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

Hedgehog信号在成人垂体腺和垂体腺瘤形成中的作用

• 批准号: 326969103
• 负责人: Privatdozentin Dr. Anja Uhmann
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/326969103?language=en
• 关键词: role; Hedgehog; signaling; adult; pituitary

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).

Hedgehog（Hh）信号通路在成体器官的稳态和病理中起着重要作用。然而，该途径在成人垂体的维持和病理学中的功能在很大程度上是未知的。为此，我们在以前的研究中分析了普遍存在的激活信号通路的影响，在小鼠成年垂体，这会导致Sox 2+垂体细胞的增殖增加，以及前叶的激素（促肾上腺皮质激素，生长激素，生长激素，催乳素）的表达增加。此外，促肾上腺皮质激素，生长激素和催乳素表达的人垂体腺瘤表现出显着较高的激活Hh信号级联相比，其他亚型，表明Hh信号的作用，在稳态和病理的成人垂体。我们的第一个资助期的数据现在表明，表达ACTH和Prl的细胞都不是来自Gli 1+细胞（即具有活性Hh信号传导的细胞）。即使在体内失调的Hh信号在Pomc-（或ACTH-）表达细胞的功能没有影响这些细胞，无论是在器官发生，也不是在成人器官。然而，促生长细胞和Sox 2表达的滤泡星状细胞（FSC）来自成年垂体的Gli 1+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来说，这可能是真的，因为高达69%的这些肿瘤的肿瘤微环境含有与肿瘤细胞直接接触的FSC。事实上，我们进一步证明，积极的Hh信号参与FSC介导的Gh生产/释放的调节在体外。此外，我们的数据表明，Hh刺激的FSC分泌神经肽血管活性肠肽（Vip），诱导激素分泌的生长激素细胞。为了阐明成人垂体的生长激素细胞和FSC的Hh信号转导的作用，并进一步研究VIP介导的激素释放是否也适用于体内情况，并可能在垂体病理学中发挥作用，我们将分析人垂体和肿瘤样品，并研究在转基因小鼠模型中生长激素细胞和/或FSC中失调的Hh信号级联的影响。如果我们的研究结果支持我们的假设，它可能会打开新的靶向治疗的新的可能性，对腺瘤和相关疾病（如库欣病，肢端肥大症和高泌乳素血症）。