Heparanase: From Basic Research to Clinical Applications (Advances in Experimental Medicine and Biology, 1221)

Contents
Contributors
About the Editors
Part I: Historical and General Background
	Chapter 1: Forty Years of Basic and Translational Heparanase Research
		1.1 Historical Introduction
			1.1.1 Key Observations Made Prior to Cloning of the HPSE Gene (Chronological Order)
		1.2 Heparanase Gene Cloning
		1.3 Studies Performed Following Cloning of the HPSE Gene
			1.3.1 Introductory Notes
			1.3.2 Key Observations Made After Cloning of the HPSE Gene
				Structural Aspects
				Gene Regulation
				Angiogenesis & Metastasis
				Animal Models
				Heparanase Uptake and Cellular Traffic
				Nuclear Heparanase and Its Transcriptional Activity
				Heparanase Non-Enzymatic and Signaling Function
				Heparanase Inhibitors
				Various Tumors
					Multiple Myeloma
				Tumor Microenvironment
				Inflammation and Cells of the Immune System
				Vaccination
				Diabetes, Diabetic Complications and Other Disorders
				Aterosclerosis & Thrombosis
				Viral Infection
		1.4 Concluding Remarks and Perspectives
		References
	Chapter 2: Heparanase – Discovery and Targets
		2.1 Introduction
		2.2 Heparanase, Early Findings
		2.3 Stereochemistry of Heparanase Target
		2.4 How Many Heparanases?
		2.5 Heparanase and Polysaccharide Metabolism
		2.6 Heparanase and the GAGosome
		References
	Chapter 3: Heparanase: Historical Aspects and Future Perspectives
		3.1 Introduction
		3.2 Historical Overview and General Properties of Heparanase
		3.3 Overview of Substrate Specificity of Heparanase
		3.4 Functions Dependent on Heparanase Enzymatic Activity
			3.4.1 HS Turnover
			3.4.2 Involvement in Cell Invasion
			3.4.3 Involvement in Release of ECM Bound Proteins
			3.4.4 Involvement in Depletion of Intracellular Anti-Oxidant Stores of HS
			3.4.5 Facilitator of Spread of HS-Binding Viruses
			3.4.6 Inhibitors of Heparanase Enzymatic Activity
		3.5 Functions Independent of Heparanase Enzymatic Activity
			3.5.1 Cell Adhesion Molecule
			3.5.2 Promoter of Signal Transduction
			3.5.3 Transcription Factor
		3.6 Future Perspectives
			3.6.1 How Does Heparanase Initiate Signalling Pathways?
			3.6.2 Do Nuclear Heparanase and HS Interact?
			3.6.3 Relationship Between Heparanase-1 and Heparanase-2
			3.6.4 Drug Development: Where to Next?
		3.7 Concluding Remarks
		References
	Chapter 4: Involvement of Syndecan-1 and Heparanase in Cancer and Inflammation
		4.1 Introduction
			4.1.1 The Syndecan Family of Heparan Sulfate Proteoglycans
			4.1.2 Heparanase – A Key Enzyme in ECM Remodeling
		4.2 The Heparanase-Syndecan Axis
			4.2.1 Heparanase Mediated Sdc1 Shedding
			4.2.2 Heparanase and Sdc1 in the Nucleus
			4.2.3 Effects on Exosome Formation and Function
			4.2.4 Effects on Growth Factor Signaling
		4.3 Functional Cooperation of Syndecan-1 and Heparanase in Inflammation
			4.3.1 Lessons from Mouse Models
				Role of Sdc1 and Heparanase in Delayed-Type Hypersensitivity
				Role of Sdc1 and Heparanase in Anti-Glomerular Basement Membrane Glomerulonephritis
				Sdc1 and Heparanase in Experimental Autoimmune Encephalitis (EAE)
				Role of Sdc1 and Heparanase in Inflammatory Bowel Disease and Colitis-Associated Colon Cancer
		4.4 Syndecan-1 and Heparanase as Pathogenesis Factors and Therapeutic Targets in Malignant Disease
		4.5 Concluding Remarks
		References
Part II: Crystal Structure, Substrate Specificity and Gene Regulation
	Chapter 5: An Overview of the Structure, Mechanism and Specificity of Human Heparanase
		5.1 Introduction
		5.2 Heparan Sulfate – The Biochemical Basics
		5.3 Historical Developments in HPSE Research
			5.3.1 Identification of a Specific Heparan Sulfate Degrading Enzyme
			5.3.2 Isolation of Heparanase Enzyme and Cloning of the HPSE Gene
			5.3.3 Production of Homogenous Recombinant HPSE
		5.4 Heparanase – Insights from Crystal Structures
			5.4.1 3-Dimensional Structure of Mature HPSE
			5.4.2 Structural Insights into HPSE Substrate Interactions
				HPSE Interactions at the −1 Subsite
				HPSE Interactions at the −2 Subsite
				HPSE Interactions at the +1 Subsite
				Beyond the +1 Subsite
			5.4.3 3-Dimensional Structure of proHPSE
		5.5 HPSE Within the Broader CAZy Classification
			5.5.1 Structural Determinants of exo vs. endo-Glycosidase Activity in the GH79 Family
				AcGH79
				BpHep
				(pro)HPSE
		5.6 Concluding Remarks and Future Challenges
		References
	Chapter 6: Molecular Aspects of Heparanase Interaction with Heparan Sulfate, Heparin and Glycol Split Heparin
		6.1 Introduction
		6.2 Mechanism of Enzymatic Hydrolysis
		6.3 Heparanase and its Active Site Structure as Predicted by Homology and x-Ray Diffraction Models
		6.4 Hse/HS Binding
		6.5 Glycol Split Heparin Inhibitors
		6.6 Conclusions
		References
	Chapter 7: Heparanase: Cloning, Function and Regulation
		7.1 Introduction
			7.1.1 Identification of Heparanase
			7.1.2 Normal Expression of Heparanase
		7.2 Gene Cloning
			7.2.1 Race of Four: The Cloning of Human Heparanase
			7.2.2 Identification of an 8 kDa Peptide in the Active HPSE Enzyme
			7.2.3 Cloning of Heparanase From Other Organisms
			7.2.4 Cloning of Heparanase for In Vitro Analysis
				Bacterial Expression Systems
				Insect Cell Expression Systems
		7.3 Function
			7.3.1 Heparan Sulfate Proteoglycans as HPSE Targets
			7.3.2 Regulation of Syndecan Function by HPSE
			7.3.3 HPSE in the Immune System
			7.3.4 HPSE Function in Pathogenesis
		7.4 Regulation of Heparanase
			7.4.1 A Lack of Methylation at the HPSE Promoter Increases HPSE Expression
			7.4.2 Regulation of HPSE Expression by Transcription Factors
			7.4.3 Regulation of Heparanase by MicroRNAs
			7.4.4 Regulation of Heparanase Activity by the Presence of the Linker Domain
			7.4.5 Regulating HPSE Activity by HS Masking
			7.4.6 The Effect of Small Biological Molecules on HPSE Expression
			7.4.7 Active Site Inhibitors of Heparanase
		References
	Chapter 8: Mechanism of HPSE Gene SNPs Function: From Normal Processes to Inflammation, Cancerogenesis and Tumor Progression
		8.1 The HPSE Gene SNPs Characterization, Distribution, and Linkage Disequilibrium
		8.2 Correlation Between the HPSE Gene SNPs and Heparanase Expression Among Healthy Individuals
		8.3 HPSE Gene SNPs and Inflammation
		8.4 Involvement of HPSE Gene SNPs in Cancer Development and Progression
		8.5 HPSE Gene SNPs and the Risk of Acute Graft Vs. Host Disease (aGVHD)
		8.6 Summary
		References
Part III: Tumor Biology
	Chapter 9: Heparanase-The Message Comes in Different Flavors
		9.1 Introduction
		9.2 Heparanase and Cancer Progression
			9.1.1 Heparanase Induction in Human Cancer
			9.1.2 Basal and Inducible Heparanase Gene Transcription
			9.1.3 Gene Methylation and Egr1
			9.1.4 ARE and Post-Transcriptional Gene Regulation
			9.1.5 Heparanase Regulation by Hormones, Tumor Suppressors, Oncogenes and Micro-RNA
		9.3 Heparanase Signaling-A Message from within
			9.1.6 HS-Dependent Signaling
			9.1.7 HS-Independent Signaling
		9.4 Heparanase Uptake – Is the Message within Lysosomes?
			9.1.8 The Lysosome as a Signaling Organelle
		9.5 Heparanase Inhibitors – Are We Targeting Well?
		9.6 Is Hpa2 the Answer?
			9.1.9 Hpa2 in Cancer Progression-an Opposite Answer
		9.7 Heparanase Message Revisited
		References
	Chapter 10: Heparanase Involvement in Exosome Formation
		10.1 Important Messages, Inserted into an Envelope
		10.2 The Making of An Exosome
		10.3 The Reception of an Exosome
		10.4 Virus-Like Vesicles, Exosome-Like Viruses?
		10.5 Syntenin, Adapting ESCRT Machinery to Endocytosed Syndecans Supports the Biogenesis of Exosomes
		10.6 Heparan Sulfate Involvement in Exosome Internalization
		10.7 Heparanase Activates the Syndecan-Syntenin-ALIX Exosomal Pathway
		10.8 Heparanase, Integrating Syndecan Lateral Associations and Spatial Constraints?
		10.9 Heparanase Effects on Exosomal Cargo
		10.10 Heparanase as Exosomal Cargo
		10.11 Conclusion and Prospects
		References
	Chapter 11: Heparanase in Cancer Metastasis – Heparin as a Potential Inhibitor of Cell Adhesion Molecules
		11.1 Introduction
		11.2 Cell Adhesion Promotes Tumor Cell and Leukocyte Migration
		11.3 Cell Adhesion as Determinant of Metastasis
			11.3.1 Selectin as Mediators of Metastasis
			11.3.2 Selected Aspects of Integrins during Cancer Metastasis
		11.4 Heparin as an Inhibitor of Cell Adhesion
		11.5 The Role of Heparin in Cancer Treatment – Clinical Evidence
		11.6 Heparanase – Another Player in Cancer Progression
		11.7 Heparin as an Inhibitor of Heparanase in Metastasis
		11.8 Dissecting the Role of Heparin in Cancer Progression
		11.9 Conclusions
		References
	Chapter 12: Heparanase: A Dynamic Promoter of Myeloma Progression
		12.1 Introduction
		12.2 Heparanase Promotes Shedding of Syndecan-1 from the Myeloma Tumor Cell Surface
		12.3 Heparanase Modulates the Expression of Proteases by Myeloma Cells
		12.4 Heparanase Regulates Gene Expression in Myeloma Cells by Altering Histone Acetylation
		12.5 How Does Heparanase Promote, Myeloma Growth, Metastasis, Angiogenesis and Osteolysis?
			12.5.1 Down-Regulation of CXCL10 Cytokine
			12.5.2 Upregulation of HGF Expression and Activity
			12.5.3 Enhanced Angiogenesis and Polarized Migration of Myeloma Cells
				Upregulation of VEGF Expression and Endothelial Invasion
				Activation of VEGFR2 Downstream of Heparanase Activity Promotes Polarized Migration of Myeloma Cells and Angiogenesis
		12.6 Impact of Heparanase on Exosome Biogenesis by Myeloma Cells and on Exosome Docking with Target Cells
			12.6.1 Exosome Biogenesis
			12.6.2 Docking of Exosomes with Target Cells
		12.7 Heparanase Modulates Sensitivity of Myeloma Cells to Therapy
		12.8 Heparanase Inhibitor for Myeloma Therapy
		12.9 Concluding Remarks
		References
	Chapter 13: Involvement of Heparanase in Gastric Cancer Progression and Immunotherapy
		13.1 Introduction
		13.2 Heparanase in Gastric Cancer Progression
			13.2.1 Heparanase Expression in Gastric Cancer
			13.2.2 Heparanase in Gastric Cancer Metastasis and Progression
			13.2.3 Regulation of Heparanase Expression in Gastric Cancer
		13.3 Heparanase as an Immunotherapeutic Target in Gastric Cancer
			13.3.1 Heparanase Gene-Based Immunotherapy
			13.3.2 Heparanase Peptide-Based Immunotherapy
			13.3.3 Multiple Antigen Peptide (MAP)-Based Immunotherapy
			13.3.4 Heparanase in CAR T-Cell Therapy
		13.4 Conclusions and Perspectives
		References
	Chapter 14: Involvement of Heparan Sulfate and Heparanase in Neural Development and Pathogenesis of Brain Tumors
		14.1 Malignant Brain Tumors
			14.1.1 Incidence and Symptoms of Brain Tumors
			14.1.2 Glioma and Glioblastoma
			14.1.3 Genetic and Epigenetic Alterations in Glioblastoma
			14.1.4 Aberrant Signaling Pathways in Glioblastoma
			14.1.5 Molecular Classification of Glioblastoma
			14.1.6 Medulloblastoma (MB)
			14.1.7 Molecular Subtypes of Medulloblastoma
		14.2 Cancer Stem Cells
			14.2.1 The Concept of Cancer Stem Cells
			14.2.2 Models of Cancer Stem Cells from Brain Tumors
		14.3 Heparan Sulfate and Heparanase in Neural Development
			14.3.1 Heparan Sulfate and Heparanase in Development
			14.3.2 Heparan Sulfate-Dependent Signaling in the Neural Stem Cell Niche
			14.3.3 Heparan Sulfate and Heparanase in Stem Cell In Vitro Differentiation
		14.4 Heparan Sulfate and Heparanase in Cancer Stem Cells
			14.4.1 HS, HPSE and Cancer Stem Cells
			14.4.2 HPSE in GBM Stem Cells
		14.5 Heparan Sulfate and Other Proteoglycans in Brain Tumors
			14.5.1 ECM Remodeling as Part of the Brain Tumor-Supporting Microenvironment
			14.5.2 Characteristics of the Extracellular Matrix in the Brain
			14.5.3 Analyzing Proteoglycans in Brain Tumors
			14.5.4 Examining the Cancer Genome Atlas for Proteoglycans with Deregulated Expression in Glioblastoma Patients
			14.5.5 Heparan Sulfate and Chondroitin Sulfate Biosynthetic Enzymes in Glioblastoma
			14.5.6 Heparan Sulfate Modifying Enzymes in Glioblastoma
			14.5.7 Heparanase in Glioma and Medulloblastoma
		14.6 Heparanase Inhibition as a Novel Brain Tumor Therapeutics?
			14.6.1 Rationale for Heparanase Inhibition
			14.6.2 Low Molecular-Weight Heparin
			14.6.3 PI-88 (Mupafostat)
			14.6.4 SST0001 (Roneparstat)
			14.6.5 M402 (Necuparanib)
			14.6.6 PG545 (Pixatimod)
			14.6.7 Small Molecule Approaches to HPSE Inhibition
		14.7 Challenges to Brain Tumor Treatment
			14.7.1 Invasiveness
			14.7.2 Heterogeneity
			14.7.3 The Blood-Brain Barrier
			14.7.4 Drug Penetration in Brain Tumor Tissue
		14.8 Summarizing the Role of Heparanase for Brain Tumor Hallmarks
			14.8.1 Promoting Proliferation
			14.8.2 Evading Cell Death
			14.8.3 Stimulating Angiogenesis
			14.8.4 Stimulating Migration and Invasion
			14.8.5 Concluding Remark
		References
	Chapter 15: Heparanase: A Potential Therapeutic Target in Sarcomas
		15.1 Sarcomas
		15.2 Heparanase in Sarcomas
		15.3 Bone Sarcomas
			15.3.1 HSPGs and Heparanase in Bone Development and Biology
			15.3.2 HSPGs and Heparanase in Bone Disorders
			15.3.3 HSPGs and Heparanase in Osteochondromas and Chondrosarcomas
			15.3.4 HSPGs and Heparanase in Osteosarcomas
		15.4 Targeting Heparanase in Sarcomas
		15.5 Concluding Remarks
		References
Part IV: Immune Cells
	Chapter 16: Heparanase is Involved in Leukocyte Migration
		16.1 Introduction
		16.2 Early Findings on the Expression of Hpse in Immune Cells
		16.3 Involvement of Heparan Sulfate Proteoglycans in Transmigration
		16.4 Engagement of Hpse Triggered by Intracellular Trafficking of This Enzyme in Monocytes
		16.5 Appearance of a “Drilling Device” on Migrating Macrophages
		16.6 Neutrophil Migration and Invasion Associated With Intracellular Trafficking of Hpse
		16.7 Evidence Provided by the Use of Hpse Gene-Deficient Mice
		16.8 Therapeutic Use of Hpse Inhibitors
		16.9 Perspectives
		References
	Chapter 17: Role of Heparanase in Macrophage Activation
		17.1 Introduction
		17.2 The Core
		17.3 The Details
			17.3.1 Macrophages Polarization toward Non-resolving Inflammation in the Presence of Microbial Products
			17.3.2 Heparanase Effects on Macrophage Responses in the Setting of Non-infectious “Aseptic” Inflammation
				Heparanase Shapes the Cancer-Promoting Phenotype of Tumor-Associated Macrophages in Pancreatic Carcinoma
				Heparanase Fosters Macrophage Activation in Kidney Disease
		References
	Chapter 18: Immunomodulatory Activities of the Heparan Sulfate Mimetic PG545
		18.1 Diversity of Mechanism of PG545
		18.2 Inhibition of Angiogenesis
		18.3 Inhibition of Tumor Cell Migration
		18.4 Tumor Cell Apoptosis
		18.5 Prolonged ER Stress Response
		18.6 Cell Autophagy
		18.7 NK Activation Through TLR9-MyD88 Pathway
		18.8 Summary
		References
Part V: Heparanase Inhibitors and Clinical Considerations
	Chapter 19: PI-88 and Related Heparan Sulfate Mimetics
		19.1 Introduction
		19.2 Synthesis and Structural Characterization of PI-88
		19.3 Inhibition of Heparanase
		19.4 Nonclinical/Preclinical Studies
		19.5 Clinical Studies
		19.6 Synthetic Studies
		19.7 PI-88 Analogs and Next-Generation Heparanase Inhibitors
		19.8 Discovery of PG545 (Pixatimod)
		19.9 Conclusions
		References
	Chapter 20: Non-Anticoagulant Heparins as Heparanase Inhibitors
		20.1 Introduction
		20.2 Heparan Sulfate
		20.3 Heparanase: Discovery and Characterization
		20.4 Heparosan-Related Heparanase Inhibitors
			20.4.1 Natural and Semi-Synthetic Derivatives
		20.5 Heparin Derivatives
			20.5.1 LMWs, Ultra LMWHs and Derivatives
			20.5.2 Supersulfated Heparins
			20.5.3 O-Desulfated Heparins
			20.5.4 N-Acyl-N-Desulfated Heparins
			20.5.5 Glycol-Split Heparins: Semisynthesis and Activities
		20.6 New Glycol-Split Non-anticoagulant Heparin as Heparanase Inhibitors
			20.6.1 N-Desulfated ROHs
			20.6.2 Dicarboxylated Oxy-Heparins (DCoxyHs)
			20.6.3 New Biotin-Conjugated N-Acetyl-Glycol Split Heparins
		20.7 Clinical Candidates and New Applications
			20.7.1 Heparin Derivatives and Oligomers Interacting with Viral Envelope
			20.7.2 Sevuparin (DF F01) and Tafoxiparin (DFX232)
			20.7.3 Necuparanib (M 402)
			20.7.4 Roneparstat (G4000, 100NA-ROH, SST0001)
			20.7.5 CX-O1 (ODSH)
		20.8 Concluding Remarks
		References
	Chapter 21: Roneparstat: Development, Preclinical and Clinical Studies
		21.1 Introduction
		21.2 Ronepartstat
		21.3 Roneparstat Preclinical Studies in Multiple Myeloma (MM)
		21.4 Roneparstat Preclinical Studies in Other Cancers
		21.5 Roneparstat in Other Disease Models
		21.6 Clinical Experience with Roneparstat
		21.7 Conclusions
		References
	Chapter 22: Heparanase Inhibition by Pixatimod (PG545): Basic Aspects and Future Perspectives
		22.1 Introduction
		22.2 Targets of Pixatimod
		22.3 In Vitro Activity
		22.4 In Vivo Activity
			22.4.1 Colorectal Cancer
			22.4.2 Pancreatic Cancer
			22.4.3 Ovarian Cancer
			22.4.4 Lung Cancer
			22.4.5 Mesothelioma
			22.4.6 Liver Cancer
			22.4.7 Lymphoma
			22.4.8 Breast Cancer
			22.4.9 Other Cancers
		22.5 Clinical Development
		22.6 Conclusion
		References
	Chapter 23: The Control of Heparanase Through the Use of Small Molecules
		23.1 Introduction
		23.2 Heparanase Inhibitors
			23.2.1 Natural Products
			23.2.2 Synthetic Small Molecule Compounds
				Urea Derivatives
				Benzazoles
				Indoles, Carbazoles and Fluorenes
				Diphenylethers
				Rhodanines
				Triazolo-Thiadiazoles
				Furanthiazole
				Quinolines and Quinazolines
				DMBO and Related Spiroheterocyclic Compounds
				Azasugars and Related Glycopolymers
				Acetylsalicylic Acid and Derivatives
				Miscellanea
		23.3 Heparanase-Inhibitor Complex Models
		23.4 Heparin Mimetics
			23.4.1 Heparanase Inhibitors Advanced to Clinical Trials
				Roneparstat, SST0001
				Necuparanib, M402
				Muparfostat, PI-88
				Pixatimod, PG545
		23.5 Conclusions and Prospects
		References
Part VI: Other Diseases and Indications
	Chapter 24: Heparanase and Type 1 Diabetes
		24.1 Introduction
		24.2 Heparan Sulfate (HS) Is Highly Expressed in Normal Pancreatic Islets
			24.2.1 Peri-Islet Basement Membrane
			24.2.2 Beta Cells
			24.2.3 Alpha Cells
		24.3 Islet Cell Heparanase
		24.4 Exogenous Heparanase: A Novel Destructive Mechanism in the Pathogenesis of T1D
		24.5 Dual Activity Heparanase Inhibitors/HS Replacers Represent a New Class of Therapeutic for T1D
		24.6 Intracellular Roles for Heparanase in Modulating Gene Transcription, Cell Differentiation/Function and Disease
			24.6.1 Direct Role for Heparanase in Regulating a Gene Transcription Complex
			24.6.2 Indirect Intracellular Functions of Heparanase
				Signalling
				Effects of High Glucose on Heparanase Levels and Gene Transcription
		24.7 Heparanase, a Contributor to the Secondary Complications of Diabetes
		24.8 Concluding Remarks
		References
	Chapter 25: Implications of Heparan Sulfate and Heparanase in Amyloid Diseases
		25.1 Amyloidosis and Amyloids
			25.1.1 Amyloid Production and Aggregation
			25.1.2 Aβ-Associated Amyloidosis (Alzheimer’s Disease)
			25.1.3 IAPP-Associated Amyloidosis (Type 2 Diabetes)
			25.1.4 AA Amyloidosis (Inflammatory-Associated Amyloid Disease)
			25.1.5 TTR-Associated Amyloidosis (Cardiomyopathy and Polyneuropathy)
		25.2 Detection of HSPG and HS in Amyloid Plaques
			25.2.1 HS in the Brain of AD Patients and Mouse Models
			25.2.2 HS in Cardiomyopathy (ATTR)
			25.2.3 HS in the Islets of Type 2 Diabetes (AIAPP)
			25.2.4 HS in the Organs of AA Amyloidosis
		25.3 In Vitro Studies on the Interaction of HS/HSPG With Amyloid Proteins
		25.4 In Vivo Observations of HS and Heparanase on Amyloid Deposition
			25.4.1 Effect of HS/HSPG-Heparanase on Amyloid Deposition
			25.4.2 Implications of HS in Amyloid Toxicity
		25.5 Heparanase in Amyloid Diseases
		25.6 Concluding Remarks
		References
	Chapter 26: Heparanase in Kidney Disease
		26.1 Glomerular Filtration Barrier in Healthy Situation
		26.2 Heparan Sulfate in Charge-Selective Filtration
		26.3 Activation of Heparanase
		26.4 Heparanase in Proteinuric Diseases
		26.5 Regulatory Factors of Heparanase in Proteinuric Diseases
		26.6 Heparanase as Key Player in Diabetic Nephropathy
		26.7 Immune Cells in Glomerular Diseases and Heparanase Mediated Sensitization
		26.8 Heparanase As a Pharmacological Target
		References
	Chapter 27: Impact of Heparanse on Organ Fibrosis
		27.1 Introduction
		27.2 Kidney Fibrosis
		27.3 Peritoneal Fibrosis
		27.4 Liver Fibrosis
		27.5 Lung Fibrosis
		27.6 Conclusions
		References
	Chapter 28: Heparanase in Acute Kidney Injury
		28.1 Introduction
			28.1.1 Heparanase Secretion in Stress
		28.2 ER Stress
		28.3 Lysosomes
		28.4 Heparanase Synthesis, Secretion, and Activity in AKI
		28.5 Non-catalytic Actions of Heparanase
		28.6 Heparanase Actions on Glycocalyx and ECM
		28.7 Heparanase and Activation of TLR and Inflammation
		28.8 Heparanase and Coagulation
		28.9 Heparanase in AKI
		28.10 Heparanase in Kidney Transplantation
		28.11 Use of Heparanase Related Biomarkers for AKI Detection
		28.12 Novel Heparanase Mechanisms-Based Therapies for AKI
		28.13 Summary and Future Perspective
		References
	Chapter 29: Heparanase in Acute Pancreatitis
		29.1 Epidemiology and Subsets of Acute Pancreatitis
		29.2 Pathogenesis and Cellular Mechanisms of Acute Pancreatitis
		29.3 Acute Pancreatitis – Current Treatments
		29.4 Heparanase and Activation of Toll-like Receptors During Inflammation
		29.5 Heparanase in Acute Pancreatitis
		29.6 Novel Heparanase Mechanism-Based Therapies for Acute Pancreatitis: Heparanase Inhibitors
		29.7 Summary and Perspectives
		References
	Chapter 30: Involvement of Heparanase in Endothelial Cell-Cardiomyocyte Crosstalk
		30.1 Introduction
		30.2 Diabetic Cardiomyopathy
		30.3 Cardiomyocyte Metabolism under Physiological Conditions
			30.3.1 Glucose
			30.3.2 Fatty Acids
		30.4 Lipoprotein Lipase (LPL)
		30.5 Vascular Endothelial Growth Factors
			30.5.1 Vascular Endothelial Growth Factor a
			30.5.2 Vascular Endothelial Growth Factor B
		30.6 Heparanase
			30.6.1 Heparanase 1
			30.6.2 Heparanase 2 (Hpa-2)
		30.7 Aberrant Fuel Utilization Following Diabetes
		30.8 Conclusion
		References
	Chapter 31: The Lacritin-Syndecan-1-Heparanase Axis in Dry Eye Disease
		31.1 Introduction
		31.2 The Approach
			31.2.1 Discovery of Lacritin
			31.2.2 Restoration of Homeostasis
		31.3 Cell Surface Targeting: Lacritin-Syndecan-1-Heparanase Axis
		31.4 Clinical: Deficiency or Absence of Active Lacritin Monomer in Dry Eye
		31.5 Concluding Remarks
		References
	Chapter 32: Heparanase, Heparan Sulfate and Viral Infection
		32.1 Heparan Sulfate
		32.2 Stages of Viral Infection
		32.3 Roles of Heparanase in Viral Infection
			32.3.1 Heparanase Is Upregulated upon Infection and Drives Viral Release
			32.3.2 Active Heparanase Drives Hallmark Features of Viral Pathogenesis
		32.4 Roles of HPSE in Pathogenesis Validated across Viral Families
		32.5 Conclusions and Future Directions
		References
	Chapter 33: Heparanase in the Coagulation System
		33.1 The Coagulation System
		33.2 Tissue Factor, Heparanase and Tissue Factor Pathway Inhibitor
		33.3 Heparanase Inhibitory Peptides and Heparanase Procoagulant Peptides
		33.4 Measuring Heparanase Procoagulant Activity
		33.5 Pregnancy and Oral Contraceptives Increase Heparanase Procoagulant Activity
		33.6 Cancer and Heparanase Procoagulant Activity
		33.7 Additional Clinical Data Supporting the Procoagulant Effect of Heparanase
		33.8 Concluding Remarks
		References
Part VII: Heparanase-2 (Hpa2)
	Chapter 34: Hpa2 Gene Cloning
		34.1 History of Oxford GlycoSciences (OGS)
		34.2 Discovery of Heparanase 2 (Hpa2/HPSE2)
			34.2.1 Hpa2/HPSE2 Cloning
			34.2.2 Tissue Distribution
			34.2.3 Key Amino Acid Features of a Beta-D- Endoglucuronidase Heparanase 1 Enzyme
			34.2.4 Heparin Binding Sites
				Cardin Weintraub Consensus Motif
				CPC Clip Motif
			34.2.5 HPSE2c Structure Homology Model
			34.2.6 HPSE2 Expression and Functional Roles
		34.3 Role of HPSE2 in Disease
			34.3.1 Oncology
				Head and Neck Cancer
				Bladder Cancer
				Pancreatic Cancer
			34.3.2 HPSE2 as a Biomarker
			34.3.3 Alzheimer
			34.3.4 Ochoa’s Syndrome
				Human HPSE2 Gene Mutations
				Xenopus HPSE2 Morpholino Knockdown Studies
				Mouse HPSE2 Gene Knockouts
				LRIG2 Mutations
			34.3.5 Is HPSE2 a Pseudoenzyme of HPSE1?
			34.3.6 Does HPSE2 Have an Elusive Substrate?
			34.3.7 Cellular Localization
			34.3.8 Conclusion and Future Perspectives
				The yin & Yang of the Heparanase Family Proteins
		References
	Chapter 35: Heparanase 2 and Urofacial Syndrome, a Genetic Neuropathy
		35.1 Introduction
		35.2 Heparanase 2 and the Urofacial Syndrome
		35.3 Emerging Roles for Heparanses in Neurobiology
		35.4 LRIG2 Mutations in Urofacial Syndrome
		References
	Chapter 36: The Good and Bad Sides of Heparanase-1 and Heparanase-2
		36.1 Extracellular Matrix: At the Crossroads of Cell-Cell and Cell-Microenvironment Relationships
			36.1.1 Glycosaminoglycans and Proteoglycans
		36.2 Heparanase: A Key Modulator of ECM Architecture at the Crossroads of Homeostasis and Diseases
			36.2.1 General Aspects
			36.2.2 Heparanase Favors Blood Coagulation
			36.2.3 Heparanase and the Tumor Microenvironment
			36.2.4 Exosomes
			36.2.5 Heparanase Inhibitors
		36.3 Heparanase-2 the Ugly Duckling or the Beautiful Swan
			36.3.1 Heparanase-2 Cloning
			36.3.2 Heparanase-2 and Urofacial Syndrome
			36.3.3 What Can we Learn from Heparanase-2 Knockout/Knockdown Studies?
			36.3.4 Colorectal Cancer
			36.3.5 Breast Cancer
			36.3.6 Cervical and Endometrial Cancer
			36.3.7 Ovarian Cancer
			36.3.8 Bladder Cancer
			36.3.9 Thyroid and Head and Neck Cancer
			36.3.10 Heparanase-2 and Alzheimer’s Disease
			36.3.11 Heparanase-2 as a Tumor Suppressor
		36.4 Conclusions
		References
	Chapter 37: Opposing Effects of Heparanase and Heparanase-2 in Head & Neck Cancer
		37.1 Head and Neck Cancer
		37.2 Heparanase
		37.3 Involvement of Heparanase in Head and Neck Cancer
		37.4 Heparanase 2 in Head and Neck Cancer
		37.5 Concluding Remarks
		References
Index