Importance of cell surface carbohydrates in cancer cell adhesion, invasion and metastasis. Does sialic acid direct metastatic behavior?

The metastatic capacity of a range of murine tumor cell lines is reported to be influenced and regulated by the degree of sialylation of specific cellular binding sites detectable by lectins. These binding sites are made up of complex, branched carbohydrate moieties which stud the cell surface and seem to determine much of the social behavior of the cells. Our studies have led us to propose a new working hypothesis, in which two of the six most commonly found sugar moieties in animal cell membranes, namely D-galactose (Gal) and N-acetylgalactosamine (GalNac) play an important role in the formation of specific binding sites. Depending on whether Gal or GalNac are in the terminal position, different structures are formed which can be distinguished by lectins, such as those from soybean or peanut, and by the organ-specific vertebrate lectin of liver cells. Such sites may mediate the adhesion of cancer cells to certain constituents of the extracellular matrix, such as collagen IV and fibronectin, and their binding to other cells of the tumor mass (e.g. other tumor cells, fibroblasts, macrophages, lymphocytes) or of particular organs (e.g. hepatocytes). Binding sites for lectins with specificity for GalNac-Gal were expressed on low metastatic cells but blocked by sialylation on high metastatic cells. Conversely, binding sites for lectins with specificity for Gal-GalNac were more sialylated on the low metastatic lines than on the high metastatic tumor lines. Low and high metastatic tumor sublines of our murine lymphoma system (Eb/ESb) showed differences in the glycosylation of glycoproteins, glycolipids and possibly also of glycosaminoglycans. Glycosylation differences could be traced in some instances and localized to particular T lymphoid structures such as differentiation antigens and H-2 membrane glycoproteins. Differences were also noticed in the shedding or secretion of protein moieties, carbohydrate moieties and of plasma membrane vesicles, and may play a role in phenomena such as invasion and immune escape. The metastatic tumor cells were found to express increased levels of enzymes facilitating degradation of subendothelial basal lamina matrix, in particular proteases and endoglycosidases. Further enzyme differences were observed in the levels of sialyl-, galactosyl- and N-acetylglucosaminyltransferases. These glycosyltransferases are suggested to play an important role in the construction of glycoconjugates which in turn influence, the biological behavior of the cells. Tumor progression may involve minute changes in the specificity of sialyltransferases which could result in masking of some sites (e.g. those recognized by soybean agglutinin) and the unmasking and de novo exposure of previously cryptic sites (e.g. those recognized by hepatocytes).