Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland

Abstract

Hedgehog (HH) signaling is known to be essential during the embryonal development of the pituitary gland but the knowledge about its role in the adult pituitary and in associated tumors is sparse. In this report we investigated the effect of excess Hh signaling activation in murine pituitary explants and analyzed the HH signaling status of human adenopituitary lobes and a large cohort of pituitary adenomas. Our data show that excess Hh signaling led to increased proliferation of Sox2+ and Sox9+ adult pituitary stem cells and to elevated expression levels of adrenocorticotropic hormone (Acth), growth hormone (Gh) and prolactin (Prl) in the adult gland. Inhibition of the pathway by cyclopamine reversed these effects indicating that active Hh signaling positively regulates proliferative processes of adult pituitary stem cells and hormone production in the anterior pituitary. Since hormone producing cells of the adenohypophysis as well as ACTH-, GH- and PRL-immunopositive adenomas express SHH and its target GLI1, we furthermore propose that excess HH signaling is involved in the development/maintenance of hormone-producing pituitary adenomas. These findings advance the understanding of physiological hormone regulation and may open new treatment options for pituitary tumors.

Pituitary stem cell regulation: who is pulling the strings?

“…The findings suggest that the SHH pathway regulates adult pituitary stem cell proliferation (Pyczek et al 2016).…”

“…No significant differences were observed between prolactinomas and normal pituitary tissue. Another study observed SHH production and GLI1 upregulation not only in somatotropinomas (and corticotropinomas), but also in prolactinomas (Pyczek et al 2016). From the studies so far, it may appear that NOTCH and SHH signaling are regulated in opposite ways in the different tumor subtypes.…”

“…Addition of the SMO inhibitor cyclopamine to adult mouse pituitaries cultured as explants was reported to reduce levels of the downstream target Gli1, indicating that SHH is also basally active in the adult pituitary (Pyczek et al 2016). The pathway receptors and/or targets Ptch1 and Smo are detected in the adult pituitary, particularly in the stem cell compartment , Vankelecom 2010 (Table 1).…”

“…mechanism (Jiang et al 2012, Yavropoulou et al 2015a. Lower expression of SHH and GLI1 in a small cohort of the rare malignant pituitary carcinoma type in comparison with various kinds of benign pituitary adenomas may rather point to a protective role (Pyczek et al 2016). SHH signaling may also be activated in ACP based on the observed increase in GLI1, GLI2, GLI3, PTCH1 and SHH expression (Gomes et al 2015, Gump et al 2015), but is not upregulated in papillary craniopharyngioma , Goschzik et al 2017.…”

Regulation of pituitary stem cells by epithelial to mesenchymal transition events and signaling pathways

“…Inducible deletion of the SHH receptor PTCH in adult mouse pituitary causes over-activated SHH signaling, increased proliferation of SOX2- and SOX9-expressing cells, and increased expression of ACTH, GH, and PRL (114). This study also found high SHH and GLI1 expression in ACTH-, GH-, and PRL-expressing human pituitary adenomas, suggesting that SHH activity could be involved in stimulating pituitary stem cells into tumorigenesis.…”