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Expression of the pituitary stem/progenitor marker GFR?2 in human pituitary adenomas and normal pituitary.

ABSTRACT: Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFR?2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary.The expression of GFR?2 and other members of the GFR receptor family (GFR?1, ?3, ?4) were analyzed using RT-PCR, western blot, and immunohistochemistry in 39 pituitary adenomas, 14 normal pituitary glands obtained at autopsy, and cDNA from 3 normal pituitaries obtained commercially.GFR?2 mRNA was ~2.6 fold under-expressed in functioning adenomas (p < 0.01) and ~3.5 fold over-expressed in non-functioning adenomas (NFAs) (p < 0.05) compared to normal pituitary. Among NFAs, GFR?2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only (p < 0.05). GFR?2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFR?2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFR?2 was localized in Rathke's remnant, the putative pituitary stem cell niche, and in corticotropes.Our results suggest that the pituitary stem cell marker GFR?2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over-expression of GFR?2 in gonadotropinomas might play a role in pituitary tumorigenesis.

SUBMITTER: Mathioudakis N

PROVIDER: S-EPMC4090297 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary.

Mathioudakis Nestoras N Sundaresh Ram R Larsen Alexandra A Ruff William W Schiller Jennifer J Guerrero-Cázares Hugo H Burger Peter P Salvatori Roberto R Quiñones-Hinojosa Alfredo A

Pituitary 20150201 1

<h4>Purpose</h4>Recent studies suggest that adult pituitary stem cells may play a role in pituitary tumorigenesis. We sought to explore whether the Glial cell-line derived neurotrophic factor receptor alpha 2 (GFRα2), a recently described pituitary stem/progenitor marker, might be differentially expressed in pituitary adenomas versus normal pituitary.<h4>Methods</h4>The expression of GFRα2 and other members of the GFR receptor family (GFRα1, α3, α4) were analyzed using RT-PCR, western blot, and ...[more]

PMID: 24402129

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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.

Dataset Information

Expression of the pituitary stem/progenitor marker GFR?2 in human pituitary adenomas and normal pituitary.

Publications

Expression of the pituitary stem/progenitor marker GFRα2 in human pituitary adenomas and normal pituitary.

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