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High Levels of Tyrosine Phosphorylated Proto-Ret in Sporadic Pheochromocytomas¹

Centre de Génétique Moléculaire, Laboratoire associé à l’Université Pierre et Marie Curie, C.N.R.S., 91190 Gif sur Yvette, France [H. L. H., N. C-B., C. T.]; Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Richerche, Facoltà di Medicina e Chirurgia, 80131 Naples, Italy [L. G. C-D., V. d. F.]; Unité d’hypertension et Laboratoire de Génétique Moléculaire, Hôpital Broussais, 75014 Paris, France [P-F. P.]; and Groupe d’Etude en Physiopathologie Endocrinienne, Institut de Génétique Moléculaire, Université René Descartes, 75014 Paris 7, France [X. B.]

Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 sporadic tumors harboring no activating mutations. A subset of highly RET-expressing tumors (50%) could be distinguished. They showed RET transcript, protein amounts as well as Ret-associated phosphotyrosine levels similar to those measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor (GFR)-1 transcript levels in tumors and in normal tissues. Whereas the GFR-1 transcripts were detected at similar levels in normal tissues and in tumors, GDNF was frequently found expressed in sporadic tumors at levels several times higher than in controls. These results led us to propose the existence of an autocrine or paracrine loop leading to chronic stimulation of the Ret signaling pathway, which could participate in the pathogenesis of a number of sporadic pheochromocytomas.