Abstract:
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Läubli H,Stevenson JL,Varki A,Varki NM,Borsig Ldoi
10.1158/0008-5472.CAN-05-3121subject
Has Abstractpub_date
2006-02-01 00:00:00pages
1536-42issue
3eissn
0008-5472issn
1538-7445pii
66/3/1536journal_volume
66pub_type
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