ENLARGED CELL-ASSOCIATED PROTEOGLYCANS ABOLISH E-CADHERIN FUNCTIONALITY IN INVASIVE TUMOR-CELLS

Mouse and dog epithelial cell lines, expressing high levels of the Ca2 +-dependent cell-cell adhesion molecule E-cadherin in vitro, generated invasive and metastatic tumors in athymic mice. From these tumors, ne oplastic cell lines were isolated. All ex vivo isolates retained high expression levels of E-cadherin at their surface. Nevertheless, some s howed a fusiform morphotype, were defective in Ca2+-dependent cell agg regation, and were invasive in vitro, indicating that E-cadherin was n ot functional. Cell-associated proteoglycans were found to be enlarged in these variants as compared to their counterparts with functional E -cadherin. Treatment of the cells with the drug 4-methylumbelliferyl b eta-D-xyloside specifically reduced the amount and size of cell-associ ated proteoglycans. This same drug induced an epithelial morphotype, i ncreased Ca2+- and E-cadherin-dependent cell aggregation, and abrogate d invasiveness without influencing E-cadherin expression levels. Our r esults indicate that enlarged proteoglycans can prevent the hemophilic binding of E-cadherin, probably by steric hindrance. This is one more mechanism by which carcinomas may counteract invasion-suppressor gene s and acquire malignancy.