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Identification of the Secretogranin II-Derived Peptide EM66 in Pheochromocytomas as a Potential Marker for Discriminating Benign Versus Malignant Tumors

European Institute for Peptide Research (Institut Fédératif de Recherches Multidisciplinaries sur les Peptides 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale, Unité 413, Unité Associée Centre National de la Recherche Scientifique, University of Rouen (L.Y., J.G., M.M., L.G., J.L., H.L., H.V., Y.A.), 76821 Mont-Saint-Aignan, France; and Department of Hypertension, Hôpital Européen Georges Pompidou (P.-F.P.), 75908 Paris, France

Address all correspondence and requests for reprints to: Dr. Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale, Unité 413, Unité Associée Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr.

EM66 is a novel secretogranin II-derived peptide present in chromaffin cells of the human adrenal gland. The aim of the present study was to investigate the possible occurrence of EM66 in benign and malignant pheochromocytomas. Immunohistochemical labeling using specific antibodies revealed intense staining in both benign and malignant tumors. Coincubation of pheochromocytoma slices with EM66 and tyrosine hydroxylase antibodies showed that the immunostaining was restricted to chromaffin cells. RIA experiments indicated that serial dilutions of extracts of benign and malignant tumors generated displacement curves that were parallel to those produced by recombinant EM66. RIA quantification revealed concentrations of EM66 immunoreactivity ranging from 3.2–210 ng/mg protein (median = 25.6 ng/mg protein) in benign pheochromocytomas, and from 2.9–6.3 ng/mg protein (median = 3.8 ng/mg protein) in malignant tumors. The EM66-like immunoreactivity contained in the pheochromocytoma extracts was characterized by HPLC analysis combined with RIA detection. All of the benign and malignant tumors examined exhibited a single immunoreactive peak coeluting with recombinant EM66. These data indicate that the secretogranin II-derived peptide EM66 is generated in human tumoral chromaffin tissue. The significant difference in EM66 concentrations observed between benign and malignant pheochromocytomas suggests that measurement of EM66 levels may help identifying patients with higher risk of progression of such tumors.

This work was supported by the COMETE-2 network (Programme Hospitalier de Recherche Clinique AOM-02068), Institut National de la Santé et de la Recherche Médicale (Unité 413), Institut Fédératif de Recherches Multidisciplinaries sur les Peptides 23, and the Conseil Régional de Haute-Normandie. J.G. is the recipient of a doctoral fellowship from the Conseil Régional de Haute-Normandie.

¹ This work is dedicated to the memory of Dr. Vincent Contesse.

Abbreviations: Cg, Chromogranin; CgA or CgB, Cg A or B; PB, phosphate buffer; SgII, secretogranin II; SN, secretoneurin; TFA, trifluoroacetic acid; TH, tyrosine hydroxylase.

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