title: A GFP-Tagged Gross Deletion on Chromosome 1 Causes Malignant Peripheral Nerve Sheath Tumors and Carcinomas in Zebrafish.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas, characterized by complex karyotypes. The molecular bases of such malignancy are poorly understood and efficient targeted molecular therapies are currently lacking. Here we describe a novel zebrafish model of MPNSTs, represented by the transgenic mutant line Tg(-8.5nkx2.2a:GFP)ia2. ia2 homozygous animals displayed embryonic lethality by 72 hpf, while the heterozygotes develop visible tumor masses with high frequency in adulthood. Histological and immunohistochemical examination revealed aggressive tumors with either mesenchymal or epithelial features. The former (54% of the cases) arose either in the abdominal cavity, or as intrathecal/intraspinal lesions and is composed of cytokeratin-negative spindle cells with fascicular/storiform growth pattern consistent with zebrafish MPNSTs. The second histotype was composed by polygonal or elongated cells, immunohistochemically positive for the pan-cytokeratin AE1/AE3. The overall histologic and immunohistochemical features were consistent with a malignant epithelial neoplasm of possible gastrointestinal/pancreatic origin. With an integrated approach, based on microsatellite (VNTR) and STS markers, we showed that ia2 insertion, in Tg(-8.5nkx2.2a:GFP)ia2 embryos, is associated with a deletion of 15.2 Mb in the telomeric portion of chromosome 1. Interestingly, among ia2 deleted genes we identified the presence of the 40S ribosomal protein S6 gene that may be one of the possible drivers for the MPNSTs in ia2 mutants. Thanks to the peculiar features of zebrafish as animal model of human cancer (cellular and genomic similarity, transparency and prolificacy) and the GFP tag, the Tg(-8.5nkx2.2a:GFP)ia2 line provides a manageable tool to study in vivo with high frequency MPNST biology and genetics, and to identify, in concert with the existing zebrafish MPNST models, conserved relevant mechanisms in zebrafish and human cancer development.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Astone
authors.affiliation: General Pathology & Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pizzi
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Peron
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Domenichini
authors.affiliation: General Pathology & Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Guzzardo
authors.affiliation: Institute for Molecular Biology/ CMBI, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Töchterle
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Tiso
authors.affiliation: General Pathology & Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
authors.affiliation: Institute for Molecular Biology/ CMBI, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Meyer
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Argenton
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vettori
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000378:metabolism; D002872:Chromosome Deletion; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D049452:Green Fluorescent Proteins