Poly-N-
acetyl-lactosamine (polyLacNAc) on N-
glycans facilitate lung specific
metastasis of
melanoma cells by serving as high affinity
ligands for
galectin-3, expressed in highest amounts in the lungs, on almost all its tissue compartments including on the surface of vascular endothelium. PolyLacNAc not only
aids in initial arrest on the organ endothelium but in all the events of extravasation. Inhibition of polyLacNAc synthesis, or competitive inhibition of its interaction with
galectin-3 all inhibited these processes and experimental
metastasis. Transgenic
galectin-3 mice, viz., gal-3(+/+) (wild type), gal-3(+/-) (hemizygous) and gal-3(-/-) (null) have been used to prove that
galectin-3/polyLacNAc interactions are indeed critical for lung specific
metastasis. Gal-3(+/-) mice which showed <50% expression of
galectin-3 on the lungs also showed proportionate decrease in the number of B16F10
melanoma metastatic colonies affirming that
galectin-3 and polyLacNAc interactions are indeed key determinants of lung
metastasis. However, surprisingly, the number and size of metastatic colonies in gal-3(-/-) mice was very similar as that seen in gal-3(+/+) mice. The levels of
lactose binding
lectins on the lungs and the transcripts of other
galectins (galectin-1, -8 and -9) which are expressed on lungs and have similar
sugar binding specificities as galectins-3, remain unchanged in gal-3(+/+) and gal-3(-/-) mice. Further, inhibition of N-glycosylation with
Swainsonine (SW) which drastically reduces
metastasis of B16F10 cells in gal-3(+/+) mice, did not affect lung
metastasis when assessed in gal-3(-/-) mice. Together, these results rule out the possibility of some other
galectin taking over the function of
galectin-3 in gal-3(-/-) mice. Chimeric mice generated to assess if absence of any effect on
metastasis is due to compromised
tumor immunity by replacing bone marrow of gal-3(-/-) mice with that from gal-3(+/+) mice, also failed to impact
melanoma metastasis. As
galectin-3 regulates several immune functions including maturation of different immune cells, compromised
tumor immunity could be the major determinant of
melanoma metastasis in gal-3(-/-) mice and warrants thorough investigation.