title: KSA antigen Ep-CAM mediates cell-cell adhesion of pancreatic epithelial cells: morphoregulatory roles in pancreatic islet development.
abstract: 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.
authors.affiliation: The Islet Research Laboratory at The Whittier Institute for Diabetes, Department of Pediatrics, University of California at San Diego, La Jolla, CA 92037, USA. vincenzo@alex.ucsd.edu
authors.forename: V
authors.initials: V
authors.lastname: Cirulli
authors.forename: L
authors.initials: L
authors.lastname: Crisa
authors.forename: G M
authors.initials: GM
authors.lastname: Beattie
authors.forename: M I
authors.initials: MI
authors.lastname: Mally
authors.forename: A D
authors.initials: AD
authors.lastname: Lopez
authors.forename: A
authors.initials: A
authors.lastname: Fannon
authors.forename: A
authors.initials: A
authors.lastname: Ptasznik
authors.forename: L
authors.initials: L
authors.lastname: Inverardi
authors.forename: C
authors.initials: C
authors.lastname: Ricordi
authors.forename: T
authors.initials: T
authors.lastname: Deerinck
authors.forename: M
authors.initials: M
authors.lastname: Ellisman
authors.forename: R A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: A
authors.initials: A
authors.lastname: Hayek
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D000071858:Epithelial Cell Adhesion Molecule; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000166:cytology; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology* / Q000196:embryology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010183:Pancreatic Ducts / Q000166:cytology / Q000196:embryology; D011247:Pregnancy
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D008562:Membrane Glycoproteins