;Adrenomedullin in Cancer;734
1.9.6.3.1;Breast Cancer;734
1.9.6.3.2;Central Nervous System;735
1.9.6.3.3;Endometrial Cancer;735
1.9.6.3.4;Lung Cancer;736
1.9.6.3.5;Mast Cells and the Tumor Microenvironment;736
1.9.6.3.6;Ovarian Cancer;737
1.9.6.3.7;Pancreatic Cancer;737
1.9.6.3.8;Prostate Cancer;739
1.9.6.3.9;Renal Cancer;740
1.9.6.4;Adrenomedullin as a Therapeutic Target;741
1.9.6.5;Conclusion;742
1.9.6.6;References;742
1.10;Index;746