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This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: ERC-10-0109v1 17/3/637    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Thouënnon, E. Articles by Anouar, Y. PubMed PubMed Citation Articles by Thouënnon, E. Articles by Anouar, Y.

INSERM, U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication (DC2N), IFRMP23, University of Rouen, 76821 Mont-Saint-Aignan, France
¹ INSERM, U911, Centre de Recherche en Oncologie et Oncopharmacologie, Université de la Mediterranée, Aix-Marseille II, 13385 Marseille, France
² Endocrinology Unit, Hôpital ND de Bon Secours, 57038 Metz, France
³ Department of Endocrinology, Hôpital de Brabois, 54500 Nancy, France
⁴ Department of Endocrinology, INSERM, U1016, Institut Cochin, 75014 Paris, France
⁵ Hypertension Unit, Hôpital Européen Georges Pompidou, AP-HP, University of Paris-5, 75908 Paris Cedex 15, France

(Correspondence should be addressed to Y Anouar; Email: youssef.anouar{at}univ-rouen.fr)

^* (E Thouënnon and A Pierre contributed equally to this work)

Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Molecular pathways of malignant transformation remain poorly understood. Pheochromocytomas express various trophic peptides which may influence tumoral cell behavior. Here, we investigated the expression of trophic amidated peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), neuropeptide Y (NPY), and adrenomedullin (AM), and their receptors in benign and malignant pheochromocytomas in order to assess their potential role in chromaffin cell tumorigenesis and malignant transformation. PACAP, NPY, and AM are expressed in the majority of pheochromocytomas studied; NPY exhibiting the highest mRNA levels relative to reference genes. Although median gene expression or peptide levels were systematically lower in malignant compared to benign tumors, no statistically significant difference was found. Among all the receptors of these peptides that were analyzed, only the AM receptor RDC1 displayed a differential expression between benign and malignant pheochromocytomas. This receptor exhibited a fourfold higher expression in malignant than in benign tumors. AM and stromal cell-derived factor 1, which has also been described as a ligand for RDC1, increased the number of human pheochromocytoma cells in primary culture and exerted anti-apoptotic activity on rat pheochromocytoma PC12 cells. In addition, RDC1 gene silencing decreased the number of viable PC12 cells. This study shows the expression of several trophic peptides and their receptors in benign and malignant pheochromocytomas, and suggests that AM and its RDC1 receptor could be involved in chromaffin cell tumorigenesis through pro-survival effects. Therefore, AM and RDC1 may represent valuable targets for the treatment of malignant pheochromocytomas.