L-Selectin Facilitation of Metastasis Involves Temporal Induction ofFut7-Dependent Ligands at Sites of Tumor Cell Arrest

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. (Cancer Res 2006; 66(3): 1536-42)

Single-molecule binding of CD44 to fibrin versus P-selectin predicts their distinct shear-dependent interactions in cancer

“…Discussion P-selectin and fibrin(ogen) have key roles in the metastatic dissemination of tumor cells. Microscopic observations of tumor cells, including colon carcinoma, trapped in the lung vasculature disclose their intimate association with platelets (mainly via Pselectin) (Borsig et al, 2001;Laubli et al, 2006) and fibrin(ogen) (Crissman et al, 1988;Im et al, 2004), which facilitate bloodborne metastasis. It is believed that platelet and fibrin(ogen) clots surrounding tumor cells provide a protective mask against the immunological and physiological stresses in the bloodstream, and facilitate their lodging to new metastatic sites (Nieswandt et al, 1999).…”

The role of platelet activation in tumor metastasis

“…Heparin is a highly sulfated glycosaminoglycan that has been in clinical use as an anticoagulant for many years. Besides its known anti-coagulant activity, heparin can also efficiently bind to P-and L-selectin and was shown to abrogate cancer cell interactions with platelets, thereby attenuating metastasis [39,56,59, 90,91]. Furthermore, we could show that heparin derivatives without any anticoagulant activity, but containing P-selectin binding activity attenuate metastasis as efficiently as native heparin [91].…”

Heparin as an Inhibitor of Cancer Progression

“…The recent evidence obtained in P-and/or L-selectin deficient mice confirms the contribution of these early response receptors to metastasis [20,36,[79][80][81][82]. Attenuation of metastasis was observed in the absence of P-selectin both with carcinomas and melanoma cells expressing selectin ligands [20,36,37,80].…”