Selectin ligands are crucial components in the interaction between endothelial cells and extravasating cancer cells and, thus, play an important role in metastasis formation. Head-and-neck squamous cell carcinoma (HNSCC) variants expressing high levels of E48, a human Ly-6 protein (E48hi), expressed higher levels of the fucose-generating FX enzyme and of the fucosylated E-selectin ligand sLea than cells expressing low levels of E48 (E48lo). Signaling through E48 upregulated expression levels of these molecules in HNSCC. In this work, we provide further evidence supporting the E48-FX-sLea link by showing that FX antisense oligonucleotides reduced sLea expression levels in HNSCC. We also show that E48 may be causally involved in regulating expression levels in HNSCC of 2 additional enzymes involved in the biosynthesis of sLea, namely, ST-30 and FucTIII. Also, selectin-mediated adhesion of E48hi variants to activated HUVECs was significantly higher than that of E48lo variants. Transfection experiments utilizing sense or antisense E48 cDNA indicated that E48 may be causally involved in this adhesion. Chemokines are involved in the extravasation process of tumor cells. The release of chemoattractants from HNSCC variants differing in E48 expression was therefore analyzed. HNSCC did not release any chemoattractants but induced the release of such factors from HUVECs. Supernatants from E48hi variants were significantly more efficient than E48lo cells at inducing the release of chemoattractants from HUVECs. Transfection experiments indicated that E48 may be causally involved in the induction of chemoattractant release from HUVECs. Angiogenesis is an important manifestation of cancer-endothelium interactions. We therefore assayed for the presence of angiogenic factors in culture supernatants of HNSCC. Supernatants from E48lo variants contained significantly higher amounts of PDGF than E48hi cells. Transfection experiments indicated that E48 may be causally involved. Taken together, our results suggest that E48 controls important interaction parameters between HNSCC and endothelial cells.