Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth

Knelson, Erik H.; Gaviglio, Angela L.; Nee, Jasmine C.; Starr, Mark D.; Nixon, Andrew B.; Marcus, S.; Blobe, Gerard C.

doi:10.1172/jci74270

Cited by 28 publications

(50 citation statements)

References 75 publications

(95 reference statements)

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“…Expression of these HSPGs and CD44 [50] is decreased in advanced-stage disease. As has been described in other cancers, HSPGs are highly expressed in the neuroblastoma tumor stroma [6, 27], where they can be released in soluble form to promote neuroblast differentiation. Heparin and non-anticoagulant 2-O, 3-O-desulfated heparin (ODSH) have similar differentiating effects and represent potential therapeutic strategies for neuroblastoma [27].…”

Section: Hs In Cancer Cell Differentiationmentioning

confidence: 98%

“…As has been described in other cancers, HSPGs are highly expressed in the neuroblastoma tumor stroma [6, 27], where they can be released in soluble form to promote neuroblast differentiation. Heparin and non-anticoagulant 2-O, 3-O-desulfated heparin (ODSH) have similar differentiating effects and represent potential therapeutic strategies for neuroblastoma [27]. These results contrast with the opposing roles of soluble and surface SDC1 discussed previously, and the opposing roles of soluble and surface TβRIII in breast cancer [63].…”

Section: Hs In Cancer Cell Differentiationmentioning

confidence: 98%

“…This effect is enhanced by heparanase expression [25], showing that interactions between HS signaling components can coordinately promote carcinogenesis. Conversely, surface expression of HSPGs and release of soluble forms from the stroma promote FGF2 signaling to suppress proliferation in neuroblastoma [26, 27]. In other circumstances, the surface and soluble forms of an HSPG have opposing effects.…”

Section: Hs In Cancer Cell Proliferationmentioning

confidence: 99%

“…HSPGs, including TβRIII, GPC1, GPC3, SDC3, and SDC4, have recently been demonstrated to promote neuronal differentiation in neuroblastoma cells to suppress proliferation and tumor growth [26, 27]. These effects were critically dependent on HS functioning as a co-receptor for FGF2 signaling.…”

Section: Hs In Cancer Cell Differentiationmentioning

confidence: 99%

“…However, the benefits of heparin treatment exceed the effects of anticoagulation, suggesting that other mechanisms are involved [66]. Multiple mechanisms likely contribute to the therapeutic effects of heparin, including inhibition of selectin binding [66], inhibition of heparanase [51] and sulfatases [67], decreased platelet signaling to suppress tumor angiogenesis [45], and enhanced terminal differentiation of cancer cells [27]. For a comprehensive review of 50 years of heparin treatment in animal models of metastasis, see [68].…”

Section: Heparins As Therapeutic Agents In Cancermentioning

confidence: 99%

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Heparan sulfate signaling in cancer

Knelson

Nee

Blobe

2014

Trends in Biochemical Sciences

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167

168

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Summary Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases and heparanases. HS has important emerging roles in oncogenesis and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network.

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Section: Hs In Cancer Cell Differentiationmentioning

confidence: 98%

Section: Hs In Cancer Cell Differentiationmentioning

confidence: 98%

Section: Hs In Cancer Cell Proliferationmentioning

confidence: 99%

Section: Hs In Cancer Cell Differentiationmentioning

confidence: 99%

Section: Heparins As Therapeutic Agents In Cancermentioning

confidence: 99%

See 3 more Smart Citations

Heparan sulfate signaling in cancer

Knelson

Nee

Blobe

2014

Trends in Biochemical Sciences

Self Cite

167

168

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Proteoglycans in brain development and pathogenesis

Schwartz

Domowicz

2018

FEBS Letters

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Edited by Sandro SonninoProteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio-active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies.Keywords: central nervous system; chondroitin sulfate; extracellular matrix; glycosaminoglycans; heparan sulfate; Proteoglycans; proteoglycaninteracting molecules Understanding the structure/function relationships, modes of interaction, spatial/temporal expression patterns, and functional roles of neural proteoglycans during brain development is essential for a full appreciation of the contributions of proteoglycans to establishment and maintenance of the nervous system. Increasingly, proteoglycans are implicated in developmental plasticity, recovery from injury, genetically induced defects that lead to intellectual disorders, and altered micro-environments that induce tumorigenesis. Lastly, promising new avenues of research exploration suggest proteoglycans may serve as biomarkers of disease and/or targets for therapy. Each of these areas is summarized in this review, highlighting how the modulation of proteoglycan structure promotes their ability to interact with diverse partners, thus regulating basic processes like proliferation and differentiation that in turn profoundly influence normal development which can lead to pathological conditions. Abbreviations ACAN,aggrecan; ADAMTS, disintegrin and metalloproteinases with thrombospondin motifs; BBB, blood-brain barrier; BCAN, brevican; BDNF, brain-derived neurotrophic factor; CHPF, chondroitin polymerazing factor; CHSY, chondroitin sulfate synthase; CNS, central nervous system;

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Improvement of the performance of anticancer peptides using a drug repositioning pipeline

Mohammadi

Tahmoorespur

Benfeitas

et al. 2021

Biotechnology Journal

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The use of anticancer peptides (ACPs) as an alternative/complementary strategy to conventional chemotherapy treatments has been shown to decrease drug resistance and/or severe side effects. However, the efficacy of the positively-charged ACP is inhibited by elevated levels of negatively-charged cell-surface components which trap the peptides and prevent their contact with the cell membrane. Consequently, this decreases ACP-mediated membrane pore formation and cell lysis. Negatively-charged heparan sulphate (HS) and chondroitin sulphate (CS) have been shown to inhibit the cytotoxic effect of ACPs.In this study, we propose a strategy to promote the broad utilization of ACPs. In this context, we developed a drug repositioning pipeline to analyse transcriptomics data generated for four different cancer cell lines (A549, HEPG2, HT29, and MCF7) treated with hundreds of drugs in the LINCS L1000 project. Based on previous studies identifying genes modulating levels of the glycosaminoglycans (GAGs) HS and CS at the cell surface, our analysis aimed at identifying drugs inhibiting genes correlated with high HS and CS levels. As a result, we identified six chemicals as likely repositionable drugs with the potential to enhance the performance of ACPs. The codes in R and Python programming languages are publicly available in https://github.com/ElyasMo/ ACPs_HS_HSPGs_CS.As a conclusion, these six drugs are highlighted as excellent targets for synergistic studies with ACPs aimed at lowering the costs associated with ACP-treatment.

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Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth

Cited by 28 publications

References 75 publications

Heparan sulfate signaling in cancer

Heparan sulfate signaling in cancer

Proteoglycans in brain development and pathogenesis

Improvement of the performance of anticancer peptides using a drug repositioning pipeline

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