O-sulfated bacterial polysaccharides with low anticoagulant activity inhibit metastasis.
Heparin-like polysaccharides possess the capacity to inhibit cancer cell proliferation, angiogenesis, heparanase-mediated cancer cell invasion, and cancer cell adhesion to vascular endothelia via adhesion receptors, such as selectins. The clinical applicability of the antitumor effect of such polysaccharides, however, is compromised by their anticoagulant activity. We have compared the potential of chemically O-sulfated and N,O-sulfated bacterial polysaccharide (capsular polysaccharide from E. COLI K5 [K5PS]) species to inhibit metastasis of mouse B16-BL6 melanoma cells and human MDA-MB-231 breast cancer cells in two in vivo models. We demonstrate that in both settings, O-sulfated K5PS was a potent inhibitor of metastasis. Reducing the molecular weight of the polysaccharide, however, resulted in lower antimetastatic capacity. Furthermore, we show that O-sulfated K5PS efficiently inhibited the invasion of B16-BL6 cells through Matrigel and also inhibited the in vitro activity of heparanase. Moreover, treatment with O-sulfated K5PS lowered the ability of B16-BL6 cells to adhere to endothelial cells, intercellular adhesion molecule-1, and P-selectin, but not to E-selectin. Importantly, O-sulfated K5PSs were largely devoid of anticoagulant activity. These findings indicate that O-sulfated K5PS polysaccharide should be considered as a potential antimetastatic agent.
Borgenström
Marjut
M
Department of Medical Biochemistry and Molecular Biology, Turku Centre for Biotechnology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
Wärri
Anni
A
Hiilesvuo
Katri
K
Käkönen
Rami
R
Käkönen
Sanna
S
Nissinen
Liisa
L
Pihlavisto
Marjo
M
Marjamäki
Anne
A
Vlodavsky
Israel
I
Naggi
Annamaria
A
Torri
Giangiacomo
G
Casu
Benito
B
Veromaa
Timo
T
Salmivirta
Markku
M
Elenius
Klaus
K
D000818:Animals; D016667:Bacterial Capsules; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D019763:Heparin Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008545:Melanoma / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D011135:Polysaccharides, Bacterial / Q000494:pharmacology* / Q000627:therapeutic use
D019040:E-Selectin; D009363:Neoplasm Proteins; D019007:P-Selectin; D011135:Polysaccharides, Bacterial; D018799:Intercellular Adhesion Molecule-1; C050673:capsular polysaccharide K5; D019763:Heparin Lyase