A Low Molecular Weight Heparin Inhibits Experimental Metastasis in Mice Independently of the Endothelial Glycocalyx

Sluis, Geerte L. van; Nieuwdorp, Max; Kamphuisen, Pieter Willem; Vlag, Johan van der; Noorden, C. J. F. Van; Spek, C. Arnold

doi:10.1371/journal.pone.0011200

Cited by 11 publications

(6 citation statements)

References 36 publications

(34 reference statements)

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“…5B, C), we examined whether genes involved in endothelial cell sprouting and guidance were affected by enzymatic degradation. HepIII is known to be anti-angiogenic (Van Sluis et al, 2010) and we found that degrading luminal HS caused a decrease in vegfa expression. This was not associated with any specific vascular defects in the HepIII treated embryos.…”

Section: Discussionmentioning

confidence: 62%

The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development

Henderson-Toth

Jahnsen

Jamarani

et al. 2012

Developmental Biology

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The glycocalyx, and the thicker endothelial surface layer (ESL), are necessary both for endothelial barrier function and for sensing mechanical forces in the adult. The goal of this study is to use a combination of imaging techniques to establish when the glycocalyx and endothelial surface layer form during embryonic development and to determine the biological significance of the glycocalyx layer during vascular development in quail embryos. Using transmission electron microscopy, we show that the glycocalyx layer is present as soon as blood flow starts (14 somites). The early endothelial glycocalyx (14 somites) lacks the distinct hair-like morphology that is present later in development (17 and 25 somites). The average thickness does not change significantly (14 somites, 182 nm ± 33 nm; 17 somites, 218 ± 30 nm; 25 somites, 212 ± 32 nm). The trapping of circulating fluorescent albumin was used to evaluate the development of the ESL. Trapped fluorescent albumin was first observed at 25 somites. In order to assess a functional role for the glycocalyx during development, we selectively degraded luminal glycosaminoglycans. Degradation of hyaluronan compromised endothelial barrier function and prevented vascular remodeling. Degradation of heparan sulfate down regulated the expression of shear-sensitive genes but does not inhibit vascular remodeling. Our findings show that the glycocalyx layer is present as soon as blood flow starts (14 somites). Selective degradations of major glycocalyx components were shown to inhibit normal vascular development, examined through morphology, vascular barrier function, and gene expression.

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Section: Discussionmentioning

confidence: 62%

The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development

Henderson-Toth

Jahnsen

Jamarani

et al. 2012

Developmental Biology

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“…Van Sluis et al . injected B16F10 melanoma cells into the tail vein of mice with a C57Bl/6 background and observed metastasis to the lung over a 14‐day period. When hyaluronidase was injected prior to the melanoma cells or when syndecan‐1 −/− mice from the same background were similarly treated with melanoma cells, metastasis to the lung was inhibited significantly.…”

Section: Association Between the Gcx And Diseasementioning

confidence: 99%

The glycocalyx and its significance in human medicine

2016

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Cells are covered by a surface layer of glycans that is referred to as the 'glycocalyx'. In this review, we focus on the role of the glycocalyx in vascular diseases (atherosclerosis, stroke, hypertension, kidney disease and sepsis) and cancer. The glycocalyx and its principal glycosaminoglycans [heparan sulphate (HS) and hyaluronic acid (HA)] and core proteins (syndecans and glypicans) are degraded in vascular diseases, leading to a breakdown of the vascular permeability barrier, enhanced access of leucocytes to the arterial intima that propagate inflammation and alteration of endothelial mechanotransduction mechanisms that protect against disease. By contrast, the glycocalyx on cancer cells is generally robust, promoting integrin clustering and growth factor signalling, and mechanotransduction of interstitial flow shear stress that is elevated in tumours to upregulate matrix metalloproteinase release which enhances cell motility and metastasis. HS and HA are consistently elevated on cancer cells and are associated with tumour growth and metastasis. Later, we will review the agents that might be used to enhance or protect the glycocalyx to combat vascular disease, as well as a different set of compounds that can degrade the cancer cell glycocalyx to suppress cell growth and metastasis. It is clear that what is beneficial for either vascular disease or cancer will not be so for the other. The overarching conclusions are that (i) the importance of the glycocalyx in human medicine is only beginning to be recognized, and (ii) more detailed studies of glycocalyx involvement in vascular diseases and cancer will lead to novel treatment modalities.

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“…Therefore, it has pro-metastatic properties. Heparin may also compete with the proteoglycan chains of heparin sulfate, which regulate metastasis formation [30]. …”

Section: Mechanisms Of Anti-cancer Actionmentioning

confidence: 99%

“…Almost complete elimination of metastatic tumors was observed in the wild type, and a lower reduction in the knock-out mice [30]. …”

Section: In Vitro and In Vivo Studiesmentioning

confidence: 99%

The antineoplastic effect of low-molecular-weight heparins – a literature review

Bochenek

Püsküllüoğlu²,

Krzemieniecki³

2013

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There is some evidence for the antitumor effect of heparins, especially the low-molecular-weight ones. The authors discuss the potential mechanism of this antineoplastic effect and present results from several in vitro and in vivo experiments. The clinical trials concerning the impact of low-molecular-weight heparins on the tumor and on the patients’ survival are described. The objective was to find out if heparins could be administered as an antitumor drug, independently of their anticoagulatory properties.The antitumor role of tissue factor, heparinase, chemokines, stromal proteins, cellular interactions as well as angiogenesis and immunology seems certain.The results of the available studies seem promising but large clinical trials are necessary in order to confirm the antineoplastic effect of the low-molecular-weight heparins and to approve them for standard anticancer treatment. It could be a breakthrough in modern oncology.

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A Low Molecular Weight Heparin Inhibits Experimental Metastasis in Mice Independently of the Endothelial Glycocalyx

Cited by 11 publications

References 36 publications

The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development

The glycocalyx is present as soon as blood flow is initiated and is required for normal vascular development

The glycocalyx and its significance in human medicine

The antineoplastic effect of low-molecular-weight heparins – a literature review

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