Growth hormone- secreting pituitary adenomas: from molecular basis to treatment options in acromegaly

Sabino, Simone Magnavita; Miranda, Paulo Augusto Carvalho; Ribeiro‐Oliveira, Antônio

doi:10.4161/cbt.9.7.11581

Cited by 9 publications

(5 citation statements)

References 116 publications

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“…GHoma accounts for 10 to 20% of all pituitary tumors, causing acromegaly in adults and gigantism in adolescent (24), but the critical molecular events in GHoma progression have not been well-identified. As recurrent genetic mutations are rare, the analysis of dysregulated gene expression in GHoma is of particular value.…”

Section: Discussionmentioning

confidence: 99%

DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

et al. 2019

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Advances in the understanding of growth hormone-producing adenomas (GHomas) are ongoing, but current therapy is limited by moderate and variable efficacy and in need of life-long treatment. In this study, the molecular signaling pathway related to GHoma was investigated by proteomics and transcriptomics. The differentially expressed proteins and genes were significantly enriched in Extracellular Matrix-Receptor Interactions, Notch Signaling, Basal Cell Carcinoma Signaling, JAK-STAT3, Wnt Signaling, and Glioblastoma Multiforme Signaling by Ingenuity Pathway Analysis. Furthermore, the Notch2/Delta-like canonical Notch ligand (DLL) signaling pathway was identified to be associated with tumorigenesis and invasiveness of GHoma. In 76 patients, Notch2 and DLL3 were upregulated in invasive compared to those in non-invasive GHoma ( p < 0.05). Disease-free survival was significantly longer in patients with low, compared with high, DLL3 expression ( p = 0.027). Notch 2 knockdown inhibited cell migration in both GH3 cells and primary GHoma cells, along with downregulation of the mRNA expression of related genes. DAPT, a γ-secretase inhibitor, inhibited tumor growth and invasion in vivo and in vitro and suppressed the release of growth hormone in primary GHoma cells. The involvement of Notch2/DLL3 signaling in GHoma progression warrants additional study of Notch inhibitor, DAPT, as a potential GHoma treatment. Importance of the Study Current treatments of GH adenomas (GHomas) are limited by their moderate and variable efficacy and in need of life-long treatment. We found that the Notch2/Delta-like Notch ligand 3 (DLL3) signaling pathway was active in GHoma tumorigenesis, progression, and invasion. The γ-secretase inhibitor DAPT is of potential use in GHoma treatment targeting Notch signaling.

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Section: Discussionmentioning

confidence: 99%

DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

et al. 2019

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“…While most cases are sporadic, there are several familial syndromes, such as multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA) and Carney complex, as well as the sporadic germline mosaic disorder McCune-Albright disease, that predispose to pituitary hyperplasia and neoplasia, causing acromegaly or gigantism [6,7]. In these cases the presentation can be quite severe, with its onset at a young age, high GH levels and poor response to medical treatment [8].…”

Section: Introductionmentioning

confidence: 99%

The Clinicopathological Spectrum of Acromegaly

Akirov

Sylvia

Amer

et al. 2019

JCM

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Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH. Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities. Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed. Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies. Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.

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“…There have been several key advances over the last two decades in this disease, including the development of assays with increased sensitivity for GH and IGF-1 [ 15 , 16 ], widespread use of magnetic resonance imaging (MRI) for pituitary examination [ 17 ], automated software to evaluate the physical changes associated with the disease [ 18 ], and several novel therapeutic approaches [ 19 ]. Despite this, the diagnosis of these patients does not seem to have changed in over 25 years, nor have the signs and symptoms associated with the disease [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

et al. 2016

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IntroductionAcromegaly is a rare, insidious disease resulting from the overproduction of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), and is associated with a range of comorbidities. The extent of associated complications and mortality risk is related to length of exposure to the excess GH and IGF-1, thus early diagnosis and treatment is imperative. Unfortunately, acromegaly is often diagnosed late, when patients already have a wide range of comorbidities. The presence of comorbid conditions contributes significantly to patient morbidity/mortality and impaired quality of life.MethodsWe conducted a retrospective literature review for information relating to the diagnosis of acromegaly, and its associated comorbidities using PubMed. The main aim of this review is to highlight the issues of comorbidities in acromegaly, and to reinforce the importance of early diagnosis and treatment.Findings and conclusionsSuccessful management of acromegaly goes beyond treating the disease itself, since many patients are diagnosed late in disease evolution, they present with a range of comorbid conditions, such as cardiovascular disease, diabetes, hypertension, and sleep apnea. It is important that patients are screened carefully at diagnosis (and thereafter), for common associated complications, and that biochemical control does not become the only treatment goal. Mortality and morbidities in acromegaly can be reduced successfully if patients are treated using a multimodal approach with comprehensive comorbidity management.

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Growth hormone- secreting pituitary adenomas: from molecular basis to treatment options in acromegaly

Cited by 9 publications

References 116 publications

DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

DAPT, a γ-Secretase Inhibitor, Suppresses Tumorigenesis, and Progression of Growth Hormone-Producing Adenomas by Targeting Notch Signaling

The Clinicopathological Spectrum of Acromegaly

Challenges in the diagnosis and management of acromegaly: a focus on comorbidities

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