Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma

Abstract

Pheochromocytomas are rare neoplasias of neural crest origin arising from chromaffin cells of the adrenal medulla and sympathetic ganglia (extra-adrenal pheochromocytoma). Pheochromocytoma that develop in rats homozygous for a loss-of-function mutation in p27Kip1 (MENX syndrome) show a clear progression from hyperplasia to tumor, offering the possibility to gain insight into tumor pathobiology. We compared the gene-expression signatures of both adrenomedullary hyperplasia and pheochromocytoma with normal rat adrenal medulla. Hyperplasia and tumor show very similar transcriptome profiles, indicating early determination of the tumorigenic signature. Overrepresentation of developmentally regulated neural genes was a feature of the rat lesions. Quantitative RT-PCR validated the up-regulation of 11 genes, including some involved in neural development: Cdkn2a, Cdkn2c, Neurod1, Gal, Bmp7, and Phox2a. Overexpression of these genes precedes histological changes in affected adrenal glands. Their presence at early stages of tumorigenesis indicates they are not acquired during progression and may be a result of the lack of functional p27Kip1. Adrenal and extra-adrenal pheochromocytoma development clearly follows diverged molecular pathways in MENX rats. To correlate these findings to human pheochromocytoma, we studied nine genes overexpressed in the rat lesions in 46 sporadic and familial human pheochromocytomas. The expression of GAL, DGKH, BMP7, PHOX2A, L1CAM, TCTE1, EBF3, SOX4, and HASH1 was up-regulated, although with different frequencies. Immunohistochemical staining detected high L1CAM expression selectively in 27 human pheochromocytomas but not in 140 nonchromaffin neuroendocrine tumors. These studies reveal clues to the molecular pathways involved in rat and human pheochromocytoma and identify previously unexplored biomarkers for clinical use. Cdkn1b | rat model | transcriptome analysis | progenitor signature

Animal models of MEN1

“…Mutant rats at 8 months of age show increased urinary concentrations of norepinephrine, normetanephrine, 3-methoxytyramine and dopamine compared to wild-type age-matched rats; hence, their tumors are noradrenergic (Wiedemann et al 2016b). This is consistent with the lack of expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts noradrenaline to adrenaline, in these tumors (Molatore et al 2010b). In patients with pheochromocytoma, high catecholamine secretion associates with an increase in blood pressure, which, if not controlled, can cause severe symptoms.…”

“…Moreover, mutant rats show pathological changes in organs such as heart and kidney, similar to those observed in the patients if blood pressure is not controlled (Wiedemann et al 2016b). Rat and human pheochromocytomas also share gene expression signatures (Molatore et al 2010b. For the diagnosis and staging of pheochromocytoma, functional imaging plays a crucial role.…”

Adrenal cortical and chromaffin stem cells: Is there a common progeny related to stress adaptation?

“…It has been suggested that a subpopulation of proliferation competent progenitor cells continues to exist in the adult adrenal medulla Ehrhart-Bornstein et al, 2010). In addition to the adaptation to physiological needs, these progenitor cells may be involved in the development of stress-related hyper activation and hyperplasia of the adrenal and potentially in tumor development (Molatore et al, 2010;Powers et al, 2007).…”

Preclinical Evaluation of 18F-LMI1195 for In Vivo Imaging of Pheochromocytoma in the MENX Tumor Model

“…The MENX syndrome is caused by a homozygous germline mutation in the cell cycle regulatory gene Cdkn1b, encoding p27Kip1 (11), leading to development of bilateral pheochromocytomas with 100% penetrance. These tumors show a clear progression from adrenal medullary hyperplasia to adenoma (12) and closely resemble their human counterpart at the histopathological and molecular level (13). Previously, we have shown that 11 C-HED and 68 Ga-DOTATOC can be used for the detection of MENX-associated pheochromocytoma in vivo (14).…”