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Pheochromocytoma in rats with multiple endocrine neoplasia (MENX) shares gene expression patterns with human pheochromocytoma.
Proc. Natl. Acad. Sci. U.S.A. 107, 18493-18498 (2010)
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.
Impact Factor
Scopus SNIP
Web of Science
Times Cited
Times Cited
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Altmetric
9.432
3.610
22
28
Anmerkungen
Besondere Publikation
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Cdkn1b; Rat model; Transcriptome analysis; Progenitor signature;Cdkn1b; rat model; transcriptome analysis; progenitor signature; MUTATIONS; PARAGANGLIOMA; CELLS; DIFFERENTIATION; INHIBITOR; P27(KIP1); TUMORS; NF1; L1
Sprache
englisch
Veröffentlichungsjahr
2010
HGF-Berichtsjahr
2010
ISSN (print) / ISBN
0027-8424
e-ISSN
1091-6490
Quellenangaben
Band: 107,
Heft: 43,
Seiten: 18493-18498
Verlag
National Academy of Sciences
Verlagsort
Washington
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Pathology (PATH)
Institute of Radiation Biology (ISB)
Institute of Experimental Genetics (IEG)
Institute of Radiation Biology (ISB)
Institute of Experimental Genetics (IEG)
POF Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30202 - Environmental Health
30201 - Metabolic Health
30202 - Environmental Health
30201 - Metabolic Health
Forschungsfeld(er)
Enabling and Novel Technologies
Radiation Sciences
Genetics and Epidemiology
Radiation Sciences
Genetics and Epidemiology
PSP-Element(e)
G-500300-001
G-500200-001
G-500600-004
G-500200-001
G-500600-004
PubMed ID
20937862
Scopus ID
78649892922
Erfassungsdatum
2010-11-30