Ascidian dermatan sulfates attenuate metastasis, inflammation and thrombosis by inhibition of P-selectin

J Thromb Haemost. 2011 Sep;9(9):1807-15. doi: 10.1111/j.1538-7836.2011.04401.x.

Abstract

Background: Cancer-associated thrombosis and enduring inflammation are strongly associated with cancer progression and metastasis. Heparin is the mostly clinically used anticoagulant/antithrombotic drug, and has recently been shown to exhibit antimetastatic and anti-inflammatory activities that are linked to inhibition of P-selectin and/or L-selectin. P-selectin-mediated platelet-tumor cell and tumor cell-endothelium interactions facilitate the initial steps of metastasis.

Objectives and methods: The aim of the present study was to determine the capacity of dermatan sulfates to inhibit P-selectin and to test their potential to affect thrombosis, inflammation and metastasis in respective experimental mouse models.

Results: Two dermatan sulfates isolated from the ascidians Styela plicata and Phallusia nigra, composed of the same disaccharide core structure (IdoA2-GalNAc)(n) , but sulfated at carbon 4 or 6 of the GalNAc, respectively, have opposed heparin cofactor II (HCII) activities and are potent inhibitors of P-selectin. The ascidian dermatan sulfates effectively attenuated metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model. Moreover, both glycosaminoglycans reduced thrombus size in an FeCl(3) -induced arterial thrombosis model, irrespective of their HCII activities. The analysis of arterial thrombi demonstrated markedly reduced platelet deposition after dermatan sulfate treatment, suggesting that the glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation.

Conclusions: Collectively, these findings provide evidence that specific inhibition of P-selectin represents a potential therapeutic target in thrombosis, inflammation and metastasis, and that ascidian dermatan sulfates may serve as antiselectin agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / secondary
  • Dermatan Sulfate / isolation & purification
  • Dermatan Sulfate / pharmacology*
  • Humans
  • Inflammation / prevention & control
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / secondary
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Metastasis / prevention & control
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / secondary
  • Neutrophils / drug effects
  • Neutrophils / physiology
  • P-Selectin / antagonists & inhibitors*
  • P-Selectin / genetics
  • P-Selectin / physiology
  • Thrombosis / prevention & control
  • Urochordata / chemistry*

Substances

  • P-Selectin
  • Dermatan Sulfate