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Heparan Sulfate and Heparin: Challenges and Controversies
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Heparan Sulfate and Heparin: Challenges and Controversies

A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 45255

Special Issue Editors

Dr. Marco Guerrini

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Guest Editor
Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, Milan, Italy
Interests: heparin analysis; glycosaminoglycan-protein interactions; nuclear magnetic resonance spectroscopy
Dr. Edwin Yates

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Guest Editor
Department of Biochemistry, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
Interests: glycosaminoglycan structure and function; protein–polysaccharide interactions; extraction; purification; spectroscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The aim of this Special Issue of Molecules is to collect contributions from leading researchers in academia and industry that address, in particular, controversial or challenging problems in this field of research. We emphasize that we would like to encourage you to tackle difficult issues head-on, identifying what you see as the major challenges. We would also welcome your opinions and speculations regarding controversies within the field.

Given your significant contributions, we thought that you would be an ideal author to address such questions. We hope that you will be willing to contribute to this volume, the aim of which is to provide stimulation to other researchers and, ultimately, to help generate new ideas and approaches.

Dr. Marco Guerrini
Dr. Edwin Alexander Yates
Guest Editors

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Keywords

  • heparin 
  • heparan sulfate 
  • biological activity
  • biosynthesis 
  • interactions 
  • structure-function 
  • applications

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Published Papers (10 papers)

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Editorial

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9 pages, 612 KiB  
Editorial
Introduction to the Molecules Special Edition Entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’: Some Outstanding Questions in Heparan Sulfate and Heparin Research
by Edwin A Yates, John T Gallagher and Marco Guerrini
Molecules 2019, 24(7), 1399; https://doi.org/10.3390/molecules24071399 - 10 Apr 2019
Cited by 10 | Viewed by 3802
Abstract
The scope of this article is to provide a brief general introduction to heparan sulfate (HS) and heparin, and attempt to identify some of the central challenges regarding research into the chemistry and biology of glycosaminoglycans (GAGs), some of which are the subject [...] Read more.
The scope of this article is to provide a brief general introduction to heparan sulfate (HS) and heparin, and attempt to identify some of the central challenges regarding research into the chemistry and biology of glycosaminoglycans (GAGs), some of which are the subject of contributions to the special issue of Molecules (published in volume 23, 2018) entitled ‘Heparan Sulfate and Heparin: Challenges and Controversies’ [...] Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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Research

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20 pages, 1848 KiB  
Article
Structural Features of Heparan Sulfate from Multiple Osteochondromas and Chondrosarcomas
by Noemi Veraldi, Alessandro Parra, Elena Urso, Cesare Cosentino, Manuela Locatelli, Serena Corsini, Elena Pedrini, Annamaria Naggi, Antonella Bisio and Luca Sangiorgi
Molecules 2018, 23(12), 3277; https://doi.org/10.3390/molecules23123277 - 11 Dec 2018
Cited by 6 | Viewed by 3202
Abstract
Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone [...] Read more.
Multiple osteochondromas (MO) is a hereditary disorder associated with benign cartilaginous tumors, known to be characterized by absence or highly reduced amount of heparan sulfate (HS) in the extracellular matrix of growth plate cartilage, which alters proper signaling networks leading to improper bone growth. Although recent studies demonstrated accumulation of HS in the cytoplasm of MO chondrocytes, nothing is known on the structural alterations which prevent HS from undergoing its physiologic pathway. In this work, osteochondroma (OC), peripheral chondrosarcoma, and healthy cartilaginous human samples were processed following a procedure previously set up to structurally characterize and compare HS from pathologic and physiologic conditions, and to examine the phenotypic differences that arise in the presence of either exostosin 1 or 2 (EXT1 or EXT2) mutations. Our data suggest that HS chains from OCs are prevalently below 10 kDa and slightly more sulfated than healthy ones, whereas HS chains from peripheral chondrosarcomas (PCSs) are mostly higher than 10 kDa and remarkably more sulfated than all the other samples. Although deeper investigation is still necessary, the approach here applied pointed out, for the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions, and could help in understanding how the structural features of HS are modulated in the presence of pathological situations also involving different tissues. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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12 pages, 1508 KiB  
Article
Solution Conformation of Heparin Tetrasaccharide. DFT Analysis of Structure and Spin–Spin Coupling Constants
by Miloš Hricovíni and Michal Hricovíni
Molecules 2018, 23(11), 3042; https://doi.org/10.3390/molecules23113042 - 21 Nov 2018
Cited by 14 | Viewed by 3741
Abstract
Density functional theory (DFT) has provided detailed information on the molecular structure and spin–spin coupling constants of heparin tetrasaccharide (GlcNS,6S-IdoA2S-GlcNS,6S-IdoA2S-OMe) representing the predominant heparin repeating-sequence. The fully optimised molecular structures of two tetrasaccharide conformations (differing from each other in the conformational form of [...] Read more.
Density functional theory (DFT) has provided detailed information on the molecular structure and spin–spin coupling constants of heparin tetrasaccharide (GlcNS,6S-IdoA2S-GlcNS,6S-IdoA2S-OMe) representing the predominant heparin repeating-sequence. The fully optimised molecular structures of two tetrasaccharide conformations (differing from each other in the conformational form of the sulphated iduronic acid residue–one 1C4 and the other 2S0) were obtained using the B3LYP/6-311+G(d,p) level of theory and applying explicit water molecules to simulate the presence of a solvent. The theoretical data provided insight into variations of the bond lengths, bond angles and torsion angles, formations of intra- and intermolecular hydrogen bonds and ionic interactions. Optimised molecular structures indicated the formation of a complex hydrogen bond network, including interresidue and intraresidue bonds. The ionic interactions strongly influence the first hydration shell and, together with hydrogen bonds, play an important role in shaping the 3D tetrasaccharide structure. DFT-derived indirect three–bond proton–proton coupling constants (3JH-C-C-H) showed that the best agreement with experiment was obtained with a weighted average of 67:33 (1C4:2S0) of the IdoA2S forms. Detailed analysis of Fermi-contact contributions to 3JH-C-C-H showed that important contributions arise from the oxygen lone pairs of neighbouring oxygen atoms. The analysis also showed that the magnitude of diamagnetic spin–orbit contributions are sufficiently large to determine the magnitude of some proton–proton coupling constants. The data highlight the need to use appropriate quantum-chemical calculations for a detailed understanding of the solution properties of heparin oligosaccharides. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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14 pages, 2473 KiB  
Article
The Low Molecular Weight Heparin Tinzaparin Attenuates Platelet Activation in Terms of Metastatic Niche Formation by Coagulation-Dependent and Independent Pathways
by Lukas Maria Gockel, Jan Moritz Ponert, Svenja Schwarz, Martin Schlesinger and Gerd Bendas
Molecules 2018, 23(11), 2753; https://doi.org/10.3390/molecules23112753 - 24 Oct 2018
Cited by 10 | Viewed by 3711
Abstract
An intimate interplay with platelets is an initial key issue for tumor cells in terms of hematogenous metastasis. Tumor cells activate platelets by different pathways and receive, upon forming a platelet cloak, protection from immune surveillance and support in metastatic niche creation. Therapeutic [...] Read more.
An intimate interplay with platelets is an initial key issue for tumor cells in terms of hematogenous metastasis. Tumor cells activate platelets by different pathways and receive, upon forming a platelet cloak, protection from immune surveillance and support in metastatic niche creation. Therapeutic intervention with this early interaction is promising to antagonize the whole metastatic cascade. Here we aimed to investigate the capability of low molecular weight heparin (LMWH), unfractionated heparin (UFH), and a non-anticoagulant heparin derivative or FXa inhibitor fondaparinux to interfere with platelet activation by tumor cells. Coagulation-dependent and independent pathways of platelet activation by three tumor cell lines, and interference therewith were analyzed by fluorigenic thrombin formation assay, platelet aggregometry, ATP and VEGF release and endothelial tube formation assay. LMWH and UFH were found to repress various routes of platelet activation, reflected by attenuated endothelial tube formation. This confirms the duality of anti-coagulative and anti-adhesive properties of heparin. While non-anticoagulative heparin (RO-heparin) depressed platelets’ ATP and VEGF release by contact inhibition sufficiently, fondaparinux just attenuated tissue factor mediated thrombin generation. Concluding, these data suggest that LMWH as a guideline-based drug for anticoagulative strategies in oncology is promising to provide additional benefit for interference with metastatic activities. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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15 pages, 1835 KiB  
Article
The Pro-Tumoral Activity of Heparan Sulfate 3-O-Sulfotransferase 3B (HS3ST3B) in Breast Cancer MDA-MB-231 Cells Is Dependent on the Expression of Neuropilin-1
by Charles Hellec, Mariama Diawara, Mathieu Carpentier, Agnès Denys and Fabrice Allain
Molecules 2018, 23(10), 2718; https://doi.org/10.3390/molecules23102718 - 22 Oct 2018
Cited by 8 | Viewed by 3835
Abstract
Heparan sulfate 3-O-sulfotransferases (HS3STs) catalyze the maturation step of heparan sulfate (HS) 3-O-sulfation. This modification is relatively rare. Moreover, only a few biological processes have been described to be influenced by 3-O-sulfated HS, and few ligands have [...] Read more.
Heparan sulfate 3-O-sulfotransferases (HS3STs) catalyze the maturation step of heparan sulfate (HS) 3-O-sulfation. This modification is relatively rare. Moreover, only a few biological processes have been described to be influenced by 3-O-sulfated HS, and few ligands have been identified so far. Among them, neuropilin-1 (Nrp1) was reported to exhibit tumor-promoting properties by enhancing the action of various growth factors. We recently demonstrated that transient overexpression of HS3ST2, 3B or 4 enhanced the proliferation of breast cancer MDA-MB-231 cells and promote efficient protection against pro-apoptotic stimuli. Hence, we hypothesized that the pro-tumoral activity of these HS3STs could depend on the expression of Nrp1. To test this, MDA-MB-231 cells were stably transfected with a construct encoding HS3ST3B and the expression of Nrp1 was down-regulated by RNA interference. First, we confirmed that stable expression of HS3ST3B effectively increased cell proliferation and viability. Silencing the expression of Nrp1 markedly attenuated the promoting effects of HS3ST3B, while the same treatment had only a moderate effect on the behavior of the parental cells. Altogether, our findings support the idea that the tumor-promoting effects of HS3ST3B could be dependent on the expression of Nrp1 in cancer cells. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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15 pages, 3031 KiB  
Article
Unfractionated and Low Molecular Weight Heparin Reduce Platelet Induced Epithelial-Mesenchymal Transition in Pancreatic and Prostate Cancer Cells
by Jan Moritz Ponert, Lukas Maria Gockel, Svenja Henze and Martin Schlesinger
Molecules 2018, 23(10), 2690; https://doi.org/10.3390/molecules23102690 - 19 Oct 2018
Cited by 11 | Viewed by 3930
Abstract
The interaction with platelets is of crucial importance for tumor cells passing through hematogenous metastasis. Platelets protect cancer cells from immune surveillance and exhibit many other prometastatic effects. Notably, platelets can change the epithelial tumor phenotype, a process termed epithelial-mesenchymal transition (EMT), which [...] Read more.
The interaction with platelets is of crucial importance for tumor cells passing through hematogenous metastasis. Platelets protect cancer cells from immune surveillance and exhibit many other prometastatic effects. Notably, platelets can change the epithelial tumor phenotype, a process termed epithelial-mesenchymal transition (EMT), which confers stem cell-like properties onto tumor cells associated with an increased motility and drug resistance. The aim of the study is to investigate the impact of heparin on the platelet induced EMT program in pancreatic and prostate tumor cells. Platelet activation and interaction with cancer cells were determined by static adhesion assays. Applying ELISAs, the platelet release of EMT inducing mediators was quantified. EMT marker protein expression by tumor cells was explored by western blot and qPCR. Our data show that different tumor cell entities have different platelet binding capacities and also that a weak interaction is sufficient to change tumor cell phenotype. Additionally, unfractionated heparin (UFH) as well as low molecular weight heparin (LMWH) reduced tumor cell platelet interaction. Subsequently, attenuated platelet-derived mediator release resulted in reduced EMT marker protein and transcription factor expression by the cancer cells and decreased cell migration. These data suggest that heparin reduces platelet induced EMT program and prevents the formation of cancer cells with stem cell-like properties. This additional mechanism argues for the use of heparin in oncological applications. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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Review

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24 pages, 11866 KiB  
Review
Cross-Species Analysis of Glycosaminoglycan Binding Proteins Reveals Some Animal Models Are “More Equal” than Others
by Eric D. Boittier, Neha S. Gandhi, Vito Ferro and Deirdre R. Coombe
Molecules 2019, 24(5), 924; https://doi.org/10.3390/molecules24050924 - 6 Mar 2019
Cited by 9 | Viewed by 5245
Abstract
Glycosaminoglycan (GAG) mimetics are synthetic or semi-synthetic analogues of heparin or heparan sulfate, which are designed to interact with GAG binding sites on proteins. The preclinical stages of drug development rely on efficacy and toxicity assessment in animals and aim to apply these [...] Read more.
Glycosaminoglycan (GAG) mimetics are synthetic or semi-synthetic analogues of heparin or heparan sulfate, which are designed to interact with GAG binding sites on proteins. The preclinical stages of drug development rely on efficacy and toxicity assessment in animals and aim to apply these findings to clinical studies. However, such data may not always reflect the human situation possibly because the GAG binding site on the protein ligand in animals and humans could differ. Possible inter-species differences in the GAG-binding sites on antithrombin III, heparanase, and chemokines of the CCL and CXCL families were examined by sequence alignments, molecular modelling and assessment of surface electrostatic potentials to determine if one species of laboratory animal is likely to result in more clinically relevant data than another. For each protein, current understanding of GAG binding is reviewed from a protein structure and function perspective. This combinatorial analysis shows chemokine dimers and oligomers can present different GAG binding surfaces for the same target protein, whereas a cleft-like GAG binding site will differently influence the types of GAG structures that bind and the species preferable for preclinical work. Such analyses will allow an informed choice of animal(s) for preclinical studies of GAG mimetic drugs. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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11 pages, 931 KiB  
Review
The Development of Assays for Heparanase Enzymatic Activity: Towards a Gold Standard
by Mohit Chhabra and Vito Ferro
Molecules 2018, 23(11), 2971; https://doi.org/10.3390/molecules23112971 - 14 Nov 2018
Cited by 20 | Viewed by 4560
Abstract
The enzyme heparanase, an endo-β-glucuronidase, degrades heparan sulfate (HS) chains on the cell surface and in the extracellular matrix. Heparanase regulates numerous biological processes that drive tumour growth, metastasis and angiogenesis. In addition to its key role in cancer progression, it has also [...] Read more.
The enzyme heparanase, an endo-β-glucuronidase, degrades heparan sulfate (HS) chains on the cell surface and in the extracellular matrix. Heparanase regulates numerous biological processes that drive tumour growth, metastasis and angiogenesis. In addition to its key role in cancer progression, it has also been implicated in an ever-growing number of other diseases, particularly those associated with inflammation. The importance of heparanase in biology has led to numerous efforts over the years to develop assays to monitor its activity and to screen for new inhibitors as potential drug candidates. Despite these efforts and the commercialization of a few kits, most heparanase assays are still complex, labour intensive, costly or have limited application. Herein we review the various methods for assaying heparanase enzymatic activity, focusing on recent developments towards new assays that hold the promise of accelerating research into this important enzyme. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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Graphical abstract

36 pages, 1581 KiB  
Review
Heparan Sulfate Mimetics in Cancer Therapy: The Challenge to Define Structural Determinants and the Relevance of Targets for Optimal Activity
by Cinzia Lanzi and Giuliana Cassinelli
Molecules 2018, 23(11), 2915; https://doi.org/10.3390/molecules23112915 - 8 Nov 2018
Cited by 43 | Viewed by 6206
Abstract
Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth [...] Read more.
Beyond anticoagulation, the therapeutic potential of heparin derivatives and heparan sulfate (HS) mimetics (functionally defined HS mimetics) in oncology is related to their ability to bind and modulate the function of a vast array of HS-binding proteins with pivotal roles in cancer growth and progression. The definition of structural/functional determinants and the introduction of chemical modifications enabled heparin derivatives to be identified with greatly reduced or absent anticoagulant activity, but conserved/enhanced anticancer activity. These studies paved the way for the disclosure of structural requirements for the inhibitory effects of HS mimetics on heparanase, selectins, and growth factor receptor signaling, as well as for the limitation of side effects. Actually, HS mimetics affect the tumor biological behavior via a multi-target mechanism of action based on their effects on tumor cells and various components of the tumor microenvironment. Emerging evidence indicates that immunomodulation can participate in the antitumor activity of these agents. Significant ability to enhance the antitumor effects of combination treatments with standard therapies was shown in several tumor models. While the first HS mimetics are undergoing early clinical evaluation, an improved understanding of the molecular contexts favoring the antitumor action in certain malignancies or subgroups is needed to fully exploit their potential. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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Graphical abstract

12 pages, 665 KiB  
Review
Low-Molecular-Weight Heparins: Reduced Size Particulate Systems for Improved Therapeutic Outcomes
by Fahad Akhtar, Xinyu Wan, Gang Wu, Samuel Kesse, Shaoda Wang and Shuying He
Molecules 2018, 23(7), 1757; https://doi.org/10.3390/molecules23071757 - 18 Jul 2018
Cited by 11 | Viewed by 6125
Abstract
A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their [...] Read more.
A wide range of diseases have been treated using low-molecular-weight heparins (LMWHs), the drug of choice for anticoagulation. Owing to their better pharmacokinetic features compared to those of unfractionated heparin (uFH), several systems incorporating LMWHs have been investigated to deliver and improve their therapeutic outcomes, especially through development of their micro- and nano-particles. This review article describes current perspectives on the fabrication, characterization, and application of LMWHs-loaded micro- and nano-particles to achieve ameliorated bioavailability. The valuable applications of LMWH will continue to encourage researchers to identify efficient delivery systems that have specific release characteristics and ameliorated bioavailability, overcoming the challenges presented by biological obstructions and the physicochemical properties of LMWHs. Full article
(This article belongs to the Special Issue Heparan Sulfate and Heparin: Challenges and Controversies)
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