Matrix Proteases in Health and Disease

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.

Preface
Introduction

MATRIX PROTEASES AND THE DEGRADOME
Introduction
Bioinformatic Tools for the Analysis of Complex Degradomes
Evolution of Mammalian Degradomes
Human Diseases of Proteolysis
Matrix Proteases and Their Inhibitors

THE PLASMINOGEN ACTIVATION SYSTEM IN NORMAL TISSUE REMODELING
Introduction
Biochemical and Enzymological Fundamentals
Biological Roles of the Plasminogen Activation System
Tissue Remodeling Processes
Conclusions

PHYSIOLOGICAL FUNCTIONS OF MEMBRANE-TYPE METALLOPROTEASES
Introduction
Historical Perspective
Activation of the Activator
Potential Roles of MT-MMPs and Discovery of a Human MMP Mutation
MT-MMP Function?
Physiological Roles of MT1-MMP in the Mouse
MT1-MMP Function in Lung Development
MT1-MMP Is Required for Root Formation and Molar Eruption
Identification of Cooperative Pathways for Collagen Metabolism
MT-MMP Activity in the Hematopoietic Environment
Physiological Role of MT2-MMP
MT-Type MMPs Work in Concert to Execute Matrix Remodeling 67MT4-MMP - an MT-MMP with Elusive Function
MT5-MMP Modulates Neuronal Growth and Nociception
Summary and Concluding Remarks

BONE REMODELING: CATHEPSIN K IN COLLAGEN TURNOVER
Introduction
Proteolytic Machinery of Bone Resorption and Cathepsin K
Specificity and Mechanism of Collagenase Activity of Cathepsin K
Role of Glycosaminoglycans in Bone Diseases
Development of Specific Cathepsin K Inhibitors and Clinical Trials
Off-Target and Off-Site Inhibition
Conclusion

TYPE-II TRANSMEMBRANE SERINE PROTEASES: PHYSIOLOGICAL FUNCTIONS AND PATHOLOGICAL ASPECTS
Introduction
Functional/Structural Properties of TTSPs
Physiology and Pathobiology

PLASMINOGEN ACTIVATORS IN ISCHEMIC STROKE
Introduction
Rationale for Thrombolysis after Stroke
Preclinical Studies
The Association of Endogenous tPA with Excitotoxic and Ischemic Brain Injury
Mechanistic Studies of tPA in Excitotoxic and Ischemic Brain Injury
tPA and the Blood-Brain Barrier-PDGF-CC
Summary

BACTERIAL ABUSE OF MAMMALIAN EXTRACELLULAR PROTEASES DURING TISSUE INVASION AND INFECTION
Introduction
Tissue and Cell Surface Remodeling Proteases
Proteases of the Blood Coagulation and the Fibrinolytic System
Contact System
Conclusion and Future Prospectives

EXPERIMENTAL APPROACHES FOR UNDERSTANDING THE ROLE OF MATRIX METALLOPROTEINASES IN CANCER INVASION
Introduction: Functional Roles of MMPs in Physiological Processes Involving the Induction and Sustaining of Cancer Invasion
EMT: a Prerequisite of MMP-Mediated Cancer Invasion or a Coordinated Response to Growth-Factor-Induced MMPs?
Escape from the Primary Tumor: MMP-Mediated Invasion of Basement Membranes
Invasive Front Formation: Evidence for MMP Involvement In Vivo
Invasion at the Leading Edge: MMP-Mediated Proteolysis of Collagenous Stroma
Tumor Angiogenesis and Cancer Invasion: MMP-Mediated Interrelationships
Cancer Cell Intravasation: MMP-Dependent Vascular Invasion
Cancer Cell Extravasation: MMP-Dependent Invasion of the Endothelial Barrier and Subendothelial Stroma
Metastatic Site: Involvement of MMPs in the Preparation, Colonization, and Invasion of Distal Organ Stroma
Perspectives: MMPs in the Early Metastatic Dissemination and Awakening of Dormant Metastases

PLASMINOGEN ACTIVATORS AND THEIR INHIBITORS IN CANCER
Introduction
The Plasminogen Activator System

PROTEASE NEXIN-1 - A SERPIN WITH A POSSIBLE PROINVASIVE ROLE IN CANCER
Introduction - Serpins and Cancer
History of PN-1
General Biochemistry of PN-1
Inhibitory Properties of PN-1
Binding of PN-1 and PN-1-Protease Complexes to Endocytosis Receptors of the Low-Density Lipoprotein Receptor Family
Pericellular Functions of PN-1 in Cell Cultures
PN-1 Expression Patterns
Functions of PN-1 in Normal Physiology
Functions of PN-1 in Cancer
Conclusions

SECRETED CYSTEINE CATHEPSINS - VERSATILE PLAYERS IN EXTRACELLULAR PROTEOLYSIS
Introduction
Structure and Function of Cysteine Cathepsins
Synthesis, Processing, and Sorting of Cysteine Cathepsins
Extracellular Enzymatic Activity of Lysosomal Cathepsins
Endogenous Cathepsin Inhibitors as Regulators of Extracellular Cathepsins
Extracellular Substrates of Cysteine Cathepsins Cysteine Cathepsins in Cancer: Clinical Associations
Cysteine Cathepsins in Cancer: Evidence from Animal Models
Molecular Dysregulation of Cathepsins in Cancer Progression
Extracellular Cathepsins in Cancer
Conclusions and Further Directions

ADAMS IN CANCER
ADAMs-Multifunctional Proteins
ADAMs in Tumors and Cancer Progression
ADAMs in Cancer - Key Questions Yet to Be Answered
The Clinical Potential of ADAMs
Concluding Remarks

UROKINASE-TYPE PLASMINOGEN ACTIVATOR, ITS RECEPTOR AND INHIBITOR AS BIOMARKERS IN CANCER
Introduction
Breast Cancer
Colorectal Cancer
Lung Cancer
Gynecological Cancers
Prostate Cancer
Conclusion and Perspectives

CLINICAL RELEVANCE OF MMP AND TIMP MEASUREMENTS IN CANCER TISSUE
Introduction
MMP Structure
MMP Biology and Pathology
Natural Inhibitors of MMPs
Regulation of MMP Function
Cancer Stromal Cell Production of MMPs
Anticancer Effects of MMPs
Tissue Levels of MMPs and TIMPs in Cancer Patients
Conclusions

NEW PROSPECTS FOR MATRIX METALLOPROTEINASE TARGETING IN CANCER THERAPY
Introduction
Lessons Learned from Preclinical and Clinical Studies of MMPIs in Cancer and Possible Alternatives
Novel Generation of MMPIs
Exploit MMP Function to Improve Drug Bioavailability
Conclusion