title: Preclinical assesement of survivin and XIAP as prognostic biomarkers and therapeutic targets in gastroenteropancreatic neuroendocrine neoplasia.
abstract: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) represent a rare and heterogenous tumor entity. Importantly, the highly proliferative subgroup of neuroendocrine carcinoma (GEP-NEC) is characterized by high resistance to conventional chemotherapy. Consequently, there is an urgent need to identify novel therapeutic targets, especially for GEP-NEC. Thus, we focused on Inhibitor of apoptosis protein (IAP) family members survivin and XIAP that orchestrate inhibition of apoptosis, induce resistance against chemotherapeutics and facilitate tumor metastasis. Copy number gains (CNGs) could be detected by microarray comparative genomic hybridization for survivin and XIAP in 60 % and 26.7 % of all GEP-NENs, respectively. Immunohistochemical staining of tissue specimens from 77 consecutive patients with GEP-NEN demonstrated increased survivin protein expression levels in tissue specimens of highly proliferative GEP-NEC or GEP-NEN located in the stomach and colon. In contrast, XIAP overexpression was associated with advanced tumor stages. Knockdown of survivin and XIAP markedly reduced cell proliferation and tumor growth. In vitro, YM155 induced apoptotic cell death accompanied by a reduction in cell proliferation and inhibited GEP-NEC xenograft growth. Taken together, our data provide evidence for a biological relevance of these IAPs in GEP-NEN and support a potential role of survivin as therapeutic target especially in the subgroup of aggressive GEP-NEC.
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Levent
authors.initials: L
authors.lastname: Dizdar
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Kira A
authors.initials: KA
authors.lastname: Oesterwind
authors.affiliation: Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Jasmin C
authors.initials: JC
authors.lastname: Riemer
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Werner
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mersch
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Möhlendick
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Sina C
authors.initials: SC
authors.lastname: Schütte
authors.affiliation: Coordination Centre for Clinical Trials, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Verde
authors.affiliation: Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Raba
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Topp
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Nikolas H
authors.initials: NH
authors.lastname: Stoecklein
authors.affiliation: Institute of Pathology, Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Department of Surgery (A), Heinrich-Heine-University and University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krieg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004305:Dose-Response Relationship, Drug; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009637:Masoprocol / Q000031:analogs & derivatives / Q000494:pharmacology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009285:Naphthoquinones / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D012189:Retrospective Studies; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009285:Naphthoquinones; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C076852:terameprocol; D009637:Masoprocol; C523798:sepantronium
keywords: GEP-NEN; XIAP; inhibitor of apoptosis protein; neuroendocrine neoplasia; survivin