Hedgehog signaling activation induces stem cell proliferation and hormone release in the adult pituitary gland.
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.
Institute of Human Genetics, Tumor Genetics Group, University of Göttingen, Germany.
Joanna
J
Pyczek
Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
Rolf
R
Buslei
Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
David
D
Schult
Institute of Neuropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
Annett
A
Hölsken
Department of Neurosurgery, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Germany.
Michael
M
Buchfelder
Institute of Human Genetics, Tumor Genetics Group, University of Göttingen, Germany.
Ina
I
Heß
Institute of Human Genetics, Tumor Genetics Group, University of Göttingen, Germany.
Heidi
H
Hahn
Institute of Human Genetics, Tumor Genetics Group, University of Göttingen, Germany.
Anja
A
Uhmann
D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis*; D000328:Adult; D000818:Animals; D049109:Cell Proliferation; D013006:Growth Hormone / Q000096:biosynthesis*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010902:Pituitary Gland / Q000502:physiology*; D011388:Prolactin / Q000096:biosynthesis*; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology*
D053823:Hedgehog Proteins; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone