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© The Rockefeller University Press, 0021-9525/1998//1519 $5.00
The Journal of Cell Biology, Volume 140, Number 6, , 1998 1519-1534

Article

KSA Antigen Ep-CAM Mediates Cell–Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development



V. Cirulli*, L. Crisa{ddagger}, G.M. Beattie*, M.I. Mally*, A.D. Lopez*, A. Fannon§, A. Ptasznik*, L. Inverardi||, C. Ricordi||, T. Deerinck, M. Ellisman, R.A. Reisfeld**, and A. Hayek*

* The Islet Research Laboratory at The Whittier Institute for Diabetes, Department of Pediatrics, The National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California 92037; {ddagger} Department of Molecular and Experimental Medicine, and ** Department of Immunology, The Scripps Research Institute, La Jolla, California 92037; || The Diabetes Research Institute, University of Miami School of Medicine, Miami, Florida 33136; and § Brookdale Center for Molecular Biology, The Mount Sinai School of Medicine, New York 10029

Cell adhesion molecules (CAMs) are important mediators of cell–cell interactions and regulate cell fate determination by influencing growth, differentiation, and organization within tissues. The human pancarcinoma antigen KSA is a glycoprotein of 40 kD originally identified as a marker of rapidly proliferating tumors of epithelial origin. Interestingly, most normal epithelia also express this antigen, although at lower levels, suggesting that a dynamic regulation of KSA may occur during cell growth and differentiation. Recently, evidence has been provided that this glycoprotein may function as an epithelial cell adhesion molecule (Ep-CAM). Here, we report that Ep-CAM exhibits the features of a morphoregulatory molecule involved in the development of human pancreatic islets. We demonstrate that Ep-CAM expression is targeted to the 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 budding from the ductal epithelium, a cell compartment thought to comprise endocrine progenitors. A surprisingly reversed pattern was observed in the human adult pancreas, displaying low levels of Ep-CAM in islet cells and high levels in ducts. We further demonstrate that culture conditions promoting epithelial cell growth induce upregulation of Ep-CAM, whereas endocrine differentiation of fetal pancreatic epithelial cells, transplanted in nude mice, is associated with a downregulation of Ep-CAM expression. In addition, a blockade of Ep-CAM function by KS1/4 mAb induced insulin and glucagon gene transcription 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.

Abbreviations used in this paper: CAM, cell adhesion molecule; DS, donkey serum; Ep-CAM, epithelial cell adhesion molecule; HFP, human fetal pancreas; ICC, islet-like cell cluster; N-CAM, neuronal cell adhesion molecule; rhGHF/SF, recombinant human hepatocyte growth factor/scatter factor.

Address all correspondence to Vincenzo Cirulli, The Islet Research Laboratories at the Whittier Institute for Diabetes, Department of Pediatrics, University of California at San Diego, 9894 Genesee Avenue, La Jolla, CA 92037. Tel.: (619) 622-8423. Fax: (619) 558-3495. E-mail: vincenzo{at}alex.ucsd.edu


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