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Mar. Drugs 2017, 15(5), 134; doi:10.3390/md15050134

Assessment of Heparanase-Mediated Angiogenesis Using Microvascular Endothelial Cells: Identification of λ-Carrageenan Derivative as a Potent Anti Angiogenic Agent

1
Université de la Rochelle, UMR CNRS 7266, LIENSs, Equipe Approches Moléculaires, Environnement-Santé, Avenue Michel Crépeau, 17000 La Rochelle, France
2
Centre de Biophysique Moléculaire, UPR CNRS 4301, 45071 Orléans, France
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Vassilios Roussis
Received: 17 March 2017 / Revised: 21 April 2017 / Accepted: 27 April 2017 / Published: 9 May 2017
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Abstract

Heparanase is overexpressed by tumor cells and degrades the extracellular matrix proteoglycans through cleavage of heparan sulfates (HS), allowing pro-angiogenic factor release and thus playing a key role in tumor angiogenesis and metastasis. Here we propose new HS analogs as potent heparanase inhibitors: Heparin as a positive control, Dextran Sulfate, λ-Carrageenan, and modified forms of them obtained by depolymerization associated to glycol splitting (RD-GS). After heparanase activity assessment, 11 kDa RD-GS-λ-Carrageenan emerged as the most effective heparanase inhibitor with an IC50 of 7.32 ng/mL compared to 10.7 ng/mL for the 16 kDa unfractionated heparin. The fractionated polysaccharides were then tested in a heparanase-rich medium-based in vitro model, mimicking tumor microenvironment, to determine their effect on microvascular endothelial cells (HSkMEC) angiogenesis. As a preliminary study, we identified that under hypoxic and nutrient poor conditions, MCF-7 cancer cells released much more mature heparanase in their supernatant than in normal conditions. Then a MatrigelTM assay using HSkMEC cultured under hypoxic conditions in the presence (or not) of this heparanase-rich supernatant was realized. Adding heparanase-rich media strongly enhanced angiogenic network formation with a production of twice more pseudo-vessels than with the control. When sulfated polysaccharides were tested in this angiogenesis assay, RD-GS-λ-Carrageenan was identified as a promising anti-angiogenic agent. View Full-Text
Keywords: heparanase; angiogenesis; endothelial cells; λ-Carrageenan; hypoxia; anti-angiogenic; sulfated polysaccharide heparanase; angiogenesis; endothelial cells; λ-Carrageenan; hypoxia; anti-angiogenic; sulfated polysaccharide
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Poupard, N.; Badarou, P.; Fasani, F.; Groult, H.; Bridiau, N.; Sannier, F.; Bordenave-Juchereau, S.; Kieda, C.; Piot, J.-M.; Grillon, C.; Fruitier-Arnaudin, I.; Maugard, T. Assessment of Heparanase-Mediated Angiogenesis Using Microvascular Endothelial Cells: Identification of λ-Carrageenan Derivative as a Potent Anti Angiogenic Agent. Mar. Drugs 2017, 15, 134.

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