Cell-Extracellular Matrix Interactions in Cancer (eBook)

Preface 5
Contents 7
Contributors 9
Introduction 13
The Extracellular Matrix: An Overview 13
Classes of Extracellular Matrix Molecules 14
Generalizations 14
Basement Membranes 14
Elastic Fibers 18
Bone, Cartilage, and Other Connective Tissues 20
Interstitial Matrices 24
Fibrosis 26
References 26
General Introduction 30
Integrin Structure and Function 30
Classification of Integrins 31
Phenotypes of Integrin Knockout Mice 31
Structure 34
Extracellular Domain 34
Transmembrane Domain 35
Cytoplasmic Domain 36
Integrin Signaling 37
Inside-Out Signaling 37
Outside-In Signaling 40
Perspective 47
References 47
Introduction 53
Cancer in Context: Importance of the Tumor Microenvironment 53
Cellular Constituents of the Tumor Microenvironment and Their Functions 54
Fibroblasts 54
Endothelial Cells 55
Pericytes 57
Immune Cells 58
Mesenchymal Stem Cells 60
Cellular Fusion in the Tumor Microenvironment 61
Molecular Constituents of the Tumor Microenvironment and Their Functions Matrix Molecules 61
Proteases and Glycosidases 62
Growth Factors and Cytokines 65
The Metabolic Microenvironment 65
Tumor pH 65
Oxygen Tension 66
Example of a Specialized Tumor Microenvironment – the Bone 67
Conclusion 68
References 69
Basement Membrane Collagens and Cancer 74
Basement Membrane Collagens 75
Collagen IV 75
Collagens XV and XVIII 79
Collagen XIX 80
Collagen-Derived Cleavage Products and Their Role in Angiogenesis and Cancer Progression 80
Anti-angiogenic and Anti-tumor Therapies Using Collagen Fragments: Pros and Contras 85
Conclusions 86
References 87
Laminins and Cancer Progression 95
Introduction 97
Laminins and Cell Proliferation 100
Laminins and Cell Death 103
Laminins and Angiogenesis 106
Laminins and Cancer Invasion and Metastasis 108
Concluding Remarks 111
References 111
Introduction 118
Fibronectins and Their Receptors in Cancer 118
Fibronectin 119
The Integrin Family of ECM Receptors 121
The b1 Integrin Subfamily 123
The av Subfamily 123
Altered Expression of Fibronectin and Its Integrin Receptors in Cancer 124
Fibronectin and Integrins in Cancer Cell Proliferation and Survival 124
Fibronectin and Integrins in Invasion and Metastasis 125
Fibronectin and Integrins in Angiogenesis and Lymphangiogenesis 126
Integrin a5b1 in Tumor Angiogenesis 127
Integrin a4b1 in Tumor Angiogenesis 127
Integrin a9b1 in Tumor Angiogenesis 128
Alpha v Integrins in Tumor Angiogenesis 128
Integrins and Lymphangiogenesis 130
Fibronectin Binding Integrins in Resistance to Chemotherapy 131
Potential Clinical Applications 132
Antibody Inhibitors of Integrins 132
Peptide Inhibitors of Integrins 133
Antibodies against Fibronectin in Therapy and Imaging 134
Integrin Targeted Tumor Imaging 134
Conclusions 135
References 135
The Basic Biology of Integrins 144
Vitronectin-Binding Integrins in Cancer 144
Integrins Are Mechanoreceptors 145
The Vitronectin-Binding Integrins Are One of Several Integrin Subfamilies 146
a v Integrin Structure 147
Domain Structure of a Vitronectin-Binding Integrin 149
Integrin avb3 Mediates Cell Attachment via an Arginine– Glycine– Aspartic Acid Target Sequence 151
Integrin a vb 3 Binds to Extracellular Components of Remodeling Tissues 151
Expression of Integrin a vb 3 on Aggressive Metastatic Tumors 153
Mechanisms of Integrin a vb 3 Potentiation of Tumor Malignancy 154
Integrins Govern RTK Signaling 155
Complexity in Signaling Is not Unique to Integrins and RTKs 156
Integrin avb5 Is an Anchorage Receptor 157
Src Activation Promotes a vb 5- Dependent Migration and Metastasis 158
Other Vitronectin-Binding Integrins and Cancer 158
a v Integrins in Stromal Cell Contributions to Tumor Development 159
Tumor Angiogenesis 161
Therapeutic Strategies Involving Vitronectin Receptors 162
Integrin a vb 3- Targeted Antibodies 163
RGD Peptides and RGD Mimetics 164
a v- Targeting of Therapeutics 166
Outlook 167
References 168
Introduction 178
The Function of SPARC in Tumor Cell Biology: SPARC as a Modulator of Cell- Extracellular Matrix Interaction 178
SPARC Structure/Function 179
ECM Assembly 181
Cellular Mechanisms of SPARC in ECM Assembly and Cell Signaling 185
Cell Motility 187
Growth Factors and Cytokines 187
Immune System 189
Conclusions 190
References 191
Introduction 197
Proteoglycans and Cancer 197
Heparan Sulfate Proteoglycans 198
Chondroitin Sulfate Proteoglycans 203
Keratan Sulfate Proteoglycans 206
Hyaluronic Acid 208
Summary 210
References 211
What are Tetraspanins 222
Tetraspanins in Cancer 222
Tetraspanins and the Tetraspanin Enriched Microdomain 223
Genealogical Appearance of Tetraspanins 226
Molecular Functioning of Tetraspanins 228
Tetraspanin Characterization, Genetics 228
Tetraspanin Characterization, Mutational Analysis 229
Tetraspanin Characterization, Tetraspanin Antibodies 229
Tetraspanin Activity: Signaling, Adhesion, Cytoskeletal Anchoring, and Protein Trafficking 233
Protein Trafficking 233
Cytoskeletal Anchoring 235
Signaling 236
Adhesion and Migration 237
Summary 240
References 240
Introduction 249
The Role of Integrin-Linked Kinase in Cancer Development and Progression 249
Structure of Integrin-Linked Kinase 250
Multiprotein Complex at Focal Adhesions 250
The Dual Functionality of ILK 254
Cytoskeletal Dynamics 254
Ser/Thr Kinase Activity 255
Overexpression and Increased Activity of ILK in Human Malignancies 257
ILK is a Vital Component of Cancer-Associated Signaling Pathways 259
Proliferation and Cell Cycle Progression 259
Survival 260
EMT 261
Adhesion, Migration, Motility, Invasion 263
Angiogenesis 263
ILK as a Therapeutic Target in Cancer 264
Inhibition of ILK Expression in Cancer Cells 264
Pharmacologic Inhibition of ILK Function 266
New Interacting Partners 267
ILK–Rictor Complex 267
New Role in Spindles/Centrosomes 268
Summary 268
References 269
Focal Adhesion Kinase with the Interacting Proteins and Signaling in Cancer 278
Introduction 279
Structure and Function of Focal Adhesion Kinase protein Gene and Promoter Structure 280
FAK Protein Structure Structure 281
FAK Function in Cancer Cells 283
FAK-Protein Binding Partners and Signaling The FAK and N-, Central and C- Terminal Domain Binding Complexes 285
FAK and RIP 286
FAK and VEGFR-3 288
FAK and p53 289
FAK and IGF-1R 292
FAK and N-MYCN Signaling in Neuroblastoma 294
Overview of MYCN Oncogene 295
MYCN Oncogene and Neuroblastoma 295
MYCN and Focal Adhesion Kinase (FAK) 296
MYCN, Mdm-2, FAK, and p53 296
FAK-Targeted Therapy FAK Inhibitors 297
Targeting Protein–Protein Interactions 297
Summary 298
References 298
Index 309