Matrix Proteases in Health and Disease

Matrix Proteases in Health and Disease

By: Niels Behrendt (editor)Hardback

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Description

Presenting a comprehensive overview of the multifaceted field of proteases in the extracellular matrix environment, this reference focuses on the recently elucidated functions of complex proteolytic systems in physiological and pathological tissue remodeling. The proteases treated include both serine proteases such as plasminogen activators and TTSPs, metalloproteases such as MMPs and ADAMS and cysteine protease cathepsins. The text specifically addresses the role of extracellular proteases in cancer cell invasion, stroke and infectious diseases, 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.

About Author

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.

Contents

List of Contributors XV Introduction 1 Niels Behrendt 1 Matrix Proteases and the Degradome 5 Clara Soria-Valles, Carlos L'opez-Ot'yn, 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 Bromme 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 Hoyer-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

Product Details

  • ISBN13: 9783527329915
  • Format: Hardback
  • Number Of Pages: 416
  • ID: 9783527329915
  • weight: 915
  • ISBN10: 3527329919

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