Autocrine stimulation of human pancreatic duct-like development by solubleisoforms of epimorphin in vitro

Epimorphin was recently described as a mesenchymal factor modulating morpho genesis of murine mammary ducts, skin, liver, and lung in vitro. In this st udy epimorphin was analyzed in a human, pancreatic adenocarcinoma cell line (A818-6) which develops single layer epithelial hollow spheres resembling normal pancreatic ductal structures in vitro, Soluble 34- and 31-kD isoform s of epimorphin were found in the culture supernatant of A818-6 cells. In l ysates of A818-6 cells we detected the 34-and 31-kD isoforms and the dimers , and in lysates of fibroblasts the 150-kD tetramers of epimorphin addition ally. A neutralizing monoclonal antibody against epimorphin (MC-1) efficien tly blocked the development of hollow sphere structures from A818-6 cells, Coculture of A818-6 cells with fibroblasts stimulated the development of ho llow sphere structures in general and increased differentiation in 5-6-d-ol d hollow spheres. A818-6 hollow sphere development in the presence of fibro blasts was also blocked by MC-1, In this novel system for human duct-like d ifferentiation of pancreatic epithelial cells, we provide evidence for an a utocrine and paracrine function of epimorphin as a major mediator for morph ogenesis.