A DEFECT IN CELL-TO-CELL ADHESION VIA INTEGRIN-FIBRONECTIN INTERACTIONS IN A HIGHLY METASTATIC TUMOR-CELL LINE

We investigated the role of integrin-fibronectin (FN) interactions in tumor cell adhesion, Two cloned tumor cell lines designated OV-LM (low -metastatic) and OV-HM (high-metastatic) were isolated from a murine o varian carcinoma, OV2944. OV-LM and OV-HM cells exhibited high and low RGDS-sequence-dependent adhesiveness to FN, respectively, Both lines expressed comparable levels of alpha 5 and alpha v integrins, which ar e capable of reacting with RGDS on FN, To compare the functions of the se integrins between the two tumor lines, the signaling mechanism foll owing FN stimulation was examined, Significant levels of phosphorylati on of focal adhesion kinase (FAK) were detected in both OV-LM and OV-H M cells before FN stimulation, Whereas the level of FAK phosphorylatio n was appreciably enhanced in OV-LM cells stimulated with FN, stimulat ion of OV-HM cells with FN induced a reduction in the FAK phosphorylat ion in association with a significant decrease in the amount of FAK pr otein in the soluble compartment of cell lysates, A difference in the deposition of FN on the cell surface was also observed between the two types of tumor lines; OV-HM cells had an appreciably smaller amount o f FN than OV-LM, Consistent with the functional abnormality of the int egrin-FAK system and the smaller amount of FN on OV-HM, this clone exh ibited a reduced cell-cell adhesion in the in vitro cell aggregation a ssay, Namely, OV-LM cells displayed a time-dependent increase in the f ormation of cell aggregates, whereas most OV-HM cells remained single, The formation of aggregates by OV-LM cells was inhibited by addition of RGDS peptide, These results indicate that the highly metastatic clo ne, OV-HM, exhibits a decreased capacity of cell-cell adhesion mediate d by integrin-FN interactions and suggest that this defect is mainly d ue to the dysfunction of integrins/FAK rather than a decrease in the a mount of integrins expressed on tumor cells.