Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

Faria‐Ramos, Isabel; Poças, Juliana; Marques, Catarina; Santos-Antunes, João; Macedo, Guilherme; Reis, Celso A.; Magalhães, Ana

doi:10.3390/biom11020136

Cited by 23 publications

(21 citation statements)

References 269 publications

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“…These macromolecules control several regulatory mechanisms related to the formation of extracellular gradients, cellular growth and proliferation, cell adhesion, migration and invasion, membrane trafficking and angiogenesis (4,5). By interfering with these cellular events, HSPGs display important functions both in physiology and pathology, controlling embryonic development, ECM assembly and maintenance, tissue remodelling, metabolism homeostasis, pathogen invasion and inflammation (6)(7)(8)(9)(10)(11)(12). Particularly in cancer, HSPGs and HS chains hold very relevant roles in the development and progression of the disease.…”

Section: Introductionmentioning

confidence: 99%

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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Heparan Sulfate Proteoglycans (HSPGs) are important cell surface and Extracellular Matrix (ECM) maestros involved in the orchestration of multiple cellular events in physiology and pathology. These glycoconjugates bind to various bioactive proteins via their Heparan Sulfate (HS) chains, but also through the protein backbone, and function as scaffolds for protein-protein interactions, modulating extracellular ligand gradients, cell signalling networks and cell-cell/cell-ECM interactions. The structural features of HS chains, including length and sulfation patterns, are crucial for the biological roles displayed by HSPGs, as these features determine HS chains binding affinities and selectivity. The large HS structural diversity results from a tightly controlled biosynthetic pathway that is differently regulated in different organs, stages of development and pathologies, including cancer. This review addresses the regulatory mechanisms underlying HS biosynthesis, with a particular focus on the catalytic activity of the enzymes responsible for HS glycan sequences and sulfation motifs, namely D-Glucuronyl C5-Epimerase, N- and O-Sulfotransferases. Moreover, we provide insights on the impact of different HS structural epitopes over HSPG-protein interactions and cell signalling, as well as on the effects of deregulated expression of HS modifying enzymes in the development and progression of cancer. Finally, we discuss the clinical potential of HS biosynthetic enzymes as novel targets for therapy, and highlight the importance of developing new HS-based tools for better patients’ stratification and cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

et al. 2021

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“…In addition, a few FDA-approved clinical drugs were tested in the human Tau P301L zebrafish model. Given that HS3ST2 induced abnormal Tau phosphorylation as aforementioned, surfen and oxalyl surfen are small molecules harboring heparan sulfate antagonist properties and well tolerated in clinical setting in cancer treatment [201,202]. These two small molecules were capable of mitigating Tau hyperphosphorylation and rescuing spinal motoneuron defects, leading to recover the touch escape response in the zebrafish Tau P301L tauopathy model [203].…”

Section: The Utility Of the Zebrafish Tauopathy Models And Their Translational Applicationsmentioning

confidence: 95%

Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models

Giong

Manivannan

et al. 2021

IJMS

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Tauopathy refers to a group of progressive neurodegenerative diseases, including frontotemporal lobar degeneration and Alzheimer’s disease, which correlate with the malfunction of microtubule-associated protein Tau (MAPT) due to abnormal hyperphosphorylation, leading to the formation of intracellular aggregates in the brain. Despite extensive efforts to understand tauopathy and develop an efficient therapy, our knowledge is still far from complete. To find a solution for this group of devastating diseases, several animal models that mimic diverse disease phenotypes of tauopathy have been developed. Rodents are the dominating tauopathy models because of their similarity to humans and established disease lines, as well as experimental approaches. However, powerful genetic animal models using Drosophila, zebrafish, and C. elegans have also been developed for modeling tauopathy and have contributed to understanding the pathophysiology of tauopathy. The success of these models stems from the short lifespans, versatile genetic tools, real-time in-vivo imaging, low maintenance costs, and the capability for high-throughput screening. In this review, we summarize the main findings on mechanisms of tauopathy and discuss the current tauopathy models of these non-rodent genetic animals, highlighting their key advantages and limitations in tauopathy research.

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“…The composition of GAG/PGs changes during cell differentiation [ 33 ], and their expression profile can be significantly different among differentiated cell types [ 34 ]. Moreover, the length, sequence, sulfation degree, membrane association, extracellular shedding, and levels of expression of GAGs/PGs themselves and of glycosidases undergo pronounced modifications in pathological conditions such as inflammation [ 35 ] or cancer [ 36 , 37 ], with some PGs even being used as markers for prognosis [ 38 ]. All these modifications further add to the structural and functional heterogeneity of GAGs/PGs ( Table 1 ).…”

Section: Fundamentals Of Gags and Pgsmentioning

confidence: 99%

A Bittersweet Computational Journey among Glycosaminoglycans

et al. 2021

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Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge.

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Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

Cited by 23 publications

References 269 publications

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

Heparan Sulfate Biosynthesis and Sulfation Profiles as Modulators of Cancer Signalling and Progression

Non-Rodent Genetic Animal Models for Studying Tauopathy: Review of Drosophila, Zebrafish, and C. elegans Models

A Bittersweet Computational Journey among Glycosaminoglycans

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