High levels of tyrosine phosphorylated proto-Ret in sporadic pheochromocytomas

Pheochromocytomas are tumors originating from chromaffin cells, the large m ajority of which are sporadic neoplasms. The genetic and molecular events d etermining their tumorigenesis continue to remain unknown. On the other han d, RET germ-line mutations cause the inheritance of familial tumors in mult iple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 spo radic tumors harboring no activating mutations. A subset of highly RET-expr essing tumors (50%) could be distinguished. They showed RET transcript, pro tein amounts as well as Ret-associated phosphotyrosine levels similar to th ose measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor alpha (GFR alpha)-1 transcript levels in tum ors and in normal tissues. Whereas the GFR alpha-1 transcripts were detecte d at similar levels in normal tissues and in tumors, GDNF was frequently fo und expressed in sporadic tumors at levels several times higher than in con trols. These results led us to propose the existence of an autocrine or par acrine loop leading to chronic stimulation of the Bet signaling pathway, wh ich could participate in the pathogenesis of a number of sporadic pheochrom ocytomas.