Pheochromocytomas in Nf1 knockout mice express a neural progenitor gene expression profile.
Pheochromocytomas are adrenal medullary tumors that typically occur in adult patients, with increased frequency in multiple endocrine neoplasia type 2, von Hippel-Lindau disease, familial paraganglioma syndromes and neurofibromatosis type 1 (NF1). Pheochromocytomas arise in adult mice with a heterozygous knockout mutation of exon 31 of the murine Nf1 gene, providing a mouse model for pheochromocytoma development in NF1. We performed a microarray-based gene expression profiling study comparing mouse pheochromocytoma tissue to normal adult mouse adrenal medulla to develop a basis for studying the pathobiology of these tumors. The findings demonstrate that pheochromocytomas from adult neurofibromatosis knockout mice express multiple developmentally regulated genes involved in early development of both the CNS and peripheral nervous system. One of the most highly overexpressed genes is receptor tyrosine kinase Ret, which is known to be transiently expressed in the developing adrenal gland, down-regulated in adult adrenals and often overexpressed in human pheochromocytomas. Real-time polymerase chain reaction validated the microarray results and immunoblots confirmed the overexpression of Ret protein. Other highly expressed validated genes include Sox9, which is a neural crest determinant, and Hey 1, which helps to maintain the progenitor status of neural precursors. The findings are consistent with the recently proposed concept that persistent neural progenitors might give rise to pheochromocytomas in adult mouse adrenals and suggest that events predisposing to tumor development might occur before formation of the adrenal medulla or migration of cells from the neural crest. However, the competing possibility that developmentally regulated neural genes arise secondarily to neoplastic transformation cannot be ruled out. In either case, the unique profile of gene expression opens the mouse pheochromocytoma model to new applications pertinent to neural stem cells and suggests potential new targets for treatment of pheochromocytomas or eradication of their precursors.
Powers
J F
JF
Department of Pathology, Tufts New England Medical Center, 750 Washington Street, Boston, MA 02111, USA. jpowers1@tufts-nemc.org
Evinger
M J
MJ
Zhi
J
J
Picard
K L
KL
Tischler
A S
AS
D000310:Adrenal Gland Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics; D025542:Neurofibromin 1 / Q000172:deficiency*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010673:Pheochromocytoma / Q000150:complications / Q000235:genetics*; D025341:Principal Component Analysis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D025542:Neurofibromin 1; D012333:RNA, Messenger; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse