Expression and Function of Sonic Hedgehog Pathway Components in Pituitary Adenomas: Evidence for a Direct Role in Hormone Secretion and Cell Proliferation

Abstract

Sonic hedgehog (Shh) belongs to a family of signaling proteins involved in development and has been recently implicated in cancer. Shh signaling is active in the corticotrophs of the adult pituitary gland, where it cross-talks with the CRH pathway and regulates ACTH secretion. Because developmental pathways are involved in pituitary tumorigenesis, we hypothesized that Shh may be important in pituitary tumors. The objective of this study was to examine the expression and function of Shh-pathway components in pituitary adenomas. Using immunohistochemistry, we determined the expression of Shh and its receptors Patched 1 (Ptc1) and Patched 2 (Ptc2) in 55 human pituitary adenomas compared with the normal pituitary gland. The AtT-20 and GH3 pituitary tumor cell lines were used as models for studying the role of Shh on cell proliferation and hormone secretion. The effect of Shh on hormone secretion was confirmed in primary cultures of normal rat pituitaries and human pituitary tumors. Ptc1 and Ptc2 were present, whereas Shh was down-regulated in pituitary adenomas and completely absent in Cushing tumors. Shh inhibited cell proliferation in AtT-20 corticotrophinoma cells and the Shh-specific inhibitor cyclopamine increased proliferation in GH3 mammosomatotrophinoma cells. On the other hand, exogenous administration of Shh increased hormone secretion from normal rat pituitaries, pituitary cell lines, and 10 different pituitary tumors. Our results suggest that Shh might maintain pituitary cells in a nonproliferative state. We conclude that Shh is a newly described hypophysiotropic cytokine and its down-regulation may be involved in the pathogenesis of pituitary adenomas.