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

✍ Scribed by Israel Vlodavsky (editor), Ralph D. Sanderson (editor), Neta Ilan (editor)

• Publisher: Springer
• Year: 2020
• Tongue: English
• Leaves: 871
• Category: Library

✦ Synopsis

Written by internationally recognized leaders in Heparanase biology, the book’s eight chapters offer an opportunity for scientists, clinicians and advanced students in cell biology, tumor biology and oncology to obtain a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications.

Proteases and their involvement in cancer progression have been well addressed and documented; however, the emerging premise presented within this book is that Heparanase is a master regulator of aggressive cancer phenotypes and crosstalk with the tumor microenvironment. This endoglycosidase contributes to tumor-mediated remodeling of the extracellular matrix and cell surfaces, augmenting the bioavailability of pro-tumorigenic and pro-inflammatory growth factors and cytokines that are bound to Heparan sulfate. Compelling evidence ties Heparanase with all steps of tumor progression including tumor initiation, growth, angiogenesis, metastasis, and chemoresistance, supporting the notion that Heparanase is an important contributor to the poor outcome of cancer patients and a validated target for therapy. Unlike Heparanase, heparanase-2, a close homolog of Heparanase, lacks enzymatic activity, inhibits Heparanase, and regulates selected genes that promote normal differentiation and tumor suppression. Written by internationally recognized leaders in Heparanase biology, this volume presents a comprehensive understanding of Heparanase’s multifaceted activities in cancer, inflammation, diabetes and other diseases, as well as its related clinical applications to scientists, clinicians and advanced students in cell biology, tumor biology and oncology.

✦ Table of Contents

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