Abstract 2363: Dual effects of unique oversulfated dermatan sulfates from ascidians (Chordata-Tunicata) on tumor invasion: inhibition of ephitelial-mesenchymal transition and hematogeneous metastasis
Authors: Pavao Mauro Sergio G. , Kozlowski Eliene O. , Borsig Lubor 
Published: June 2012

Metastatic disease is responsible for most cancer-associated deaths and epithelial-mesenchymal transition (EMT) along with hematogeneous metastasis are critical steps in cancer progression. Therefore, inhibition of these events could be an effective approach to reduce the metastatic disease. Heparin has been show to modulate EMT-associated growth factors and also to inhibit P-selectin, leading to attenuation of metastasis. Previously, we showed that unique dermatan sulfates (DS) from Styela plicata and Pallusia nigra, composed by 2,4-O-sulfated and 2,6-O-sulfated disaccharide units, respectively, bind with high affinity (KD of ∼ 33nM) to the EMT-related growth factor, hepatocyte growth factor (HGF), modulating its MET-dependent intracellular signaling. In the present work, the effect of the ascidian DSs on EMT-mediated cell migration and P-selectin-mediated metastasis in experiments in vitro and in vivo were evaluated. To investigate migration, confluent human mammary cells were scraped with a pipette tip and cultured for 3 days in the presence of the ascidian DSs. The migration of human mammary cells in the wound-healing cell migration assay was drastically inhibited by the glycans. The anti-selectin activity was evaluated by the binding of LS180 cells to immobilized P-selectin in the presence of the ascidian DSs. The ascidian DSs inhibited the binding of tumor cells to P-selectin with IC50 values of 13.51 μg/mL (2,4-DS) and 12.19 μg/mL (2,6-DS) and were better inhibitors than unfractionated heparin (IC50 of 24.51 μg/mL). DS from porcine skin had no effect. To investigate the effect of ascidian DSs in vivo, mice were injected with LS180 cells 10 minutes after treatment with PBS, UFH (1 mg/mouse) or ascidian DSs (100 μg/mouse) and the presence of platelets-tumor cells aggregates in the lung microvasculature was evaluated. The ascidian DSs inhibited the adhesion of platelets to tumor cells in vivo in a concentration 10-fold lower than heparin. The inhibitory effect of glycans could be observed as early as 30 minutes upon cells injection or 3 hours later. Metastasis mice in vivo was investigated by injecting 100 μg of each ascidian DSs or PBS 10 minutes prior injection of MC-38 cells. Twenty-eight days later, lungs were harvested for macroscopic evaluation of metastasis. Both ascidian DSs drastically reduced metastasis of MC-38 cells. PBS had no effect. Metastasis was drastically reduced in P-sel-/- mice and neither 2,4- nor 2,6-DS had any additional effect. In conclusion, ascidian DSs inhibit cell migration and reduce hematogeneous metastasis by a EMT- and P-selectin mediated events and could be used therapeutically to prevent tumor invasion and metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2363. doi:10.1158/1538-7445.AM2011-2363