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 (E48(hi)), expressed higher levels of the
fucose-generating
FX enzyme and of the fucosylated
E-selectin ligand sLe(a) than cells expressing low levels of E48 (E48(lo)). Signaling through E48 upregulated expression levels of these molecules in
HNSCC. In this work, we provide further evidence supporting the E48-FX-sLe(a) link by showing that FX
antisense oligonucleotides reduced sLe(a) 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 sLe(a), namely, ST-30 and FucTIII. Also,
selectin-mediated adhesion of E48(hi) variants to activated HUVECs was significantly higher than that of E48(lo) 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 E48(hi) variants were significantly more efficient than E48(lo) 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 E48(lo) variants contained significantly higher amounts of PDGF than E48(hi) 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.