Functional role of sialyl Lewis X and fibronectin-derived RGDS peptide analogue on tumor-cell arrest in lungs followed by extravasation

Our study demonstrates that synthetic sialyl Lewis X (SLe(x)) as a ligand for selectins and fibronectin-derived PODS peptide analogue[Ar(DRGDS)₃] inhibits lung metastases produced by i.v. co-injection of B16 BL6 melanoma cells. To investigate the inhibitory mechanisms in a living animal, we performed positron-emission tomography (PET) analysis after i.v. injection of [2-¹⁸F]2-fluoro-2-deoxy-D-glucose-labeled tumor cells with or without liposomal SLe(x) or Ar(DRGDS)₃. The real-time PET measurement for the first 120 min, started immediately after injection, showed that tumor cell arrest, i.e., accumulation in the target organ (lung) was remarkably inhibited by liposomal SLe(x), but not inhibited by Ar(DRGDS), or liposomal Me-SLe(x), which is not recognized by selectins. In contrast, Ar(DRGDS)3 inhibited the invasion of B16-BL6 cells into reconstituted basement membrane (Matrigel) following tumor arrest, whereas SLe(x)- or Me-SLe(x)-entrapped liposomes did not affect tumor invasion. In the metastatic processes containing tumor-cell lodgement and arrest in the target organ followed by extravasation (invasion), SLe(x) resulted in the inhibition of initial arrest of tumor cells, presumably tumor-endothelium interaction, while Ar(DRGDS), achieved inhibition of tumor invasion into basement membrane at later steps of the cascade, consequently leading to inhibition of metastasis. Thus, tumor-cell arrest in lungs in the metastatic processes must be precisely and properly controlled by different adhesion molecules at different stages, which are similar to those observed in leukocyte-endothelium interaction.