Matrix Proteases in Health and Disease

by Behrendt, Niels

• ISBN13: 9783527329915
• ISBN10: 3527329919
• Edition: 1st
• Format: Hardcover
• Copyright: 2012-07-10
• Publisher: Wiley-VCH

Summary

Presenting a comprehensive overview of the multifaceted field of extracellular matrix degradation by extracellular proteases, this reference focuses on the recently elucidated functions of proteolytic systems, such as plasminogen activators, ADAMS and other matrix proteases in physiological and pathological tissue remodeling. It specifically addresses the role of extracellular proteases in cancer cell invasion, stroke and Alzheimers disease, describing the basic biochemistry behind these disease states, as well as therapeutic strategies based on protease inhibition. With its trans-disciplinary scope, this reference bridges the gap between fundamental research and biomedical and pharmaceutical application, making this required reading for basic and applied scientists in the molecular life sciences.

Author Biography

Niels Behrendt is a research group leader at the Finsen Laboratory at the Rigshospitalet (Copenhagen University Hospital), Denmark. He obtained his Ph.D. in 1989 and his D.Sc. degree from Copenhagen University in 2004. The main focus of his work is in protease-dependent tissue remodeling, the interplay of these processes with other cellular functions and their role in cancer invasion.

Table of Contents

List of Contributors XV

Introduction 1
Niels Behrendt

1 Matrix Proteases and the Degradome 5
Clara Soria-Valles, Carlos L´opez-Ot´?n, and Ana Guti´errez-Fern´andez

1.1 Introduction 5

1.2 Bioinformatic Tools for the Analysis of Complex Degradomes 6

1.3 Evolution of Mammalian Degradomes 8

1.3.1 Human Degradome 8

1.3.2 Rodent Degradomes 10

1.3.3 Chimpanzee Degradome 10

1.3.4 Duck-Billed Platypus Degradome 11

1.3.5 Other Degradomes 12

1.4 Human Diseases of Proteolysis 13

1.5 Matrix Proteases and Their Inhibitors 14

Acknowledgments 17

References 17

2 The Plasminogen Activation System in Normal Tissue Remodeling 25
Vincent Ellis

2.1 Introduction 25

2.2 Biochemical and Enzymological Fundamentals 26

2.2.1 Plasminogen 27

2.2.2 Regulation of the Plasminogen Activation System 28

2.3 Biological Roles of the Plasminogen Activation System 30

2.3.1 Congenital Plasminogen Deficiencies 31

2.3.2 Intravascular Fibrinolysis 32

2.3.3 Extravascular Fibrinolysis – Ligneous Conjunctivitis 32

2.3.4 Congenital Inhibitor Deficiencies 33

2.4 Tissue Remodeling Processes 34

2.4.1 Wound Healing 34

2.4.2 Vascular Remodeling 35

2.4.3 Fibrosis 36

2.4.4 Nerve Injury 38

2.4.5 Rheumatoid Arthritis 38

2.4.6 Complex Tissue Remodeling 40

2.4.7 Angiogenesis 40

2.4.8 uPAR – Cinderella Finds Her Shoe 42

2.5 Conclusions 44

References 45

3 Physiological Functions of Membrane-Type Metalloproteases 57
Kenn Holmbeck

3.1 Introduction 57

3.2 Historical Perspective 57

3.3 Activation of the Activator 59

3.4 Potential Roles of MT-MMPs and Discovery of a Human MMP Mutation 59

3.5 MT-MMP Function? 60

3.6 Physiological Roles of MT1-MMP in the Mouse 61

3.7 MT1-MMP Function in Lung Development 63

3.8 MT1-MMP Is Required for Root Formation and Molar Eruption 64

3.9 Identification of Cooperative Pathways for Collagen Metabolism 64

3.10 MT-MMP Activity in the Hematopoietic Environment 65

3.11 Physiological Role of MT2-MMP 66

3.12 MT-Type MMPs Work in Concert to Execute Matrix Remodeling 67

3.13 MT4-MMP – an MT-MMP with Elusive Function 69

3.14 MT5-MMP Modulates Neuronal Growth and Nociception 69

3.15 Summary and Concluding Remarks 70

Acknowledgment 71

References 71

4 Bone Remodeling: Cathepsin K in Collagen Turnover 79
Dieter Br¨omme

4.1 Introduction 79

4.2 Proteolytic Machinery of Bone Resorption and Cathepsin K 80

4.3 Specificity and Mechanism of Collagenase Activity of Cathepsin K 82

4.4 Role of Glycosaminoglycans in Bone Diseases 86

4.5 Development of Specific Cathepsin K Inhibitors and Clinical Trials 87

4.6 Off-Target and Off-Site Inhibition 89

4.7 Conclusion 91

Acknowledgments 91

References 91

5 Type-II Transmembrane Serine Proteases: Physiological Functions and Pathological Aspects 99
Gregory S. Miller, Gina L. Zoratti, and Karin List

5.1 Introduction 99

5.2 Functional/Structural Properties of TTSPs 99

5.3 Physiology and Pathobiology 104

5.3.1 Hepsin/TMPRSS Subfamily 104

5.3.2 Corin Subfamily 105

5.3.3 Matriptase Subfamily 106

5.3.4 HAT/DESC1 Subfamily 110

5.3.5 TTSPs in Cancer 111

References 114

6 Plasminogen Activators in Ischemic Stroke 127
Gerald Schielke and Daniel A. Lawrence

6.1 Introduction 127

6.2 Rationale for Thrombolysis after Stroke 128

6.2.1 Clinical Trials: Overview 129

6.3 Preclinical Studies 131

6.3.1 Localization of PAs, Neuroserpin, and Plasminogen in the Brain 131

6.4 The Association of Endogenous tPA with Excitotoxic and Ischemic Brain Injury 134

6.4.1 Excitotoxicity 134

6.4.2 Focal Ischemia 135

6.4.3 Global Ischemia 137

6.5 Mechanistic Studies of tPA in Excitotoxic and Ischemic Brain Injury 137

6.5.1 tPA and the NMDA Receptor 137

6.5.2 tPA and the Blood–Brain Barrier 138

6.5.3 tPA and the Blood–Brain Barrier – MMPs 139

6.5.4 tPA and the Blood–Brain Barrier – LRP 140

6.6 tPA and the Blood–Brain Barrier–PDGF-CC 141

6.7 Summary 143

Acknowledgments 144

References 145

7 Bacterial Abuse of Mammalian Extracellular Proteases during Tissue Invasion and Infection 157
Claudia Weber, Heiko Herwald, and Sven Hammerschmidt

7.1 Introduction 157

7.2 Tissue and Cell Surface Remodeling Proteases 158

7.2.1 Matrix Metalloproteinases (MMPs) 158

7.2.2 A Disintegrin and Metalloproteinases (ADAMs) 160

7.2.3 A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) 161

7.3 Proteases of the Blood Coagulation and the Fibrinolytic System 162

7.3.1 Proteases of the Blood Coagulation System 162

7.3.2 Proteases of the Fibrinolytic System 164

7.4 Contact System 168

7.4.1 Mechanisms of Bacteria-Induced Contact Activation 169

7.5 Conclusion and Future Prospectives 170

Acknowledgments 172

References 172

8 Experimental Approaches for Understanding the Role of Matrix Metalloproteinases in Cancer Invasion 181
Elena Deryugina

8.1 Introduction: Functional Roles of MMPs in Physiological Processes Involving the Induction and Sustaining of Cancer Invasion 181

8.2 EMT: a Prerequisite of MMP-Mediated Cancer Invasion or a Coordinated Response to Growth-Factor-Induced MMPs? 182

8.2.1 MMP-Induced EMT 183

8.2.2 EMT-Induced MMPs 185

8.3 Escape from the Primary Tumor: MMP-Mediated Invasion of Basement Membranes 186

8.3.1 In vitro Models of BM Invasion: Matrigel Invasion in Transwells 186

8.3.2 Ex Vivo Models of BM Invasion: Transmigration through the Intact BM 188

8.3.3 In Vivo Models of BM Invasion: Invasion of the CAM in Live Chick Embryos 189

8.4 Invasive Front Formation: Evidence for MMP Involvement In Vivo 189

8.4.1 MMP-Dependent Invasion in Spontaneous Tumors Developing in Transgenic Mice 190

8.4.2 MMP-Dependent Invasion of Tumor Grafts in MMP-Competent Mice 191

8.4.3 Invasion of MMP-Competent Tumor Grafts in MMP-Deficient Mice 192

8.5 Invasion at the Leading Edge: MMP-Mediated Proteolysis of Collagenous Stroma 193

8.5.1 Collagen Invasion in Transwells 193

8.5.2 Invasion of Collagen Matrices by Overlaid Tumor Cells 194

8.5.3 Models of 3D Collagen Invasion 195

8.5.4 Invasion of Collagenous Stroma In Vivo 196

8.5.5 Dynamic Imaging of ECM Proteolysis during Path-Making In vitro and In Vivo 197

8.6 Tumor Angiogenesis and Cancer Invasion: MMP-Mediated Interrelationships 197

8.6.1 Angiogenic Switch: MMP-9-Induced Neovascularization as a Prerequisite for Blood-Vessel-Dependent Cancer Invasion 198

8.6.2 Mutual Reliance of MMP-Mediated Angiogenesis and Cancer Invasion 200

8.6.3 Apparent Distinction between MMP-Mediated Tumor Angiogenesis and Cancer Invasion 201

8.7 Cancer Cell Intravasation: MMP-Dependent Vascular Invasion 202

8.8 Cancer Cell Extravasation: MMP-Dependent Invasion of the Endothelial Barrier and Subendothelial Stroma 204

8.8.1 Transmigration across Endothelial Monolayers In Vitro 204

8.8.2 Tumor Cell Extravasation In Vivo 205

8.9 Metastatic Site: Involvement of MMPs in the Preparation, Colonization, and Invasion of Distal Organ Stroma 206

8.9.1 MMPs as Determinants of Organ-Specific Metastases 207

8.9.2 MMP-Dependent Preparation of the PreMetastatic Microenvironment 208

8.9.3 Invasive Expansion of Cancer Cells at the Metastatic Site 210

8.10 Perspectives: MMPs in the Early Metastatic Dissemination and Awakening of Dormant Metastases 211

References 212

9 Plasminogen Activators and Their Inhibitors in Cancer 227
Joerg Hendrik Leupold and Heike Allgayer

9.1 Introduction 227

9.2 The Plasminogen Activator System 228

9.2.1 Molecular Characteristics and Physiological Functions of the u-PA System 228

9.2.2 Expression in Cancer 230

9.2.3 Regulation of Expression of the u-PA System in Cancer 231

9.2.4 Regulation of Cell Signaling by the u-PA System 235

9.2.5 Conclusion 238

References 238

10 Protease Nexin-1 – a Serpin with a Possible Proinvasive Role in Cancer 251
Tina M. Kousted, Jan K. Jensen, Shan Gao, and Peter A. Andreasen

10.1 Introduction – Serpins and Cancer 251

10.2 History of PN-1 252

10.3 General Biochemistry of PN-1 253

10.4 Inhibitory Properties of PN-1 254

10.5 Binding of PN-1 and PN-1-Protease Complexes to Endocytosis Receptors of the Low-Density Lipoprotein Receptor Family 257

10.6 Pericellular Functions of PN-1 in Cell Cultures 260

10.7 PN-1 Expression Patterns 261

10.7.1 Expression of PN-1 in Cultured Cells 261

10.7.2 Mechanisms of Transcriptional Regulation of PN-1 Expression 262

10.7.3 Expression of PN-1 in the Intact Organism 263

10.8 Functions of PN-1 in Normal Physiology 263

10.8.1 Reproductive Organs 263

10.8.2 Neurobiological Functions 264

10.8.3 Vascular Functions 265

10.9 Functions of PN-1 in Cancer 266

10.9.1 PN-1 Expression is Upregulated in Human Cancers, and a High Expression Is a Marker for a Poor Prognosis 266

10.9.2 Studies with Cell Cultures and Animal Tumor Models Indicate a Proinvasive Role of PN-1 267

10.10 Conclusions 270

References 271

11 Secreted Cysteine Cathepsins –Versatile Players in Extracellular Proteolysis 283
Fee Werner, Kathrin Sachse, and Thomas Reinheckel

11.1 Introduction 283

11.2 Structure and Function of Cysteine Cathepsins 283

11.3 Synthesis, Processing, and Sorting of Cysteine Cathepsins 284

11.4 Extracellular Enzymatic Activity of Lysosomal Cathepsins 286

11.5 Endogenous Cathepsin Inhibitors as Regulators of Extracellular Cathepsins 286

11.6 Extracellular Substrates of Cysteine Cathepsins 287

11.7 Cysteine Cathepsins in Cancer: Clinical Associations 287

11.8 Cysteine Cathepsins in Cancer: Evidence from Animal Models 288

11.9 Molecular Dysregulation of Cathepsins in Cancer Progression 289

11.10 Extracellular Cathepsins in Cancer 289

11.11 Conclusions and Further Directions 290

Acknowledgments 291

References 291

12 ADAMs in Cancer 299
Dorte Stautz, Sarah Louise Dombernowsky, and Marie Kveiborg

12.1 ADAMs–Multifunctional Proteins 299

12.1.1 Structure and Biochemistry 299

12.1.2 Biological Functions 300

12.1.3 Pathological Functions 301

12.2 ADAMs in Tumors and Cancer Progression 301

12.2.1 Self-Sufficiency in Growth Signals 303

12.2.2 Evasion of Apoptosis 303

12.2.3 Sustained Angiogenesis 304

12.2.4 Tissue Invasion and Metastasis 305

12.2.5 Cancer-Related Inflammation 306

12.2.6 Tumor–Stroma Interactions 307

12.3 ADAMs in Cancer–Key Questions Yet to Be Answered 307

12.3.1 ADAM Upregulation 308

12.3.2 Isoforms 308

12.3.3 Proteolytic versus Nonproteolytic Effect 309

12.4 The Clinical Potential of ADAMs 309

12.4.1 Diagnostic or Prognostic Biomarkers 309

12.4.2 ADAMs as Therapeutic Targets 310

12.5 Concluding Remarks 311

References 311

13 Urokinase-Type Plasminogen Activator, Its Receptor and Inhibitor as Biomarkers in Cancer 325
Tine Thurison, Ida K. Lund, Martin Illemann, Ib J. Christensen, and Gunilla Høyer-Hansen

13.1 Introduction 325

13.2 Breast Cancer 327

13.3 Colorectal Cancer 331

13.4 Lung Cancer 333

13.5 Gynecological Cancers 334

13.6 Prostate Cancer 335

13.7 Conclusion and Perspectives 337

Acknowledgment 339

Abbreviations 339

References 339

14 Clinical Relevance of MMP and TIMP Measurements in Cancer Tissue 345
Omer Bashir, Jian Cao, and Stanley Zucker

14.1 Introduction 345

14.2 MMP Structure 346

14.3 MMP Biology and Pathology 346

14.4 Natural Inhibitors of MMPs 347

14.5 Regulation of MMP Function 347

14.5.1 MMPs in Cancer 347

14.6 Cancer Stromal Cell Production of MMPs 348

14.7 Anticancer Effects of MMPs 348

14.8 Tissue Levels of MMPs and TIMPs in Cancer Patients 349

14.8.1 Breast Cancer 349

14.8.2 Gastrointestinal (GI) Cancer 351

14.8.2.1 Colorectal Cancer 351

14.8.2.2 Gastric Cancer 353

14.8.2.3 Pancreatic Cancer 355

14.8.2.4 Non-Small-Cell Lung Cancer (NSCLC) 355

14.8.3 Genitourinary Cancers 357

14.8.3.1 Bladder Cancer 357

14.8.3.2 Renal Cancer 359

14.8.3.3 Prostate Cancer 359

14.8.3.4 Ovarian Cancer 359

14.8.4 Brain Cancer 363

14.9 Conclusions 364

Acknowledgments 365

References 365

15 New Prospects for Matrix Metalloproteinase Targeting in Cancer Therapy 373
Emilie Buache and Marie-Christine Rio

15.1 Introduction 373

15.2 Lessons Learned from Preclinical and Clinical Studies of MMPIs in Cancer and Possible Alternatives 374

15.2.1 Improve Specificity/Affinity/Selectivity 374

15.2.2 Increase Knowledge of Multifaceted Activities for a given MMP 375

15.2.2.1 Target an Active MMP 375

15.2.2.2 Fully Characterize the Spatio-Temporal Function of Each MMP: the MMP-11 Example 376

15.2.3 Minimize Negative Side Effects 377

15.2.4 Optimize MMPI Administration Schedule 378

15.3 Novel Generation of MMPIs 379

15.3.1 Target the Hemopexin Domain 379

15.3.2 Antibodies as MMPIs 379

15.3.3 Immunotherapy 380

15.4 Exploit MMP Function to Improve Drug Bioavailability 380

15.5 Conclusion 381

Acknowledgments 381

References 381

Index 389