ENGAGEMENT OF VARIANT CD44 CONFERS RESISTANCE TO ANTI-INTEGRIN ANTIBODY-MEDIATED APOPTOSIS IN A COLON-CARCINOMA CELL-LINE

The LIM 1863 colon carcinoma cell line grows as structured organoids a round a central lumen, and we have previously demonstrated that the th ree-dimensional arrangement protects the individual cells from apoptos is induced by an anti-alpha integrin antibody, 23C6 (Bates et al., 199 4). Here we show that the intercellular forces which drive spheroid fo rmation can be overcome by exposure of the cells to a collagen substra te, or more specifically through ligation of the CD44 receptor by a mo noclonal antibody. Binding to immobilized anti-CD44 antibody induced a monolayer morphology which is accompanied by fibronectin production a nd secretion, and expression of the integrin alpha v beta(6). Signific antly, the cells of the monolayer acquired resistance to 23C6 antibody -mediated apoptosis over time and this property was sustained even aft er removal from the monolayer. We provide data to show that this resis tance is not dependent on monolayer morphology, constant engagement of the CD44 receptor, loss of the 23C6 antigen, or elevation of Bcl-2 or Bcl-X-L protein. The CD44 expressed by LIM 1863 is shown to be the me tastatic variant of the molecule therefore these results provide a pos sible explanation for the selective advantages conferred by expression of this variant for metastasizing colon cancer cells. Overall, the fi ndings of this study support a model for the development of malignancy through the production of specific survival and growth signals as a d irect consequence of a signaling event induced by stimulation of an ep ithelial variant of CD44.