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Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior.

ABSTRACT: Objective: Epidermal growth factor receptor (EGFR) has been found to localize in several human neoplasms and has been shown to have a significant correlation with adenomaigenesis and patient prognosis. EGFR is also overexpressed in pituitary corticotroph adenomas. However, its clinical significance and relationship with tumor behavior, especially tumor recurrence status, remain obscure. The purpose of the present study was to identify the expression patterns of EGFR and its downstream signaling pathway molecules in pituitary corticotroph adenomas and to investigate the association of EGFR with clinicopathological characteristics and tumor recurrence. Methods: Fifty-two sporadic pituitary adenoma specimens and six normal pituitary glands were collected. The expression levels of EGFR and its downstream signaling molecules in each sample were evaluated and quantified using immunohistochemistry and Western blot. The relationships of EGFR expression with clinicopathological characteristics and tumor recurrence status were analyzed. Results: EGFR was overexpressed in 55.8% of the pituitary corticotroph adenomas and in 1 of 6 of the normal adenohypophysial tissues. The expression degree was significantly higher in pituitary corticotroph adenomas than in normal adenohypophysial tissues. In EGFR-overexpressing adenomas, the downstream pathway phosphorylated Erk (p-Erk) was also significantly activated. Moreover, the expression levels of EGFR were positively correlated with the adrenocorticotropic hormone (ACTH) and cortisol levels but were not correlated with age, sex or symptom duration. The expression levels of EGFR, phosphorylated EGFR (p-EGFR) and p-Erk were significantly up-regulated in the recurrent adenoma group compared with those in the non-recurrent adenoma group (all p < 0.05). The expression levels of EGFR were strongly correlated with the recurrence-free interval (p = 0.005, CC = -0.31). Conclusion: The expression levels of EGFR and its downstream pathway components were significantly increased in pituitary corticotroph adenomas compared to the levels in normal adenohypophysial tissues. EGFR expression levels were positively associated with the ACTH and cortisol levels and with tumor recurrence status. Pituitary corticotroph adenomas with high EGFR expression levels were correlated with an increased recurrence rate and a decreased recurrence-free interval. EGFR could be used as a promising biomarker for predicting pituitary corticotroph tumor recurrence.

SUBMITTER: Liu X

PROVIDER: S-EPMC6867968 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior.

Liu Xiaohai X Feng Ming M Dai Congxin C Bao Xinjie X Deng Kan K Yao Yong Y Wang Renzhi R

Frontiers in endocrinology 20191114

<b>Objective:</b> Epidermal growth factor receptor (EGFR) has been found to localize in several human neoplasms and has been shown to have a significant correlation with adenomaigenesis and patient prognosis. EGFR is also overexpressed in pituitary corticotroph adenomas. However, its clinical significance and relationship with tumor behavior, especially tumor recurrence status, remain obscure. The purpose of the present study was to identify the expression patterns of EGFR and its downstream sig ...[more]

PMID: 31798535

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Project description:Background and aimAbout a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.MethodsWe performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.ResultsEighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.ConclusionsPD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.

Project description:Stress-related illness represents a major burden on health and society. Sex differences in stress-related disorders are well documented, with women having twice the lifetime rate of depression compared to men and most anxiety disorders. Anterior pituitary corticotrophs are central components of the hypothalamic-pituitary-adrenal (HPA) axis, receiving input from hypothalamic neuropeptides corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), while regulating glucocorticoid output from the adrenal cortex. The dynamic control of electrical excitability by CRH/AVP and glucocorticoids is critical for corticotroph function; however, whether corticotrophs contribute to sexually differential responses of the HPA axis, which might underlie differences in stress-related disorders, is very poorly understood. Using perforated patch clamp electrophysiology in corticotrophs from mice expressing green fluorescent protein under the control of the Pomc promoter, we characterized basal and secretagogue-evoked excitability. Both male and female corticotrophs show predominantly single-spike action potentials under basal conditions; however, males predominantly display spikes with small-amplitude (<20 mV) afterhyperpolarizations (B-type), whereas females displayed a mixture of B-type spikes and spikes with a large-amplitude (>25 mV) afterhyperpolarization (A-type). In response to CRH, or CRH/AVP, male cells almost exclusively transition to a predominantly pseudo-plateau bursting, whereas only female B-type cells display bursting in response to CRH±AVP. Treatment of male or female corticotrophs with 1 nM estradiol (E2) for 24-72 h has no effect on the proportion of cells with A- or B-type spikes in either sex. However, E2 results in the cessation of CRH-induced bursting in both male and female corticotrophs, which can be partially reversed by adding a BK current using a dynamic clamp. RNA-seq analysis of purified corticotrophs reveals extensive differential gene expression at the transcriptional level, including more than 71 mRNAs encoding ion channel subunits. Interestingly, there is a two-fold lower level (p < 0.01) of BK channel pore-forming subunit (Kcnma1) expression in females compared to males, which may partially explain the decrease in CRH-induced bursting. This study identified sex differences at the level of the anterior pituitary corticotroph ion channel landscape and control of both spontaneous and CRH-evoked excitability. Determining the mechanisms of sex differences of corticotroph and HPA activity at the cellular level could be an important step for better understanding, diagnosing, and treating stress-related disorders.

Dataset Information

Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior.

Publications

Expression of EGFR in Pituitary Corticotroph Adenomas and Its Relationship With Tumor Behavior.

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