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Expression of the Angiogenesis Markers Vascular Endothelial Growth Factor-A, Thrombospondin-1, and Platelet-Derived Endothelial Cell Growth Factor in Human Sporadic Adrenocortical Tumors: Correlation with Genotypic Alterations¹

INSERM U-244, Département de Biologie Moléculaire et Structurale/Biochimie des Régulations Cellulaires Endocrines, Commissariat à l’Energie Atomique (F.d.F., E.M.C., J.J.F.), F-38054 Grenoble, France; Service de Biochimie A, Centre Hospitalier Régional Universitaire de Grenoble (F.d.F., M.E.A., E.M.C.), 38700 La Tronche, France; Laboratoire d’Explorations Fonctionnelles Endocriniennes, Hôpital Trousseau (C.G.), 75012 Paris, France; and Clinique des Maladies Endocriniennes et Métaboliques, Hôpital Cochin (X.B.), 75014 Paris, France

Address all correspondence and requests for reprints to: Dr. J. J. Feige, INSERM U-244, Département de Biologie Moléculaire et Structurale/Biochimie des Régulations Cellulaires Endocrines, Commissariat à l’Energie Atomique de Grenoble, 17 rue des Martyrs, F-38054 Grenoble Cedex 9, France.

Several studies have supported the hypothesis that adrenocortical tumor formation is the result of a multistep process. The angiogenic switch has been proposed to be a key step in tumor progression from adenoma to carcinoma. In this study we measured the cytosolic concentrations of three proteins involved in angiogenesis [namely platelet-derived endothelial cell growth factor vascular endothelial cell growth factor A (VEGF-A), and thrombospondin-1 (TSP1)] in a series of 43 human sporadic adrenocortical tumors. The tumors were classified as adenomas (n = 18), transitional tumors (n = 12), or carcinomas (n = 13) according to the histological criteria defined by Weiss. Platelet-derived endothelial cell growth factor/thymidine phosphorylase levels were not significantly different among these three groups. One hundred percent of the adenomas and 73% of the transitional tumors showed VEGF-A concentrations under the threshold value of 107 ng/g protein, whereas 75% of the carcinomas had VEGF-A concentrations above this threshold value. Similarly, 89% of the adenomas showed TSP1 concentrations above the threshold value of 57 µg/g protein, whereas only 25% of the carcinomas and 33% of the transitional tumor samples did so. Insulin-like growth factor II overexpression, a common genetic alteration of adrenocortical carcinomas, was significantly correlated with higher VEGF-A and lower TSP1 concentrations. The tumors from the 6 patients with tumor recurrence after surgical ablation showed significantly higher VEGF-A values than the carcinomas and the transitional tumors from patients that did not relapse. Taken together, these data suggest that a decrease in TSP1 expression is an event that precedes an increase in VEGF-A expression during adrenocortical tumor progression. The population of premalignant tumors with low TSP1 and normal VEGF-A levels could represent a selective target for antiangiogenic therapies.

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