Targeted expression of human MYCN selectively causes pancreatic neuroendocrine tumors in transgenic zebrafish.
The zebrafish model organism has been used extensively for studies of genetic pathways in development, indicating its potential applicability to cancer. Here we show that targeted expression of MYCN in cells of the pancreatic islet induces neuroendocrine carcinoma. Four transgenic fish developed abdominal tumors between 4 and 6 months of age, and histologic analysis revealed lobulated arrangements of neoplastic cells with expression of the MYCN transgene. The tumors also expressed insulin mRNA, and pancreatic exocrine cells and ducts were identified within the neoplasms, indicating a pancreatic origin for the tumor. Transmission electron microscopy revealed cytoplasmic, endocrine-dense core granules, analogous to those found in human neuroendocrine tumors. Our studies establish a zebrafish transgenic model of pancreatic neuroendocrine carcinoma, setting the stage to evaluate molecular pathways downstream of MYCN in this vertebrate forward genetic model system.
Yang
Hong Wei
HW
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kutok
Jeffery L
JL
Lee
Nam Hyuk
NH
Piao
Hui Ying
HY
Fletcher
Christopher D M
CD
Kanki
John P
JP
Look
A Thomas
AT
D000818:Animals; D030801:Animals, Genetically Modified; D018273:Carcinoma, Islet Cell / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics; D007515:Islets of Langerhans / Q000473:pathology; D000071447:N-Myc Proto-Oncogene Protein; D017599:Neuroectodermal Tumors / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019076:Transgenes; D015027:Zebrafish / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger