Plurihormonal pituitary adenomas (PHPAs) are defined as those pituitary adenomas secreting two or more hormones that differ in chemical composition, immunoreactivity, and biologic effects. Since the pathogenesis of these adenomas is not well understood, our study aimed to explore mechanisms underlying the pathogenesis of PHPAs. We used bead-based fiber-optic arrays (Illumina Human GeneChip WG-6 v3.0) to examine the gene expression profiles in seven PHPAs compared with three normal pituitary glands. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse-transcription polymerase chain reaction. We then performed pathway analysis of all differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Our array analysis showed significant increases in the expression of 6 genes and decreases in 334 genes and 15 expressed sequence tags in the PHPAs. Bioinformatic analysis showed that genes HIGD1B, EPS8, ECT2, and BTG2 might play an important role in the tumorigenesis and progression of PHPAs. Pathway analysis showed that the p53 and Notch signaling pathways may play an important role in tumorigenesis and progression of PHPAs, and extracellular matrix (ECM)-receptor interactions likely play a role in the inhibition of invasion and metastasis in these tumors. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of PHPAs. Bead-based fiber-optic arrays combined with pathway analysis of gene expression data appears to be a valid method for investigating the pathogenesis of tumors.
"In addition, the homologues of several genes up-regulated in the rat tumors had also been already implicated in human non-functioning/gonadotroph PAs. Examples are ECT2, NEUROD1, PTTG1, VEGFA and the oncogene c-fos [22, 25, 31, 32]. NOS1 and DAX1, regulated by and/or regulating the transcription factor SF-1, are highly expressed in human gonadotroph adenomas [20, 39]. "
[Show abstract][Hide abstract] ABSTRACT: Gonadotroph adenomas comprise 15-40 % of all pituitary tumors, are usually non-functioning and are often large and invasive at presentation. Surgery is the first-choice treatment, but complete resection is not always achieved, leading to high recurrence rates. As gonadotroph adenomas poorly respond to conventional pharmacological therapies, novel treatment strategies are needed. Their identification has been hampered by our incomplete understanding of the molecular pathogenesis of these tumors. Recently, we demonstrated that MENX-affected rats develop gonadotroph adenomas closely resembling their human counterparts. To discover new genes/pathways involved in gonadotroph cells tumorigenesis, we performed transcriptome profiling of rat tumors versus normal pituitary. Adenomas showed overrepresentation of genes involved in cell cycle, development, cell differentiation/proliferation, and lipid metabolism. Bioinformatic analysis identified downstream targets of the transcription factor SF-1 as being up-regulated in rat (and human) adenomas. Meta-analyses demonstrated remarkable similarities between gonadotroph adenomas in rats and humans, and highlighted common dysregulated genes, several of which were not previously implicated in pituitary tumorigenesis. Two such genes, CYP11A1 and NUSAP1, were analyzed in 39 human gonadotroph adenomas by qRT-PCR and found to be up-regulated in 77 and 95 % of cases, respectively. Immunohistochemistry detected high P450scc (encoded by CYP11A1) and NuSAP expression in 18 human gonadotroph tumors. In vitro studies demonstrated for the first time that Cyp11a1 is a target of SF-1 in gonadotroph cells and promotes proliferation/survival of rat pituitary adenoma primary cells and cell lines. Our studies reveal clues about the molecular mechanisms driving rat and human gonadotroph adenomas development, and may help identify previously unexplored biomarkers for clinical use.
[Show abstract][Hide abstract] ABSTRACT: Introduction: Pituitary adenomas (PA) are frequent and typically benign endocrine neoplasia, which clinical
prevalence is estimated around 1/1000 inhabitants . The vast majority are sporadic. PA are
endowed with significant clinical morbidity related to hormonal hypersecretion, neurological
symptoms due to intracranial mass effects or invasion of the surrounding structures and/or
secondary hypopituitarism. Their evolution is quite variable, ranging from indolent tumours
with an extremely slow growing potential, to recurrent, aggressive, and exceptionally
malignant tumours. Their current clinical management is based on pharmacological treatment,
mainly dopamine-agonists (DA) and somatostatin analogues (SSA), surgery and radiotherapy
. Despite considerable progress in the management of PA, a significant subset of patients
are not satisfactorily controlled. Long-term uncontrolled pituitary hormone hypersecretion,
leading to potential severe systemic diseases, and tumour recurrence or aggressiveness still
represent a difficult clinical challenge. Understanding the mechanisms involved in the
pathogenesis of PA is essential for the development of new therapeutic strategies. In this
chapter, we will summarize current concepts in pituitary tumorigenesis and focus our
attention on the most recent insights and new perspectives in this field.
Hot Topics in Endocrine and Endocrine-Related Diseases, Edited by Dr. Monica Fedele, 01/2013: chapter Chapter 2 - New Insights in the Pathogenesis of Pituitary Tumours: pages 28-84; InTech., ISBN: 978-953-51-1080-4
[Show abstract][Hide abstract] ABSTRACT: Pituitary adenomas are usually benign tumors that cause symptoms by compression of surrounding structures or impaired hormone secretion. Treatment, whether surgical or medical depends, on the tumor subtype and degree of compression; however, a significant proportion of patients do not achieve optimal control of mass effects or hormonal hypersecretion. Unraveling the pathogenesis of pituitary adenomas is a critical step in the quest for new subcellular treatment targets that will decrease morbidity and mortality related to these tumors. A large diversity of pathogenetic mechanisms has been described so far including deregulation of cell cycle, molecular pathways and angiogenesis. Major signaling pathways such as Notch, Wnt and Hedgehog, which are mainly active in the early phase of pituitary organogenesis and are essential for the development of somatotrophs, lactotrophs thyrotrophs and corticotrophs, have been implicated in the pathogenesis of pituitary adenomas. In this review we present novel data regarding the role of Notch and Hedgehog regulatory networks in pituitary development and pathogenesis of pituitary adenomas.
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