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P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins

Nina Hostettler^*, Annamaria Naggi, Giangiacomo Torri, Riva Ishai-Michaeli, Benito Casu, Israel Vlodavsky and Lubor Borsig^*,1

^* Zürich Center for Integrative Human Physiology, Institute of Physiology, University of Zürich, Zürich, Switzerland;

G. Ronzoni Institute for Chemical and Biochemical Research, Milano, Italy; and

Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

¹Correspondence: Institute of Physiology University of Zürich–Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail: lborsig{at}access.unizh.ch

Vascular cell adhesion molecules, P- and L-selectins, facilitate metastasis of cancer cells in mice by mediating interactions with platelets, endothelium, and leukocytes. Heparanase is an endoglycosidase that degrades heparan sulfate of extracellular matrix, thereby promoting tumor invasion and metastasis. Heparin is known to efficiently attenuate metastasis in different tumor models. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanase-specific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P- and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase.—Hostettler, N., Naggi, A., Torri, G., Ishai-Michaeli, R., Casu, B., Vlodavsky, I., Borsig, L. P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins.

Key Words: thrombin generation • LMWH • selectin interactions • heparin derivatives