A GFP-Tagged Gross Deletion on Chromosome 1 Causes Malignant Peripheral Nerve Sheath Tumors and Carcinomas in Zebrafish

PLoS One. 2015 Dec 22;10(12):e0145178. doi: 10.1371/journal.pone.0145178. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified* / genetics
  • Animals, Genetically Modified* / metabolism
  • Chromosome Deletion*
  • Chromosomes* / genetics
  • Chromosomes* / metabolism
  • Green Fluorescent Proteins
  • Humans
  • Neoplasms, Experimental* / genetics
  • Neoplasms, Experimental* / metabolism
  • Neoplasms, Experimental* / pathology
  • Nerve Sheath Neoplasms* / genetics
  • Nerve Sheath Neoplasms* / metabolism
  • Nerve Sheath Neoplasms* / pathology
  • Zebrafish* / genetics
  • Zebrafish* / metabolism

Substances

  • Green Fluorescent Proteins

Grants and funding

This work was supported by Associazione Italiana per la Ricerca sul Cancro Project IG 10274, European Union Grant ZF-HEALTH CT-2010-242048, Italian Ministry of Health project Trambigen (RF-2010-2309484), and the AFM-Telethon project Polygon (18572). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.