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

Lasse Lehnert1, Markus M. Lerch2, Yohei Hirai3, Marie-Luise Kruse4, Wolff Schmiegel5 and Holger Kalthoff1

1Molecular Oncology, Department of General and Thoracic Surgery, Christian-Albrechts-University, Kiel, Germany, 2Department of Medicine B, Westfälische Wilhelms-University, Münster, Germany, 3Sumitomo Industries, Yokohama, Japan, 4First Department of Medicine, Laboratory for Molecular Gastroenterology and Hepatology, Christian-Albrechts-University, Kiel, Germany, 5Medical Clinic, Knappschaftskrankenhaus, Ruhr-University of Bochum, Germany

Epimorphin was recently described as a mesenchymal factor modulating morphogenesis of murine mammary ducts, skin, liver and lung in vitro. In the present study 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 kDa and 31 kDa isoforms of epimorphin were found in the culture supernatant of A818-6 cells. In lysates of A818-6 cells we detected the 34 kDa, 31 kDa isoforms and the dimers, and in lysates of fibroblasts additionally the 150 kDa tetramers of epimorphin. A neutralizing monoclonal antibody against epimorphin (MC-1) efficiently blocked the development of hollow sphere structures from A818-6 cells. Co-culture of A818-6 cells with fibroblasts stimulated the development of hollow sphere structures in general and increased differentiation in 5-6 day old hollow spheres. A818-6 hollow sphere development in the presence of fibroblasts was also blocked by MC-1. In this novel system for human duct-like differentiation of pancreatic epithelial cells we provide evidence for an autocrine and paracrine function of epimorphin as a major mediator for morphogenesis. Autocrine stimulation of human pancreatic duct-like development by soluble isoforms of epimorphin in vitro. J Cell Biol. 2001 Mar 5;152(5):911-22.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Pathology.