title: New model for gastroenteropancreatic large-cell neuroendocrine carcinoma: establishment of two clinically relevant cell lines.
abstract: Recently, a novel WHO-classification has been introduced that divided gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) according to their proliferation index into G1- or G2-neuroendocrine tumors (NET) and poorly differentiated small-cell or large-cell G3-neuroendocrine carcinomas (NEC). Our knowledge on primary NECs of the GEP-system is limited due to the rarity of these tumors and chemotherapeutic concepts of highly aggressive NEC do not provide convincing results. The aim of this study was to establish a reliable cell line model for NEC that could be helpful in identifying novel druggable molecular targets. Cell lines were established from liver (NEC-DUE1) or lymph node metastases (NEC-DUE2) from large cell NECs of the gastroesophageal junction and the large intestine, respectively. Morphological characteristics and expression of neuroendocrine markers were extensively analyzed. Chromosomal aberrations were mapped by array comparative genomic hybridization and DNA profiling was analyzed by DNA fingerprinting. In vitro and in vivo tumorigenicity was evaluated and the sensitivity against chemotherapeutic agents assessed. Both cell lines exhibited typical morphological and molecular features of large cell NEC. In vitro and in vivo experiments demonstrated that both cell lines retained their malignant properties. Whereas NEC-DUE1 and -DUE2 were resistant to chemotherapeutic drugs such as cisplatin, etoposide and oxaliplatin, a high sensitivity to 5-fluorouracil was observed for the NEC-DUE1 cell line. Taken together, we established and characterized the first GEP large-cell NEC cell lines that might serve as a helpful tool not only to understand the biology of these tumors, but also to establish novel targeted therapies in a preclinical setup.
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krieg
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mersch
authors.affiliation: Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Boeck
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Levent
authors.initials: L
authors.lastname: Dizdar
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Neuroscience, Philipps University Marburg, Marburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Weihe
authors.affiliation: Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Zena
authors.initials: Z
authors.lastname: Hilal
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krausch
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Möhlendick
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Topp
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.affiliation: Institute of Forensic Medicine, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huckenbeck
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Nikolas H
authors.initials: NH
authors.lastname: Stoecklein
authors.affiliation: Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Anlauf
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Duesseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000473:pathology* / Q000648:ultrastructure; D018278:Carcinoma, Neuroendocrine / Q000473:pathology* / Q000648:ultrastructure; D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D020732:Cytogenetic Analysis; D004067:Digestive System Neoplasms / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008954:Models, Biological; D017481:Receptors, Somatostatin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D017481:Receptors, Somatostatin