Interactions between molecules on the surface of
tumor cells and those on the target organ endothelium play an important role in their arrest in an organ.
Galectin-3 on the lung endothelium and high affinity
ligands poly-N-acetyllactosamine (polyLacNAc) on N-
oligosaccharides on
melanoma cells facilitate such interactions. However, to extravasate and colonize an organ the cells must stabilize these interactions by spreading to retract endothelium, degrade exposed basement membrane (BM) and move into parenchyma and proliferate. Here, we show that
galectin-3 is expressed on all the major compartments of the lungs and participates in not just promoting adhesion but also in spreading. We for the first time demonstrate that both soluble and immobilized
galectin-3 induce secretion of MMP-9 required to breach vascular BM. Further, we show that immobilized
galectin-3 is used as
traction for the movement of cells. Downregulation of
galactosyltransferases-I and -V resulted in significant loss in expression of polyLacNAc and thus reduced binding of
galectin-3. This was accompanied with a loss in adhesion, spreading, MMP-9 secretion and motility of the cells on
galectin-3 and thus their
metastasis to lungs.
Metastasis could also be inhibited by blocking surface polyLacNAc by pre-incubating cells with truncated
galectin-3 (which lacked oligomerization domain) or by feeding mice with modified
citrus pectin in
drinking water. Overall, these results unequivocally show that polyLacNAc on
melanoma cells and
galectin-3 on the lungs play a critical role in arrest and extravasation of cells in the lungs and strategies that target these interactions inhibit lung
metastasis.