Hematogenous metastasis of carcinomas is accompanied by aggregation of 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. Recently, we have shown that L-selectin deficiency attenuates hematogenous metastasis even in T- and B-cell deficient mice (PNAS 99: 2193-2198). Thus, L-selectin on monocytes and/or neutrophils can influence the metastatic process. Here we study how L-selectin facilitates establishment of pulmonary metastatic foci in syngeneic mice using experimental metastasis to follow the time sequence of events. While 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. The intravenous injection of an L-selectin function blocking antibody reduced metastasis. When heparin was administered at times when L-selectin interactions could be blocked, attenuation of metastasis was observed, underlining the temporal nature of leukocyte L-selectin involvement in this process. Endogenous L-selectin ligands were concomitantly induced adjacent to established intravascular tumor cell emboli in a similar time window, when leukocytes were detected. The induced expression of L-selectin ligands around arrested tumor cells was not observed in Fucosyltransferase-7 deficient mice. The absence of endogenous L-selectin ligand induction due to Fucosyltransferase-7 deficiency resulted in reduction of metastasis. These results provide further insights into the mechanism of L-selectin action during metastasis, while showing the first evidence that leukocyte-endothelial interactions could facilitate this process.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]