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L-Selectin Facilitation of Metastasis Involves Temporal Induction of Fut7-Dependent Ligands at Sites of Tumor Cell Arrest

¹ Institute of Physiology, University of Zürich, Zurich, Switzerland; ² Biomedical Sciences Graduate Program; ³ Glycobiology Research and Training Center, Departments of Medicine, Pathology and Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California

Requests for reprints: Lubor Borsig, Institute of Physiology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. Phone: 41-1-635-5134; Fax: 41-1-635-6814; E-mail: lborsig{at}access.unizh.ch.

Hematogenous carcinoma metastasis is supported by aggregated platelets and leukocytes, forming tumor cell emboli. Early tumor cell-platelet interactions can be mediated by P-selectin binding to tumor cell surface ligands and this process is blocked by heparin. We previously showed that L-selectin deficiency also attenuates experimental metastasis. However, the mechanisms and timing of L-selectin action remained unknown. Here, we study how L-selectin facilitates establishment of pulmonary metastatic foci in syngeneic mice by using experimental metastasis to time events following entry of tumor cells into the bloodstream. Although L-selectin deficiency did not affect platelet aggregation or initial tumor cell embolization, the association of leukocytes with tumor cells was reduced and tumor cell survival was diminished 24 hours later. Temporal inhibition of L-selectin by a function-blocking antibody reduced metastasis. Moreover, although selectin blockade by heparin 6 to 18 hours after tumor cell injection was synergistic with P-selectin deficiency in reducing metastasis, there was no further effect in L-selectin-deficient animals. Thus, heparin apparently works at these time points primarily by blocking L-selectin. Endogenous L-selectin ligands were concomitantly induced adjacent to established intravascular tumor cell emboli in a similar time window when leukocytes were also present. Metastasis was attenuated in mice missing these induced endogenous L-selectin ligands due to fucosyltransferase-7 deficiency. Thus, L-selectin facilitation of metastasis progression involves leukocyte-endothelial interactions at sites of intravascular arrest supported by local induction of L-selectin ligands via fucosyltransferase-7. These data provide the first explanation for how leukocyte L-selectin facilitates tumor metastasis. (Cancer Res 2006; 66(3): 1536-42)

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