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.