The extent of maturation of the
oligosaccharide subunits of
tumor cell
glycoproteins appears to correlate with malignant potential, suggesting that modification of
oligosaccharide structures may alter metastatic capacity.
Castanospermine, a recently discovered inhibitor of
glucosidase I, was tested for its effect on experimental
metastasis of B16-F10 murine
melanoma cells and was compared to treatment with
swainsonine and
tunicamycin. All three drugs block different steps in the pathway of
glycoprotein processing yet each was a potent inhibitor of pulmonary colonization after i.v. injection of treated cells into C57BL/6 mice (greater than or equal to 80% inhibition). This result indicates a generality of inhibition of experimental
metastasis by blockage of protein glycosylation or
oligosaccharide processing and strongly implicates
carbohydrate residues in at least one critical step of the metastatic cascade. Cytotoxic side effects could not account for the inhibitory activity. In order to identify a possible mechanism of inhibition of colonization, the adhesive behavior and pulmonary retention properties of B16-F10 cells treated with the above inhibitors were examined.
Tunicamycin-treated B16-F10 cells exhibited poor adhesion to substrate-adsorbed
fibronectin and
laminin, whereas both
castanospermine- and
swainsonine-treated cells possessed near normal adhesive capacity; furthermore, the initial rate of loss of
tunicamycin-treated cells from the lungs of mice was substantially greater than either control,
castanospermine- or
swainsonine-treated cells. These data suggest that these processing inhibitors can block experimental
metastasis by at least two different mechanisms. The antimetastatic effect of
tunicamycin may be related to interference in
tumor cell-extracellular matrix interactions, whereas treatment with
castanospermine or
swainsonine appears to block at a stage distal to initial
tumor cell arrest.