title: Myofibroblast-induced tumorigenicity of pancreatic ductal epithelial cells is L1CAM dependent.
abstract: Pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis, representing one risk factor for PDAC, are characterized by a marked desmoplasia enriched of pancreatic myofibroblasts (PMFs). Thus, PMFs are thought to essentially promote pancreatic tumorigenesis. We recently demonstrated that the adhesion molecule L1CAM is involved in epithelial-mesenchymal transition of PMF-cocultured H6c7 human ductal epithelial cells and that L1CAM is expressed already in ductal structures of chronic pancreatitis with even higher elevation in primary tumors and metastases of PDAC patients. This study aimed at investigating whether PMFs and L1CAM drive malignant transformation of pancreatic ductal epithelial cells by enhancing their tumorigenic potential. Cell culture experiments demonstrated that in the presence of PMFs, H6c7 cells exhibit a profound resistance against death ligand-induced apoptosis. This apoptosis protection was similarly observed in H6c7 cells stably overexpressing L1CAM. Intrapancreatic inoculation of H6c7 cells together with PMFs (H6c7co) resulted in tumor formation in 7/8 and liver metastases in 6/8 severe combined immunodeficiency (SCID) mice, whereas no tumors and metastases were detectable after inoculation of H6c7 cells alone. Likewise, tumor outgrowth and metastases resulted from inoculation of L1CAM-overexpressing H6c7 cells in 5/7 and 3/7 SCID mice, respectively, but not from inoculation of mock-transfected H6c7 cells. Treatment of H6c7co tumor-bearing mice with the L1CAM antibody L1-9.3/2a inhibited tumor formation and liver metastasis in 100 and 50%, respectively, of the treated animals. Overall, these data provide new insights into the mechanisms of how PMFs and L1CAM contribute to malignant transformation of pancreatic ductal epithelial cells in early stages of pancreatic tumorigenesis.
authors.affiliation: Department of Internal Medicine I, Laboratory of Molecular Gastroenterology and Hepatology, UKSH-Campus Kiel, 24105 Kiel, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.forename: Claudia
authors.initials: C
authors.lastname: Geismann
authors.forename: Carola
authors.initials: C
authors.lastname: Heneweer
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.forename: Olena
authors.initials: O
authors.lastname: Korniienko
authors.forename: Helena
authors.initials: H
authors.lastname: Kiefel
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.forename: Max G
authors.initials: MG
authors.lastname: Bachem
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Peter
authors.initials: P
authors.lastname: Altevogt
authors.forename: Susanne
authors.initials: S
authors.lastname: Sebens
mesh_terms: D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D051379:Mice; D016513:Mice, SCID; D058628:Myofibroblasts / Q000502:physiology*; D039842:Neural Cell Adhesion Molecule L1 / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000209:etiology* / Q000473:pathology
chemical_list: D039842:Neural Cell Adhesion Molecule L1