Corrigendum to "Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models".

[This corrects the article DOI: 10.1155/2014/608497.].

Inhibition of Notch signaling attenuates pituitary adenoma growth in Nude mice.

Preclinical and clinical studies support that Notch signaling may play an important oncogenic role in cancer, but there is scarce information for pituitary tumors. We therefore undertook a functional study to evaluate Notch participation in pituitary adenoma growth. Tumors generated in Nude mice by subcutaneous GH3 somatolactotrope cell injection were treated in vivo with DAPT, a γ-secretase inhibitor, thus inactivating Notch signaling. This treatment led to pituitary tumor reduction, lower prolactin and GH tumor content and a decrease in angiogenesis. Furthermore, in silico transcriptomic and epigenomic analyses uncovered several tumor suppressor genes related to Notch signaling in pituitary tissue, namely Btg2, Nr4a1, Men1, Zfp36 and Cnot1. Gene evaluation suggested that Btg2, Nr4a1 and Cnot1 may be possible players in GH3 xenograft growth. Btg2 mRNA expression was lower in GH3 tumors compared to the parental line, and DAPT increased its expression levels in the tumor in parallel with the inhibition of its volume. Cnot1 mRNA levels were also increased in the pituitary xenografts by DAPT treatment. And the Nr4a1 gene was lower in tumors compared to the parental line, though not modified by DAPT. Finally, because DAPT in vivo may also be acting on tumor microenvironment, we determined the direct effect of DAPT on GH3 cells in vitro. We found that DAPT decreases the proliferative, secretory and migration potential of GH3 cells. These results position selective interruption of Notch signaling as a potential therapeutic tool in adjuvant treatments for aggressive or resistant pituitary tumors.

Notch system is differentially expressed and activated in pituitary adenomas of distinct histotype, tumor cell lines and normal pituitaries.

Pituitary adenomas are among the most frequent intracranial neoplasms and treatment depends on tumor subtype and clinical features. Unfortunately, non responder cases occur, then new molecular targets are needed. Notch system component expression and activation data are scarce in pituitary tumorigenesis, we therefore aimed to characterize Notch system in pituitary tumors of different histotype. In human pituitary adenomas we showed NOTCH1-4 receptors, JAGGED1 ligand and HES1 target gene expression with positive correlations between NOTCH1,2,4 and HES1, and NOTCH3 and JAGGED1 denoting Notch system activation in a subset of tumors. Importantly, NOTCH3 positive cells were higher in corticotropinomas and somatotropinomas compared to non functioning adenomas. In accordance, Notch activation was evidenced in AtT20 tumor corticotropes, with higher levels of NOTCH1-3 active domains, Jagged1 and Hes1 compared to normal pituitary. In the prolactinoma cell lines GH3 and MMQ, in vivo GH3 tumors and normal glands, Notch system activation was lower than in corticotropes. In MMQ cells only the NOTCH2 active domain was increased, whereas NOTCH1 active domain was higher in GH3 tumors. High levels of Jagged1 and Dll1 were found solely in GH3 cells, and Hes1, Hey1 and Hey2 were expressed in a model dependent pattern. Prolactinomas harbored by lacDrd2KO mice expressed high levels of NOTCH1 active domain and reduced Hes1. We show a differential expression of Notch system components in tumoral and normal pituitaries and specific Notch system involvement depending on adenoma histotype, with higher activation in corticotropinomas. These data suggest that targeting Notch pathway may benefit non responder pituitary adenomas.

Angiogenesis in pituitary adenomas: human studies and new mutant mouse models.

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.