The role of Hedgehog signaling in the adult pituitary gland and the formation of pituitary adenoma

Hedgehog(HH)信号通路在成体器官的动态平衡和病理学中起着重要作用。然而，该通路在成年垂体的维持和病理中的作用在很大程度上是未知的。为此，我们在之前的一项研究中分析了小鼠成年垂体中普遍存在的信号通路激活的影响，这导致Sox2+垂体细胞的增殖增加，以及前叶激素(ACTH，促肾上腺皮质激素；Gh，生长激素；PRL，催乳素)的表达增加。此外，在表达ACTH、GH和PRL的人垂体腺瘤中，HH信号通路的激活程度明显高于其他亚型，提示HH信号在成年垂体的动态平衡和病理过程中起着重要作用。我们第一个资助期的数据现在表明，ACTH和PRL表达的细胞都不是来自Gli1+细胞(即具有活跃的HH信号的细胞)。即使在体内解除表达Pomc-(或ACTH-)细胞中HH信号的调控，也不会影响这些细胞的功能，无论是在器官发生过程中，还是在成年器官中。然而，促生长激素细胞和表达Sox2的滤泡星状细胞(FSC)来自成人脑垂体的Gli1+细胞。由于FSC调节内分泌细胞的激素分泌，并控制离子、营养物质和废物的微循环，这些数据表明HH信号参与了FSC与内分泌细胞的细胞间通讯和旁分泌交换。对于健康的腺体和垂体腺瘤也是如此，因为这些肿瘤中高达69%的肿瘤微环境中含有与肿瘤细胞直接接触的FSC。事实上，我们进一步证明，在体外，活跃的HH信号参与了FSC介导的GH产生/释放的调节。此外，我们的数据显示，HH刺激的FSC分泌神经肽血管活性肠肽(VIP)，该神经肽可诱导生长激素分泌。为了阐明HH信号转导生长激素细胞和FSC的作用，并进一步研究VIP介导的激素释放是否也适用于体内情况并可能在垂体病理中发挥作用，我们将分析人垂体和肿瘤样本，并在转基因小鼠模型中研究HH信号通路在生长激素细胞和/或FSC中的作用。如果我们的结果支持我们的假设，可能会为针对产生激素的腺瘤和相关疾病(如Morbus Cushy、肢端肥大症和高催乳素血症)的新的靶向治疗打开新的可能性。

The Hedgehog (Hh) signaling pathway plays an important role in homeostasis and pathology of adult organs. However, the function of the pathway in maintenance and pathology of the adult pituitary is largely unknown. To this end we analyzed in a previous study the impact of a ubiquitous activation of the signaling pathway in the murine adult pituitary, which causes an increased proliferation of Sox2+ pituitary cells as well as an increased expression of hormones of the anterior lobe (Acth, adrenocorticotropic hormone; Gh, growth hormone; Prl, prolactin). In addition, ACTH-, GH- and PRL-expressing human pituitary adenomas show significantly higher activation of the Hh signaling cascade compared to other subtypes, indicating a role of Hh signaling in homeostasis and pathology of the adult pituitary. Our data of first funding period now show that neither Acth- nor Prl-expressing cells are derived from Gli1+ cells (i.e. cells with active Hh signaling). Even an in vivo deregulation of Hh signaling in Pomc- (or Acth-) expressing cells has no effect on the functionality of these cells, neither during organogenesis nor in the adult organ. However, somatotropic cells and Sox2-expressing folliculostellate cells (FSC) are derived from Gli1+ cells of the adult pituitary. Since FSC regulate hormone secretion by endocrine cells and control the microcirculation of ions, nutrients and waste products, these data suggest that Hh signaling is involved in intercellular communication and paracrine exchange of FSC with endocrine cells. This could be true for the healthy gland as well as for pituitary adenomas, since the tumor micro environment of up to 69% of these tumors contains FSC in direct contact with tumor cells. Indeed, we furthermore demonstrated that active Hh signaling is involved in FSC-mediated regulation of Gh production/release in vitro. Moreover, our data show that Hh-stimulated FSC secrete the neuropeptide Vasoactive intestinal peptide (Vip) which induces hormone secretion from somatotrophs. To elucidate the role of Hh signaling somatotrophs and FSC of the adult pituitary and to furthermore investigate whether the Vip-mediated hormone release also applies to the in vivo situation and possibly plays a role in pituitary pathology, we will analyse human pituitary and tumor samples and investigate the effects of a deregulated Hh signaling cascade in somatotrophs and/or FSC in transgenic mouse models. If our results should support our hypothesis, it might open new possibilities for novel targeted therapies against hormone-producing adenoma and associated diseases (e.g. Morbus Cushing, acromegaly and hyperprolactinemia).