The Tumor Microenvironment (eBook)

Rebecca Bagley is a senior scientist at Genzyme Corporation and has worked in the biotechnology industry for 20 years with degrees in biology from Wellesley College and Harvard University. Her expertise in drug development spans a wide range of approaches including immunotherapies, gene and protein therapies, and small molecule delivery with publications in journals such as Molecular Cancer Therapeutics, Cancer Research, and Microvascular Research . Her current research focuses on stem cells, tumor vasculature, and target validation.

The Tumor Microenvironment 3
Preface 5
Contents 7
Contributors 11
Part I Physiological Parameters 19
Chapter 1: Combination Strategies Targeting Hypoxia Inducible Factor 1 (HIF-1) for Cancer Therapy 20
Introduction 20
Small Molecule Inhibitors of HIF-1 22
Targeting HIF-1: Single Agent or Combination? 25
Molecularly Targeted Agents and HIF-1 Inhibition 26
Hypoxic Cells Are More Resistant to Chemotherapy and Radiation Therapy 27
Combination of HIF-1 Inhibitors with Chemotherapy 27
Combination of HIF-1 Inhibitors with Radiation Therapy 28
Intratumor Hypoxia as a Potential Mechanism of Resistance to Anti-angiogenic Therapies 29
Combination of Anti-angiogenic Therapies and HIF-1 Inhibitors 30
Cancer Cell Metabolism and the Hypoxic Tumor Microenvironment 31
HIF-1 Inhibitors in Combination Strategies Targeting Tumor Metabolism 31
Conclusion 32
References 32
Chapter 2: The Tumor Microenvironment: New Insights into Regulation of Tumor pH by Carbonic Anhydrases 39
Biological Importance of pH 39
Sources of Cellular Acid 41
Cellular Respiration 41
The Warburg Effect 42
Transport of Acid Across the Surface Membrane 44
Intracellular and Extracellular pH in Tumors 44
Regulation of Tumor pH by Membrane Transport 44
Efflux of Metabolic Acid 45
Buffering of H+ Ions 46
Extrusion of H+ Ions 46
Regulation of pH Using Nonrespiratory Sources of H+ Ions 47
Role of Carbonic Anhydrase in Acid-Equivalent Transport 48
Intracellular and Extracellular Carbonic Anhydrase Isoforms 48
Facilitated CO2 Diffusion 48
Facilitated H+ Diffusion 50
The Transport Metabolon 50
The Dominant Role for Carbonic Anhydrase in Tumors 51
Future Directions and Outlook for Therapy 51
References 53
Chapter 3: Hypoxia, Gene Expression, and Metastasis 58
The Link Between Hypoxia and Metastasis 59
Causes and Consequences of Tumor Hypoxia 60
HIF Regulation by Oxygen 61
HIF Regulation by Genetic Alterations of Upstream Regulators 62
HIF Target Genes Involved in the Metastatic Process 64
Hypoxia, Cancer Stem Cells, and Metastasis 66
Conclusion 68
References 68
Chapter 4: Molecular Mechanisms Regulating Expression and Function of Cancer-Associated Carbonic Anhydrase IX 74
Abstract 74
Carbonic Anhydrases 74
Molecular Features of CA IX 77
CA IX Tissue Distribution 79
Regulation of CA IX Expression 80
Role of CA IX in Cancer 83
Clinical Value of CA IX 87
CA IX Targeting Strategies 90
Conclusion 95
References 95
Chapter 5: Glycolytic Pathway as a Target for Tumor Inhibition 106
Introduction 106
Alterations of Glucose Metabolism in Cancer 109
Overexpression of Glycolytic Enzymes in Cancer Favors Aerobic Glycolysis 110
GLUT1 110
HKII 111
PFK1 111
PKM2 112
LDH-A 112
The PPP 113
Mitochondrial Dysfunction and Increased Glycolysis in Cancer 114
Tumor Microenvironment and Selection of Highly Glycolytic Cancer Cells 115
HIF-1 and Glycolysis 115
HIF-1 and Mitochondria 116
Mutations of Tumor Suppressor Genes and Metabolic Alterations 118
p53 Regulation of Glycolysis and Mitochondrial Respiration 118
AMPK and Glycolytic Regulation 119
Activation of Oncogenes and Increased Glycolysis 119
c-Myc 119
Ras 120
PI3K/Akt Pathway 120
Glycolytic Pathway as a Target for Tumor Inhibition 121
2-Deoxyglucose 122
3-Bromopyruvate 122
Lonidamine 123
Oxythiamine and 6-Aminonicotinamide 124
Dichloroacetate 124
Other Metabolic Modulators 125
Summary 125
References 126
Part II Malignant Cells 134
Chapter 6: Aberrant DNA Methylation in Cancer Cells 135
Introduction 135
Characteristics of DNA Methylation 136
Maintenance of DNA Methylation Statuses 136
Regulation of Gene Transcription by DNA Methylation 138
Maintenance and De Novo DNA Methylases 139
Methylation Alterations in Cancer Cells 139
Genome-Overall Hypomethylation 139
Aberrant DNA Methylation of CpG Islands 140
Driver Methylation and Passenger Methylation 141
Possible Involvement of Altered Methylation in Tumor Microenvironments 141
Unique Natures of Aberrant DNA Methylation, in Contrast with Mutations 141
Field for Cancerization and DNA Methylation 142
Epithelial-Mesenchymal Transition and DNA Methylation 142
Tumor Microenvironments and DNA Methylation 143
Epilogue 144
References 144
Chapter 7: DNA Repair and Redox Signaling 147
Introduction 150
Overview of DNA Repair Pathways 151
DR 151
BER 153
MMR 154
NER 155
NHEJ Repair 157
HR 157
Overview of Redox Signaling 158
The Thioredoxin (Trx) System 159
The Glutaredoxin/Glutathione (GRX/GSH) System 160
Roles of Redox Systems 160
The Redox Activity of APE1 161
How APE1 Performs Its Redox Functions 162
APE1-Regulated Transcription Factors and Their Link to DNA Damage Repair 162
p53 163
AP-1 166
HIF-1a 167
Other Global Influences of APE1 168
Cell Survival 169
Angiogenesis 170
Inflammation 171
DNA Repair in the Tumor Microenvironment 172
Modulating APE1’s Activities as a Cancer Therapeutic Approach 173
Conclusions 176
References 176
Chapter 8: Cancer Stem Cells and Microenvironment 183
Introduction 183
ESCs: A Prototype Model of Stem Cell Biology 186
Stem Cells and Microenvironment 190
CSCs and the Microenvironment 192
Concluding Remarks 194
References 195
Chapter 9: Epithelial–Mesenchymal Transition in Development and Diseases 200
Overview of EMT 200
Type 1 EMT in the Formation of Mesoderm and Neural Crest 202
Mesoderm Formation 203
Neural Crest Formation 204
MET 204
Type 2 EMT in Tissue and Organ Fibrosis 204
Implications of EMT in Fibrosis 204
Re-epithelialization of Wounded Skin 205
Type 3 EMT in Cancer Metastasis 206
EMT Stimuli from Tumor Microenvironment 206
Molecular Regulation of EMT 209
Signaling Pathways 210
Cytokines 212
Hypoxia 214
EMT Generates Cancer Stem Cells 215
Genetic and Epigenetic Control of EMT 215
Micro RNA for EMT 216
Perspective 217
References 218
Chapter 10: Invasion and Metastasis 225
Tumors as Tissues 225
Metastatic Disease 226
Metastatic Cascades 226
Migration, Invasion, and Metastasis 228
Rethinking Metastasis 233
Conclusions 236
References 237
Chapter 11: Dormancy of Disseminated Tumor Cells: Reciprocal Crosstalk with the Microenvironment 241
General Concepts on Tumor Cell Dormancy in the Context of Cancer Progression 241
Dormancy of Micrometastasis 243
Angiogenic Dormancy 243
Immunity-Driven Dormancy of Micrometastasis 246
Cellular Dormancy 248
Cellular Dormancy and the Microenvironment 250
Stroma-Associated Factors and Tumor Cell Dormancy 253
Collagen Matrix Signaling 253
Hormone Depletion and Dormancy 254
TGFb Signaling 255
Models to Study Dormancy 257
References 260
Part III Vasculature And Stroma 267
Chapter 12: Impact of Endothelial Progenitor Cells on Tumor Angiogenesis and Outcome of Antiangiogenic Therapy: New Perspecti 268
Introduction 268
The Identification of EPCs 270
The Controversy Surrounding Functions of EPCs 270
The Controversy About the Definition of EPCs 273
EPCs as a Surrogate Biomarker for Antiangiogenic Therapy 275
Therapy-Induced EPC Mobilization and Tumor Vessel Incorporation 276
Conclusions 280
References 280
Chapter 13: Bone Marrow Derived Mesenchymal Stem/Stromal Cells and Tumor Growth 285
Introduction 286
Characteristics of CAFs 286
Bone Marrow Derived MSCs as Source of CAFs 287
Alterations in Tumor Associated Stromal Cells 289
Implications of MSCs as a Source of CAFs: A Model to Study Tumor Stroma Interactions 290
Activation of BMD MSCs and Growth of Tumors 291
Speculation on Role of Chemokines on Activation of Circulating MSCs and Effect on Tumor Growth in African American Individuals 291
Lack of DARC Expression, Circulating Chemokines and Pathological Conditions 292
DARC Expression and Cancer in African American Men 293
Activation of Bone Marrow-Derived MSCs and Metastasis 293
Conclusion 295
References 295
Chapter 14: Integrin Signaling in Lymphangiogenesis 299
Introduction 299
Lyphangiogenesis 300
Lymphatic Vasculature 300
Lymphatic Makers 301
Induction of Lymphangiogenesis 301
Lymphangiogenesis and Pathology 303
Integrins 304
Integrin Expression and Function 304
Role of Integrins in Promoting Endothelial Cells Migration, Proliferation, and Survival 306
Ligand Specificity of Integrins 306
Integrin Signaling 307
Fak 307
Shc 309
Rho Family of Small GTPases 310
Talin 310
Vinculin 311
Paxillin 311
Intergrins and Lymphangiogenesis 311
a9ß1 311
a1ß1 and a2ß1 312
a5ß1 312
a4ß1 312
Conclusion 313
References 313
Chapter 15: Role of Pericytes in Resistance to Antiangiogenic Therapy 320
Introduction 320
Biology, Physiology, and Pathology of Pericytes 321
Pericytes and Tumor Angiogenesis 322
Pericytes and Resistance to Antiangiogenic Therapy 324
VEGF Pathway and Pericytes in Tumor Angiogenesis 324
Resistance to Antiangiogenic Therapy 324
Targeting Pericytes for Antivascular Strategies 326
Conclusions 327
References 329
Chapter 16: Tumour-Promoting Stromal Myofibroblasts in Human Carcinomas 333
Introduction 333
Myofibroblasts Involved in Tissue Fibrosis Share Characteristics with Tumour-Associated Myofibroblasts 335
Carcinoma-Associated Fibroblast Characterised as Tumour-Promoting Myofibroblasts 336
Somatic Genetic and Epigenetic Alterations in Tumour-Associated Stroma 339
Heterogeneous Cellular Origins of Carcinoma-Associated Myofibroblasts 341
Normal Stroma-Derived Tumour-Suppressive Signalling and Tumour Stroma-Derived Tumour-Promoting Signalling 343
Tumour-Associated Stroma Promotes Neoangiogenesis 345
Roles of Tumour-Associated Stroma in Promoting Cancer Cell Invasion and Metastasis 348
Conclusions/Perspectives 350
References 351
Part IV Immune-Mediated Cells 358
Chapter 17: Mast Cells and Tumor Microenvironment 359
Introduction 360
Mast Cell Biology 362
Mast Cells Could Be Beneficial to the Tumor 363
Breast Cancer 365
Melanoma and Basal Cell Carcinoma 366
Pancreatic Cancer 366
Lung Cancer 367
Mast Cells Could be Detrimental to the Tumor 368
Conclusion 369
References 370
Chapter 18: Macrophages in the Tumor Microenvironment 377
Pro-tumor Aspects 378
Immunosuppressive Phenotype 379
Macrophages and Inflammation 381
Role in Angiogenesis and Metastasis 382
Anti-tumor Potential/.Therapeutic Implications 385
References 386
Chapter 19: The Prognostic Significance of Tumor-Infiltrating Lymphocytes 390
Introduction 390
Antitumor Functions of T Lymphocytes 391
CD8+ T Cells 392
CD4+ T Cells 393
CD4+ T Cells Help for Cytotoxic T Lymphocytes Induction 394
CD4+ T Cells for Maintenance of a Cytotoxic T Lymphocytes Response 396
CD4+ T Cells for the Induction and Maintenance of CD8+ T Cell Memory Responses 396
T helper 1 Versus T helper 2 Responses for Antitumor Immunity 397
Regulatory CD4+ Cells 398
Existence of Different Types of CD4+ Regulatory T Cells In Vivo 399
Markers to Identify CD4+ Regulatory T Cells In Vivo 399
Tumor-Induced CD4+ Regulatory T Cells 400
CD4+CD25+ Regulatory T Cells in Mice and Human 401
Suppression Occurred Inside Tumor Tissues 402
Origins of Tumor-Induced CD4+ Regulatory T Cells 403
Th17 Cells 403
Other Aspects That Complicate the Relationship Between the Tumor-Infiltrating Lymphocytes and Prognosis 404
Targeted Tumor Tissues to Recruit and Train T Cells 406
Concluding Remarks 407
References 408
Chapter 20: The Pro-inflammatory Milieu and Its Role in Malignant Epithelial Initiation 413
Introduction 414
Acute Versus Chronic Inflammation in the Context of the Tumor Microenvironment 415
Malignant Epithelial Initiation Within a Pro-inflammatory Milieu 418
Tumor Immune Evasion and Progression Within Sustained Chronic Inflammation 419
Tumor Progression, Metastatic Potential, and Inflammation 420
Soluble Mediators of the Immune Response in the Pro-inflammatory Milieu Responsible for Cancer Development as well as Maintena 421
Oxidative Stress Species and Their Functional Significance in Cancer Development 421
The Role of Matrix Remodeling Proteases in the Tumor Microenvironment 422
Functional Significance of Specific Transcription Factors and Primary Inflammatory Cytokines 423
Functional Significance of Myeloid Cell Recruitment Within Tumors 426
Relationship of Bone Marrow-Derived Cells and the Tumor Microenvironment 428
Conclusion 428
References 429
Chapter 21: Natural Killer Cells for Adoptive Immunotherapy 435
Introduction 435
Immunophenotype 436
Ontogeny 436
Localization and Trafficking 437
Activation of NK Cells by Cytokines and Accessory Cells 438
Cytokine Secretion 438
Cytotoxicity 439
Activating and Inhibitory Signals 439
Activating Receptors 440
Licensing 441
NK Cells and Anti-tumor Response 441
Tumor Infiltrating Lymphocytes 442
NK Cells and Haploidentical Transplantation 442
Umbilical Cord Transplantation 444
Non-myeloablative Transplantation 444
Killer Cell Immunotherapy 445
NK Cell Adoptive Therapy 445
Haploidentical NK Cells 445
In Vitro NK Cell Expansion 446
Alternative NK Cell Sources 447
NK Cell Lines 447
Engraftment and In Vivo Expansion of Adoptively Transferred NK Cells 448
Adjunctive Strategies 448
Host Factors 449
Summary 449
References 450
Part V Extracellular Matrix 459
Chapter 22: Fibronectin 460
The Tumor Stroma 460
Fibronectin 461
Molecular Structure of Fibronectin 461
Gene Structure and FN-Knock Out 461
Synthesis and Matrix Assembly 462
Fibronectin Knock Out Mice and Phenotype 463
Fibronectin and Cancer 464
Fibronectin and Tumor Growth 464
Tumor Angiogenesis 465
EDB-FN in Tumor Growth and Angiogenesis 465
Potential Function of the EDB-Domain 466
EDA-FN in Tumor Growth and Angiogenesis 466
EDA/EDB-Double Null Mutants 467
Cryptic Site Exposure as a Result of EDB Alternative Splicing 467
FN as a Modulator of Tumor Invasion and Metastasis 468
Migration-Stimulating Factor 468
FN and Tumor Dormancy 469
Fibronectin: Beyond Fibrils 470
Therapeutic Interventions 470
Targeted Delivery to FN Isoforms 471
Anti-a5b1 Integrin Function-Blocking Antibody (Volociximab) 472
Endogenous Inhibitors of Angiogenesis 472
Endostatin and Tumstatin 472
Anastellin (III1-C) 473
References 473
Chapter 23: Collagen in Cancer 480
The Collagen Family of Proteins 480
The Extracellular Matrix 482
Role of Collagen in Cancer: Overview 484
Adhesion Receptor Binding to Collagen 486
Protein–Collagen Interactions 491
Matrix Metalloproteinases 494
Collagen Fragments 496
Fibronectin Fragments 499
References 500
Chapter 24: Integrins and Cancer 511
Integrin Structure and Function 512
Background 512
Focal Adhesion Kinase 512
Integrin-Linked Kinase 515
Integrins, Motility, and Invasion 516
Integrins and Epithelial–Mesenchymal Transition 519
Integrins, Mechanotransduction, and Cancer 522
Integrin Signaling as a Therapeutic Target 523
References 525
Chapter 25: Matrix Metalloproteinases and Cancer Cell Invasion/Metastasis 532
Introduction 532
Classification of Proteases 533
MMP Biology 533
MMP Chemistry 534
Natural Inhibitors of MMPs 536
Regulation of MMP Function 536
Participation of MMPs in Various Aspects of Cancer 539
Gene Expression Signatures in Cancer 540
Anticancer Effects of MMPs 541
Stromal Cell Production of MMPs: Contribution to Cancer Progression 542
MMP Involvement in Tumor Angiogenesis 543
Involvement of MMPs in Transition to an Invasive/Metastatic Cancer Phenotype 544
Cancer Cell Invasion in a Three-Dimensional Matrix 544
Protease-Independent Cell Invasion: Fact or Fantacy 546
Epithelial-to-Mesenchymal Transition in Cancer 546
Premetastatic Niche 547
Inflammation and Cancer: Role of MMPs 548
MMPs as Therapeutic Targets in Cancer 548
Exocyte Binding and Alosteric Inhibitors of MMPs 550
RNA Interference (RNAi) Technology to Target MMPs in Cancer 550
References 551
Chapter 26: Tetraspanins and Cancer Metastasis 556
Structure, Organization, and Major Functions of Tetraspanins 557
The Structure of Tetraspanins 557
The Tetraspanin Web 557
Major Functional Activities of Tetraspanins: Migration and Membrane Fusion 561
Tetraspanins, Metastasis, Angiogenesis, and Thrombosis 563
Metastasis and Angiogenesis 563
Tetraspanins and Metastasis Suppression 564
The Metastasis Suppressor Gene CD82/KAI1 and Tumor Cell Migration 564
CD9 Interferes with Distinct Steps of the Metastatic Cascade 567
CD81 and CD63 and Metastasis Suppression 570
Tetraspanins and Tumor Progression 571
CD151 and Tumor Cell Motility 571
Tspan8 and Metastasis 573
Tetraspanins, Premetastatic Niche, Angiogenesis, Thrombosis, and Exosomes 574
Tetraspanins and Exosomes 574
Tetraspanins and the Premetastatic Niche 576
Tetraspanins and Angiogenesis 577
Tetraspanins and Cancer Therapy 579
Rescuing the Metastasis Suppressor Gene CD82 579
Interfering with Metastasis-Promoting Activities of Tetraspanins 580
Conclusion 581
References 583
Part VI Secreted Proteins 600
Chapter 27: Chemokines and Metastasis 601
Introduction 601
Chemokines and Their Receptors 603
Chemokines on Leukocyte Recruitment and Activation in Malignant Tumors 608
Chemokines in Tumor Angiogenesis 610
Chemokines in Tumor Growth and Metastasis 613
Chemokines Targeting and Chemotherapy 617
Conclusion and Future Perspective 618
References 618
Chapter 28: Transforming Growth Factor-b in Lung Cancer, Carcinogenesis, and Metastasis 632
Introduction 632
Transforming Growth Factor-b Signaling 635
Transforming Growth Factor-b Isoforms 637
Transforming Growth Factor-b Receptors 639
Smads 644
Microenvironment 645
Epithelial-to-Mesenchymal Transition 648
Immune System 652
Drugs, Treatments, and Therapies 653
Genomics 657
Animal Models 659
Conclusions 663
References 664
Chapter 29: Cooperative Interactions Between Integrins and Growth Factor Signaling in Pathological Angiogenesis 671
Introduction 671
Blood Vessel Formation 673
Pathological Angiogenesis 674
Integrins and Their ECM Ligands in Angiogenesis 675
Modulation of Growth Factor/Growth Factor Receptor Systems within Different Tissue Microenvironments 677
Integrin–ECM Interactions Regulate Growth Factor Expression and Bio-distribution 677
Modulation of Growth Factor Signaling by Integrins 679
Integrin/Growth Factor Cooperation in Angiogenesis 680
Integrin/Growth Factor Receptor Cooperation in Angiogenesis 683
Conclusions 686
References 687
Chapter 30: The Extracellular Matrix and the Growth and Survival of Tumors 692
Introduction 692
Mechanical Forces and the ECM in Cancer Progression 693
Contact Between ECM and Tumor Cells Regulates Proliferation and Survival 695
Regulation of Tumor Cell Proliferation by ECM Proteins 695
Regulation of Apoptosis by ECM Proteins 696
Stimulation of Apoptosis by ECM Proteins 697
Proteolytic Modification of the ECM and Tumor Growth and Survival 698
Proteolytic Modification of the ECM and Cancer Progression 698
Proteolytic Modification of the ECM Reveals Cryptic Domains in ECM Proteins (Matricryptins) 699
Proteolytic Modification of the ECM Releases Soluble Active Peptides (Matrikines) 699
Proteolytic Degradation of the ECM Releases Soluble Growth Factors 701
Clinical Implications 702
Broad Inhibitors of ECM Degradation 702
Integrin Inhibitors 702
Protease Inhibitors 703
Angiogenesis Inhibitors 703
Conclusion 704
References 704
Chapter 31: Secreted Growth Factors as Therapeutic Targets 708
Pro-angiogenic and Lymphangiogenic Factors 709
Pro-stromal Factors 715
Immune System Modulators 718
Malignant Cell Growth Factors 719
References 725
Chapter 32: Adrenomedullin 730
Structure and Function 730
Angiogenesis 732
Adrenomedullin in Cancer 734
Breast Cancer 734
Central Nervous System 735
Endometrial Cancer 735
Lung Cancer 736
Mast Cells and the Tumor Microenvironment 736
Ovarian Cancer 737
Pancreatic Cancer 737
Prostate Cancer 739
Renal Cancer 740
Adrenomedullin as a Therapeutic Target 741
Conclusion 742
References 742
Index 746