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

Marques, Catarina; Reis, Celso A.; Vivès, Romain R.; Magalhães, Ana

doi:10.3389/fonc.2021.778752

Cited by 48 publications

(49 citation statements)

References 154 publications

(194 reference statements)

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“…3). To avoid loss of clustering, HSPG biosynthetic genes involved in tumor development and growth was not considered, as most HSPG are altered in cancer 16,20,21 .…”

Section: Resultsmentioning

confidence: 99%

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

Ouidja

Biard

Chantepie

et al. 2022

Preprint

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Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could be predictable. Moreover, ubiquitous NDST1, GLCE, HS2ST1, and HS6ST1 appeared to generate ubiquitous heparan sulfate (HS) sequences essential for normal development and homeostasis, whereas the tissue restricted NDST2-4, HS6ST2-3, and HS3ST1-6 appeared to generate specialized HS sequences mainly involved in responsiveness to stimuli. Supported by data on genetic polymorphism and clinical variants, we afford a new vision of HSPG involvement in homeostasis, disease, vulnerability to disease, and behavioral disorders.

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“…3). To avoid loss of clustering, HSPG biosynthetic genes involved in tumor development and growth was not considered, as most HSPG are altered in cancer 16,20,21 .…”

Section: Resultsmentioning

confidence: 99%

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

Ouidja

Biard

Chantepie

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, recent data suggest that their activity is regulated by cell-specific posttranslational modifications 46 . We know that SULFs regulate oncogenic pathways but they also adjust matrix structure, angiogenesis, or immune responses 3,4,7,8,10,[15][16][17]47,48 and their function at the tumor/stroma interface in different cancers needs further study. 28…”

Section: Discussionmentioning

confidence: 99%

“…We know, however, that heparan 6-O-sulfation is essential for binding of many ligands including VEGF, FGF-1, FGF-10, IL8, HGF, Wnt ligands or L-and P-selectins 4,10 . SULFs represent, therefore, an essential regulatory element that controls the HS-dependent developmental and pathophysiological processes including cancer progression [15][16][17] .…”

Section: Introductionmentioning

confidence: 99%

Extracellular heparan 6-O-endosulfatases SULF1 and SULF2 in HNSC and other malignancies

Yang

Ahn

Edwards

et al. 2022

Preprint

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SULF1 and SULF2 are oncogenic in a number of human malignancies, including head and neck squamous cell carcinoma (HNSC). The function of these two heparan sulfate editing enzymes was previously considered largely redundant but the biology of cancer suggests differences that we explore in our RNAseq and RNAScope studies of HNSC and in a pan cancer analysis using the TCGA and CPTAC (proteomics) data. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer. Meanwhile, SULF1 showed low expression in cancer cell lines and a scRNAseq study of HNSC shows that SULF1 is not supplied by epithelial tumor cells, like SULF2, but is secreted by cancer associated fibroblasts. Our RNAScope and PDX analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, the SULF1 enzyme, supplied by a subset of cancer associated fibroblasts, is upregulated and negatively impacts HNSC survival at an early stage of the disease progression while the SULF2 enzyme, supplied by tumor cells, impacts survival at later stages of HNSC. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.

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“…Structural heterogeneity of the GAG chains also varies when cells undergo transformation ( 191 ). Alterations in GAG structure and function have been implicated in cancer growth, progression, and tumor metastasis ( 37 ).…”

Section: Glycosaminoglycan Regulation In Human Diseasementioning

confidence: 99%

Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease

Basu

Patel

Nicholson

et al. 2022

American Journal of Physiology-Cell Physiology

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Glycosaminoglycans (GAGs) are long, linear polysaccharides that are ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These complex carbohydrates play important roles in many cellular processes and have been implicated in many disease states, including cancer, inflammation, and genetic disorders. GAGs are among the most complex molecules in biology with enormous information content and extensive structural and functional heterogeneity. GAG biosynthesis is a non-template driven process facilitated by a large group of biosynthetic enzymes that have been extensively characterized over the past few decades. Interestingly, the expression of the enzymes and the consequent structure and function of the polysaccharide chains can vary temporally and spatially during development and under certain pathophysiological conditions, suggesting their assembly is tightly regulated in cells. Due to their many key roles in cell homeostasis and disease, there is much interest in targeting the assembly and function of GAGs as a therapeutic approach. Recent advances in genomics and GAG analytical techniques have pushed the field and generated new perspectives on the regulation of mammalian glycosylation. This review highlights the spatiotemporal diversity of GAGs and the mechanisms guiding their assembly and function in human biology and disease.

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

Cited by 48 publications

References 154 publications

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

Extracellular heparan 6-O-endosulfatases SULF1 and SULF2 in HNSC and other malignancies

Spatiotemporal diversity and regulation of glycosaminoglycans in cell homeostasis and human disease

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