Glycans in Diseases and Therapeutics (eBook)

Foreword 6
Preface 8
Contents 12
Chapter 1: Heparan Sulfate Proteoglycan in Inflammation and Angiogenesis 14
1.1 Introduction 14
1.2 The Anti-inflammatory Function of Heparin 15
1.2.1 Leukocyte Trafficking and Inflammation 15
1.2.2 Heparin Inhibits Inflammation Mainly Through Blockage of L- and P-Selectin-Mediated Leukocyte Recruitment 16
1.2.3 The Anti-inflammatory Effect of Heparin Does Not Correlate with Its Anticoagulant Activity and Critically Depends on the Presence of 6-O-Sulfate of Glucosamine Residues 18
1.3 The Role of Heparan Sulfate in Leukocyte Recruitment in Inflammation 20
1.3.1 Generation of Endothelial- and Leukocyte-Specific Ndst1-Deficient Mice 21
1.3.2 Endothelial Heparan Sulfate Critically Modulates Inflammatory Responses In Vivo 22
1.3.3 Endothelial Heparan Sulfate Interacts with L-Selectin to Mediate Leukocyte Rolling During Inflammation 24
1.3.4 Endothelial Heparan Sulfate Presents Chemokines on Luminal Surfaces to Mediate Leukocyte Firm Adhesion During Inflammation 27
1.3.5 Endothelial Heparan Sulfate Participates in Abluminal-to-Luminal Transcytosis of Chemokine During Inflammation 28
1.3.6 Endothelial Heparan Sulfate Directs Intraluminal Crawling of Neutrophils by Retaining a Chemotactic Chemokine Gradient 30
1.4 The Role of Heparan Sulfate in Angiogenesis 31
1.4.1 Deficiency of Endothelial Ndst1 Does Not Affect Physiological Angiogenesis In Vivo 31
1.4.2 Deficiency of Endothelial Ndst1 Disturbs Tumor Angiogenesis In Vivo 32
1.4.3 Deficiency of Endothelial Ndst1 Disturbs VEGF Signaling Which Correlates with Enhanced Endothelial Apoptosis in Tumor Vasculature 33
1.5 Conclusions and Prospective 35
References 37
Chapter 2: Heparan Sulfate Proteoglycans in Infection 43
2.1 Primer on HSPG Biology 44
2.2 Methods for HSPG Studies in Infectious Diseases 46
2.3 HSPGs in Microbial Attachment and Internalization 47
2.3.1 Papillomaviruses 50
2.3.2 Dengue Virus 53
2.3.3 Listeria monocytogenes 54
2.4 HSPG as a Receptor for Virulence Factors 54
2.5 HSPGs in Tissue Tropism of Pathogens 56
2.6 Multiple Roles of HSPG in the Pathogenesis of a Single Pathogen 57
2.7 HSPG Shedding in Bacterial Pathogenesis 59
2.7.1 Pseudomonas aeruginosa 59
2.7.2 Staphylococcus aureus 60
2.7.3 Streptococcus pneumoniae 62
2.8 Future Perspectives 63
References 64
Chapter 3: Glycans in Cancer 75
3.1 Introduction 75
3.2 Glycosylation During Cancer 76
3.2.1 Synthesis of Glycans 76
3.2.2 Alteration of Glycosylation During Cancer 77
3.2.3 Alterations of N-Linked Glycosylation in Cancer 78
3.2.3.1 N-Linked Glycosylation 78
3.2.3.2 Biosynthesis of N-Glycans 78
3.2.3.3 N-Glycan Branching: The Role of GnT-V 79
3.2.3.4 GnT-III Versus GnT-V 80
3.2.4 Alterations of O-Linked Glycosylation in Cancer 81
3.2.4.1 O-Linked Glycosylation and Carcinoma Mucins 81
3.2.4.2 Biosynthesis of O-Glycans 81
3.2.4.3 Carcinoma-Associated Alterations of O-Glycans 82
3.2.4.4 Carcinoma Mucins and Cancer Progression 84
3.2.4.5 MUC1 84
3.2.4.6 MUC2 85
3.2.4.7 MUC4 85
3.2.5 Altered Glycosylation Affects Biology of Cancer 86
3.2.5.1 Altered Glycosylation and Metastasis 86
3.2.5.2 Cell-Cell Interactions During Metastasis 87
3.3 Conclusions and Perspective 88
References 88
Chapter 4: Glycosaminoglycans in Atherosclerosis and Thrombosis 94
4.1 The Vascular System 94
4.2 Atherosclerosis 96
4.3 Diabetes and Hyperglycemia 98
4.4 Glycosaminoglycans and Proteoglycans in Atherosclerosis 98
4.4.1 Heparan Sulfate 101
4.4.2 Chondroitin/dermatan Sulfate Proteoglycans 103
4.4.3 Hyaluronic Acid 106
4.5 Glycosaminoglycans and Thrombosis 106
4.5.1 Heparin 108
4.5.2 Heparan Sulfate 109
4.5.3 Dermatan Sulfate 110
4.5.4 Decorin 113
4.5.5 Intimatan 113
4.6 Conclusions 114
References 115
Chapter 5: Glycans in Embryonic Stem Cells 123
5.1 Glycosaminoglycans 123
5.1.1 Heparan Sulphate Proteoglycans: Structure and Biosynthesis 124
5.1.2 Functions of HS 126
5.1.3 HS Biosynthetic Enzyme Mouse Knockout Studies 127
5.1.3.1 Chain Polymerisation and N-Sulphation 127
5.1.3.2 Epimerisation and 2-O-Sulphation 128
5.1.3.3 6-O-Sulphation 128
5.1.3.4 6-O-Desulphation 129
5.1.3.5 3-O-Sulphation 129
5.1.3.6 Summary 130
5.2 Overview of ES Cell Biology 131
5.2.1 Deriving and Defining Embryonic Stem Cells 131
5.2.2 Pluripotency and Self Renewal 132
5.2.3 Culture of Mouse ES Cells 133
5.2.4 Culture of Human ES Cells 133
5.2.4.1 A Suitable Substrate 134
5.2.4.2 Culture Media 134
5.3 The Role of HSPGs in mES Cell Early Lineage Events 136
5.3.1 The Role of HS in Neuroectodermal Differentiation of mES Cells 136
5.3.2 The Role of HS in Early Mesodermal Differentiation of ES Cells 138
5.4 HSPGs and Human ES Cells 140
References 141
Chapter 6: Heparan Sulfate Proteoglycans in Cancer Therapy 148
6.1 Introduction 148
6.2 Contribution of Dysregulated Molecular Functions of HSPGs to Tumor Progression 150
6.2.1 Heparan Sulfate-Dependent Regulation of Tumor Growth 150
6.2.1.1 Heparan Sulfate as a Modulator of Tumor Cell Proliferation 150
6.2.1.2 Heparan Sulfate as a Modulator of Tumor Cell Apoptosis 152
6.2.2 Invasion and Metastasis of Tumor Cells 153
6.2.2.1 HSPG-Dependent Modulation of Cell Motility 153
6.2.2.2 HSPGs as Targets and Regulators of Protease and Heparanase Activity 154
6.2.3 HSPGs and Tumor Angiogenesis 156
6.3 Heparan Sulfate-Centered Approaches of Cancer Therapy 157
6.3.1 Heparin and Heparinoids 157
6.3.2 Inhibitors of Heparan Sulfate Biosynthesis 158
6.3.3 Peptide-Based Inhibition of HSPG Function 159
6.3.4 Inhibitors of Heparan Sulfate-Processing Enzymes 159
6.3.5 HS and HSPGs as Angiogenesis Inhibitors 160
6.4 Perspective 161
References 162
Chapter 7: Structure and Biological Activities of Glycosaminoglycan Analogs from Marine Invertebrates: New Therapeutic Agents? 168
7.1 Diversity of Sea-Life and Unique Biological Molecules 169
7.2 Glycosaminoglycans from Marine Invertebrate Phyla and Their Biological Properties 170
7.2.1 Cnidaria 178
7.2.1.1 Galactosaminoglycans 178
7.2.1.2 Glucosaminoglycans 178
7.2.2 Arthopoda 179
7.2.2.1 Galactosaminoglycans 179
7.2.2.2 Glucosaminoglycans 179
7.2.3 Mollusca 180
7.2.3.1 Galactosaminoglycans 180
7.2.3.2 Glucosaminoglycans 181
7.2.4 Echinodermata 182
7.2.4.1 Galactosaminoglycans 182
7.2.4.2 Glucosaminoglycans 183
7.2.5 Chordata 184
7.2.5.1 Galactosaminoglycans 184
7.2.5.2 Glucosaminoglycans 185
7.3 Therapeutic Possibilities Involving the Marine Invertebrate Glycans 187
References 188
Index 194