KSA ANTIGEN EP-CAM MEDIATES CELL-CELL ADHESION OF PANCREATIC EPITHELIAL-CELLS - MORPHOREGULATORY ROLES IN PANCREATIC-ISLET DEVELOPMENT

Cell adhesion molecules (CAMS) are important mediators of cell-cell in teractions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcin oma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interesti ngly, most normal epithelia also express this antigen, although at low er levels, suggesting that a dynamic regulation of KSA may occur durin g cell growth and differentiation. Recently, evidence has been provide d that this glycoprotein may function as an epithelial cell adhesion m olecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human panc reatic islets. We demonstrate that Ep-CAM expression is targeted to th e lateral domain of epithelial cells of the human fetal pancreas, and that it mediates calcium-independent cell-cell adhesion. Quantitative confocal immunofluorescence in fetal pancreata identified the highest levels of Ep-CAM expression in developing islet-like cell clusters bud ding from the ductal epithelium, a cell compartment thought to compris e endocrine progenitors. A surprisingly reversed pattern was observed pattern was observed in the human adult pancreas, displaying low level s of Ep-CAM in islet cells and high levels in ducts. We further demons trate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pan creatic epithelial cells, transplanted in nude mice, is associated wit h a downregulation of Ep-CAM expression. In addition, a blockade of Ep -CAM function by KS1/4 mAb induced insulin and glucagon gene transcrip tion and translation in fetal pancreatic cell clusters. These results indicate that developmentally regulated expression and function of Ep- CAM play a morphoregulatory role in pancreatic islet ontogeny.