| Preface |
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xiii | |
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xv | |
| Introduction |
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1 | (4) |
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1 Matrix Proteases and the Degradome |
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5 | (20) |
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5 | (1) |
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1.2 Bioinformatic Tools for the Analysis of Complex Degradomes |
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6 | (2) |
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1.3 Evolution of Mammalian Degradomes |
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8 | (5) |
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8 | (2) |
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10 | (1) |
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1.3.3 Chimpanzee Degradome |
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10 | (1) |
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1.3.4 Duck-Billed Platypus Degradome |
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11 | (1) |
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12 | (1) |
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1.4 Human Diseases of Proteolysis |
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13 | (1) |
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1.5 Matrix Proteases and Their Inhibitors |
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14 | (11) |
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17 | (1) |
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17 | (8) |
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2 The Plasminogen Activation System in Normal Tissue Remodeling |
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25 | (32) |
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25 | (1) |
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2.2 Biochemical and Enzymological Fundamentals |
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26 | (4) |
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27 | (1) |
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2.2.2 Regulation of the Plasminogen Activation System |
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28 | (2) |
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2.3 Biological Roles of the Plasminogen Activation System |
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30 | (4) |
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2.3.1 Congenital Plasminogen Deficiencies |
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31 | (1) |
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2.3.2 Intravascular Fibrinolysis |
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32 | (1) |
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2.3.3 Extravascular Fibrinolysis - Ligneous Conjunctivitis |
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32 | (1) |
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2.3.4 Congenital Inhibitor Deficiencies |
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33 | (1) |
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2.4 Tissue Remodeling Processes |
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34 | (10) |
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34 | (1) |
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2.4.2 Vascular Remodeling |
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35 | (1) |
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36 | (2) |
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38 | (1) |
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2.4.5 Rheumatoid Arthritis |
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38 | (2) |
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2.4.6 Complex Tissue Remodeling |
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40 | (1) |
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40 | (2) |
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2.4.8 uPAR - Cinderella Finds Her Shoe |
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42 | (2) |
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44 | (13) |
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45 | (12) |
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3 Physiological Functions of Membrane-Type Metalloproteases |
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57 | (22) |
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57 | (1) |
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3.2 Historical Perspective |
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57 | (2) |
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3.3 Activation of the Activator |
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59 | (1) |
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3.4 Potential Roles of MT-MMPs and Discovery of a Human MMP Mutation |
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59 | (1) |
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60 | (1) |
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3.6 Physiological Roles of MT1-MMP in the Mouse |
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61 | (2) |
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3.7 MT1-MMP Function in Lung Development |
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63 | (1) |
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3.8 MT1-MMP Is Required for Root Formation and Molar Eruption |
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64 | (1) |
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3.9 Identification of Cooperative Pathways for Collagen Metabolism |
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64 | (1) |
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3.10 MT-MMP Activity in the Hematopoietic Environment |
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65 | (1) |
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3.11 Physiological Role of MT2-MMP |
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66 | (1) |
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3.12 MT-Type MMPs Work in Concert to Execute Matrix Remodeling |
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67 | (2) |
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3.13 MT4-MMP - an MT-MMP with Elusive Function |
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69 | (1) |
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3.14 MT5-MMP Modulates Neuronal Growth and Nociception |
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69 | (1) |
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3.15 Summary and Concluding Remarks |
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70 | (9) |
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71 | (1) |
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71 | (8) |
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4 Bone Remodeling: Cathepsin K in Collagen Turnover |
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79 | (20) |
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79 | (1) |
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4.2 Proteolytic Machinery of Bone Resorption and Cathepsin K |
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80 | (2) |
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4.3 Specificity and Mechanism of Collagenase Activity of Cathepsin K |
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82 | (4) |
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4.4 Role of Glycosaminoglycans in Bone Diseases |
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86 | (1) |
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4.5 Development of Specific Cathepsin K Inhibitors and Clinical Trials |
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87 | (2) |
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4.6 Off-Target and Off-Site Inhibition |
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89 | (2) |
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91 | (8) |
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92 | (5) |
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97 | (2) |
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5 Type-II Transmembrane Serine Proteases: Physiological Functions and Pathological Aspects |
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99 | (28) |
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99 | (1) |
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5.2 Functional/Structural Properties of TTSPs |
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99 | (5) |
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5.3 Physiology and Pathobiology |
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104 | (23) |
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5.3.1 Hepsin/TMPRSS Subfamily |
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104 | (1) |
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105 | (1) |
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5.3.3 Matriptase Subfamily |
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106 | (4) |
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5.3.4 HAT/DESC1 Subfamily |
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110 | (2) |
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112 | (2) |
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114 | (13) |
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6 Plasminogen Activators in Ischemic Stroke |
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127 | (30) |
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127 | (1) |
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6.2 Rationale for Thrombolysis after Stroke |
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128 | (3) |
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6.2.1 Clinical Trials: Overview |
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129 | (2) |
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131 | (3) |
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6.3.1 Localization of PAs, Neuroserpin, and Plasminogen in the Brain |
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131 | (3) |
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6.4 The Association of Endogenous tPA with Excitotoxic and Ischemic Brain Injury |
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134 | (3) |
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134 | (101) |
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235 | |
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137 | (1) |
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6.5 Mechanistic Studies of tPA in Excitotoxic and Ischemic Brain Injury |
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137 | (105) |
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6.5.1 tPA and the NMDA Receptor |
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237 | |
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6.5.2 tPA and the Blood-Brain Barrier |
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138 | (1) |
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6.5.3 tPA and the Blood-Brain Barrier - MMPs |
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139 | (101) |
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6.5.4 tPA and the Blood-Brain Barrier - LRP |
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240 | (2) |
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6.6 tPA and the Blood-Brain Barrier-PDGF-CC |
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242 | (1) |
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243 | |
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244 | (1) |
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245 | |
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7 Bacterial Abuse of Mammalian Extracellular Proteases during Tissue Invasion and Infection |
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157 | (24) |
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257 | (1) |
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7.2 Tissue and Cell Surface Remodeling Proteases |
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258 | |
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7.2.1 Matrix Metalloproteinases (MMPs) |
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158 | (2) |
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7.2.2 A Disintegrin and Metalloproteinases (ADAMs) |
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160 | (1) |
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7.2.3 A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) |
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161 | (1) |
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7.3 Proteases of the Blood Coagulation and the Fibrinolytic System |
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162 | (6) |
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7.3.1 Proteases of the Blood Coagulation System |
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162 | (2) |
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7.3.2 Proteases of the Fibrinolytic System |
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164 | (4) |
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168 | (2) |
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7.4.1 Mechanisms of Bacteria-Induced Contact Activation |
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169 | (1) |
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7.5 Conclusion and Future Prospectives |
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170 | (11) |
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172 | (1) |
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172 | (9) |
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8 Experimental Approaches for Understanding the Role of Matrix Metalloproteinases in Cancer Invasion |
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181 | (46) |
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8.1 Introduction: Functional Roles of MMPs in Physiological Processes Involving the Induction and Sustaining of Cancer Invasion |
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181 | (1) |
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8.2 EMT: a Prerequisite of MMP-Mediated Cancer Invasion or a Coordinated Response to Growth-Factor-Induced MMPs? |
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182 | (4) |
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183 | (2) |
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185 | (1) |
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8.3 Escape from the Primary Tumor: MMP-Mediated Invasion of Basement Membranes |
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186 | (3) |
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8.3.1 In vitro Models of BM Invasion: Matrigel Invasion in Transwells |
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186 | (2) |
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8.3.2 Ex Vivo Models of BM Invasion: Transmigration through the Intact BM |
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188 | (1) |
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8.3.3 In Vivo Models of BM Invasion: Invasion of the CAM in Live Chick Embryos |
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189 | (1) |
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8.4 Invasive Front Formation: Evidence for MMP Involvement In Vivo |
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189 | (4) |
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8.4.1 MMP-Dependent Invasion in Spontaneous Tumors Developing in Transgenic Mice |
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190 | (1) |
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8.4.2 MMP-Dependent Invasion of Tumor Grafts in MMP-Competent Mice |
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191 | (1) |
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8.4.3 Invasion of MMP-Competent Tumor Grafts in MMP-Deficient Mice |
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192 | (1) |
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8.5 Invasion at the Leading Edge: MMP-Mediated Proteolysis of Collagenous Stroma |
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193 | (4) |
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8.5.1 Collagen Invasion in Transwells |
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193 | (1) |
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8.5.2 Invasion of Collagen Matrices by Overlaid Tumor Cells |
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194 | (1) |
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8.5.3 Models of 3D Collagen Invasion |
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195 | (1) |
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8.5.4 Invasion of Collagenous Stroma In Vivo |
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196 | (1) |
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8.5.5 Dynamic Imaging of ECM Proteolysis during Path-Making In vitro and In Vivo |
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197 | (1) |
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8.6 Tumor Angiogenesis and Cancer Invasion: MMP-Mediated Interrelationships |
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197 | (5) |
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8.6.1 Angiogenic Switch: MMP-9-Induced Neovascularization as a Prerequisite for Blood-Vessel-Dependent Cancer Invasion |
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198 | (2) |
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8.6.2 Mutual Reliance of MMP-Mediated Angiogenesis and Cancer Invasion |
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200 | (1) |
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8.6.3 Apparent Distinction between MMP-Mediated Tumor Angiogenesis and Cancer Invasion |
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201 | (1) |
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8.7 Cancer Cell Intravasation: MMP-Dependent Vascular Invasion |
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202 | (2) |
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8.8 Cancer Cell Extravasation: MMP-Dependent Invasion of the Endothelial Barrier and Subendothelial Stroma |
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204 | (2) |
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8.8.1 Transmigration across Endothelial Monolayers In Vitro |
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204 | (1) |
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8.8.2 Tumor Cell Extravasation In Vivo |
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205 | (1) |
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8.9 Metastatic Site: Involvement of MMPs in the Preparation, Colonization, and Invasion of Distal Organ Stroma |
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206 | (5) |
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8.9.1 MMPs as Determinants of Organ-Specific Metastases |
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207 | (1) |
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8.9.2 MMP-Dependent Preparation of the PreMetastatic Microenvironment |
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208 | (2) |
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8.9.3 Invasive Expansion of Cancer Cells at the Metastatic Site |
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210 | (1) |
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8.10 Perspectives: MMPs in the Early Metastatic Dissemination and Awakening of Dormant Metastases |
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211 | (16) |
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212 | (15) |
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9 Plasminogen Activators and Their Inhibitors in Cancer |
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227 | (24) |
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227 | (1) |
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9.2 The Plasminogen Activator System |
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228 | (23) |
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9.2.1 Molecular Characteristics and Physiological Functions of the u-PA System |
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228 | (2) |
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9.2.2 Expression in Cancer |
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230 | (1) |
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9.2.3 Regulation of Expression of the u-PA System in Cancer |
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231 | (4) |
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9.2.4 Regulation of Cell Signaling by the u-PA System |
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235 | (3) |
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238 | (1) |
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238 | (13) |
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10 Protease Nexin-1 - a Serpin with a Possible Proinvasive Role in Cancer |
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251 | (32) |
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10.1 Introduction - Serpins and Cancer |
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251 | (1) |
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252 | (1) |
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10.3 General Biochemistry of PN-1 |
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253 | (1) |
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10.4 Inhibitory Properties of PN-1 |
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254 | (3) |
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10.5 Binding of PN-1 and PN-1-Protease Complexes to Endocytosis Receptors of the Low-Density Lipoprotein Receptor Family |
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257 | (3) |
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10.6 Pericellular Functions of PN-1 in Cell Cultures |
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260 | (1) |
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10.7 PN-1 Expression Patterns |
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261 | (2) |
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10.7.1 Expression of PN-1 in Cultured Cells |
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261 | (1) |
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10.7.2 Mechanisms of Transcriptional Regulation of PN-1 Expression |
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262 | (1) |
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10.7.3 Expression of PN-1 in the Intact Organism |
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263 | (1) |
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10.8 Functions of PN-1 in Normal Physiology |
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263 | (3) |
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10.8.1 Reproductive Organs |
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263 | (1) |
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10.8.2 Neurobiological Functions |
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264 | (1) |
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10.8.3 Vascular Functions |
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265 | (1) |
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10.9 Functions of PN-1 in Cancer |
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266 | (4) |
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10.9.1 PN-1 Expression is Upregulated in Human Cancers, and a High Expression Is a Marker for a Poor Prognosis |
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266 | (1) |
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10.9.2 Studies with Cell Cultures and Animal Tumor Models Indicate a Proinvasive Role of PN-1 |
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267 | (3) |
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270 | (13) |
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271 | (12) |
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11 Secreted Cysteine Cathepsins - Versatile Players in Extracellular Proteolysis |
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283 | (16) |
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283 | (1) |
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11.2 Structure and Function of Cysteine Cathepsins |
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283 | (1) |
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11.3 Synthesis, Processing, and Sorting of Cysteine Cathepsins |
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284 | (2) |
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11.4 Extracellular Enzymatic Activity of Lysosomal Cathepsins |
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286 | (1) |
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11.5 Endogenous Cathepsin Inhibitors as Regulators of Extracellular Cathepsins |
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286 | (1) |
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11.6 Extracellular Substrates of Cysteine Cathepsins |
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287 | (1) |
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11.7 Cysteine Cathepsins in Cancer: Clinical Associations |
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287 | (1) |
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11.8 Cysteine Cathepsins in Cancer: Evidence from Animal Models |
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288 | (1) |
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11.9 Molecular Dysregulation of Cathepsins in Cancer Progression |
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289 | (1) |
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11.10 Extracellular Cathepsins in Cancer |
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289 | (1) |
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11.11 Conclusions and Further Directions |
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290 | (9) |
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291 | (1) |
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291 | (8) |
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299 | (26) |
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Sarah Louise Dombernowsky |
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12.1 ADAMs-Multifunctional Proteins |
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299 | (2) |
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12.1.1 Structure and Biochemistry |
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299 | (1) |
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12.1.2 Biological Functions |
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300 | (1) |
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12.1.3 Pathological Functions |
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301 | (1) |
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12.2 ADAMs in Tumors and Cancer Progression |
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301 | (6) |
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12.2.1 Self-Sufficiency in Growth Signals |
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303 | (1) |
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12.2.2 Evasion of Apoptosis |
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303 | (1) |
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12.2.3 Sustained Angiogenesis |
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304 | (1) |
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12.2.4 Tissue Invasion and Metastasis |
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305 | (1) |
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12.2.5 Cancer-Related Inflammation |
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306 | (1) |
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12.2.6 Tumor-Stroma Interactions |
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307 | (1) |
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12.3 ADAMs in Cancer-Key Questions Yet to Be Answered |
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307 | (2) |
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308 | (1) |
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308 | (1) |
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12.3.3 Proteolytic versus Nonproteolytic Effect |
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309 | (1) |
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12.4 The Clinical Potential of ADAMs |
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309 | (2) |
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12.4.1 Diagnostic or Prognostic Biomarkers |
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309 | (1) |
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12.4.2 ADAMs as Therapeutic Targets |
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310 | (1) |
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311 | (14) |
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311 | (14) |
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13 Urokinase-Type Plasminogen Activator, Its Receptor and Inhibitor as Biomarkers in Cancer |
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325 | (20) |
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325 | (2) |
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327 | (4) |
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331 | (2) |
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333 | (1) |
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13.5 Gynecological Cancers |
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334 | (1) |
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335 | (2) |
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13.7 Conclusion and Perspectives |
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337 | (8) |
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339 | (1) |
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339 | (1) |
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339 | (6) |
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14 Clinical Relevance of MMP and TIMP Measurements in Cancer Tissue |
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345 | (28) |
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345 | (1) |
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346 | (1) |
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14.3 MMP Biology and Pathology |
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346 | (1) |
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14.4 Natural Inhibitors of MMPs |
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347 | (1) |
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14.5 Regulation of MMP Function |
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347 | (1) |
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347 | (1) |
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14.6 Cancer Stromal Cell Production of MMPs |
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348 | (1) |
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14.7 Anticancer Effects of MMPs |
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348 | (1) |
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14.8 Tissue Levels of MMPs and TIMPs in Cancer Patients |
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349 | (15) |
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349 | (2) |
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14.8.2 Gastrointestinal (GI) Cancer |
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351 | (1) |
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14.8.2.1 Colorectal Cancer |
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351 | (2) |
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353 | (2) |
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14.8.2.3 Pancreatic Cancer |
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355 | (1) |
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14.8.2.4 Non-Small-Cell Lung Cancer (NSCLC) |
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355 | (2) |
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14.8.3 Genitourinary Cancers |
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357 | (1) |
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357 | (2) |
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359 | (1) |
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359 | (1) |
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359 | (4) |
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363 | (1) |
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364 | (9) |
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365 | (1) |
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365 | (8) |
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15 New Prospects for Matrix Metalloproteinase Targeting in Cancer Therapy |
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373 | (16) |
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373 | (1) |
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15.2 Lessons Learned from Preclinical and Clinical Studies of MMPIs in Cancer and Possible Alternatives |
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374 | (5) |
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15.2.1 Improve Specificity/Affinity/Selectivity |
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374 | (1) |
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15.2.2 Increase Knowledge of Multifaceted Activities for a given MMP |
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375 | (1) |
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15.2.2.1 Target an Active MMP |
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375 | (1) |
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15.2.2.2 Fully Characterize the Spatio-Temporal Function of Each MMP: the MMP-11 Example |
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376 | (1) |
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15.2.3 Minimize Negative Side Effects |
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377 | (1) |
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15.2.4 Optimize MMPI Administration Schedule |
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378 | (1) |
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15.3 Novel Generation of MMPIs |
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379 | (1) |
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15.3.1 Target the Hemopexin Domain |
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379 | (1) |
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15.3.2 Antibodies as MMPIs |
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379 | (1) |
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380 | (1) |
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15.4 Exploit MMP Function to Improve Drug Bioavailability |
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380 | (1) |
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381 | (8) |
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381 | (1) |
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381 | (8) |
| Index |
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389 | |
