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.