A Postnatal Pax7 Progenitor Gives Rise to Pituitary Adenomas.
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ABSTRACT:
SUBMITTER: Hosoyama T
PROVIDER: S-EPMC2930793 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Wingless (Wnt)/?-catenin signaling plays an essential role during normal development, is a critical regulator of stem cells, and has been associated with cancer in many tissues. Here we demonstrate that genetic expression of a degradation-resistant mutant form of ?-catenin in early Rathke's pouch (RP) progenitors leads to pituitary hyperplasia and severe disruption of the pituitary-specific transcription factor 1-lineage differentiation resulting in extreme growth retardation and hypopituitarism. Mutant mice mostly die perinatally, but those that survive weaning develop lethal pituitary tumors, which closely resemble human adamantinomatous craniopharyngioma, an epithelial tumor associated with mutations in the human ?-catenin gene. The tumorigenic effect of mutant ?-catenin is observed only when expressed in undifferentiated RP progenitors, but tumors do not form when committed or differentiated cells are targeted to express this protein. Analysis of affected pituitaries indicates that expression of mutant ?-catenin leads to a significant increase in the total numbers of pituitary progenitor/stem cells as well as in their proliferation potential. Our findings provide insights into the role of the Wnt pathway in normal pituitary development and demonstrate a causative role for mutated ?-catenin in an undifferentiated RP progenitor in the genesis of murine and human craniopharyngioma.
| S-EPMC3136310 | biostudies-literature
Project description:Severe liver diseases are characterized by expansion of liver progenitor cells (LPC), which correlates with disease severity. However, the origin and role of LPC in liver physiology and in hepatic injury remains a contentious topic. We found that ductular reaction cells in human cirrhotic livers express hepatocyte nuclear factor 1 homeobox B (HNF1?). However, HNF1? expression was not present in newly generated epithelial cell adhesion molecule (EpCAM)-positive hepatocytes. In order to investigate the role of HNF1?-expressing cells we used a tamoxifen-inducible Hnf1?CreER/R26R(Yfp/LacZ) mouse to lineage-trace Hnf1?(+) biliary duct cells and to assess their contribution to LPC expansion and hepatocyte generation. Lineage tracing demonstrated no contribution of HNF1?(+) cells to hepatocytes during liver homeostasis in healthy mice or after loss of liver mass. After acute acetaminophen or carbon tetrachloride injury no contribution of HNF1?(+) cells to hepatocyte was detected. We next assessed the contribution of Hnf1?(+) -derived cells following two liver injury models with LPC expansion, a diethoxycarbonyl-1,4-dihydro-collidin (DDC)-diet and a choline-deficient ethionine-supplemented (CDE)-diet. The contribution of Hnf1?(+) cells to liver regeneration was dependent on the liver injury model. While no contribution was observed after DDC-diet treatment, mice fed with a CDE-diet showed a small population of hepatocytes derived from Hnf1?(+) cells that were expanded to 1.86% of total hepatocytes after injury recovery. Genome-wide expression profile of Hnf1?(+) -derived cells from the DDC and CDE models indicated that no contribution of LPC to hepatocytes was associated with LPC expression of genes related to telomere maintenance, inflammation, and chemokine signaling pathways.HNF1?(+) biliary duct cells are the origin of LPC. HNF1?(+) cells do not contribute to hepatocyte turnover in the healthy liver, but after certain liver injury, they can differentiate to hepatocytes contributing to liver regeneration.
| S-EPMC4410184 | biostudies-literature
Project description:PurposeRecent 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.MethodsThe expression of GFRα2 and other members of the GFR receptor family (GFRα1, α3, α4) 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.ResultsGFRα2 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, GFRα2 was significantly over-expressed (~5-fold) in the gonadotropinoma subtype only (p < 0.05). GFRα2 protein expression appeared to be higher in most NFAs, although there was heterogeneity in protein expression in this group. GFRα2 protein expression appeared consistently lower in functioning adenomas by IHC and western blot. In normal pituitary, GFRα2 was localized in Rathke's remnant, the putative pituitary stem cell niche, and in corticotropes.ConclusionOur results suggest that the pituitary stem cell marker GFRα2 is under-expressed in functioning adenomas and over-expressed in NFAs, specifically gonadotropinomas. Further studies are required to elucidate whether over-expression of GFRα2 in gonadotropinomas might play a role in pituitary tumorigenesis.
| S-EPMC4090297 | biostudies-literature
Project description:We investigate chromosome organization within the nucleus using polymer models whose formulation is closely guided by experiments in live yeast cells. We employ bead-spring chromosome models together with loop formation within the chains and the presence of nuclear bodies to quantify the extent to which these mechanisms shape the topological landscape in the interphase nucleus. By investigating the genome as a dynamical system, we show that domains of high chromosomal interactions can arise solely from the polymeric nature of the chromosome arms due to entropic interactions and nuclear confinement. In this view, the role of bio-chemical related processes is to modulate and extend the duration of the interacting domains.
| S-EPMC4937343 | biostudies-literature
Project description:The genetic landscape of pituitary adenomas (PAs) is diverse and many of the identified cases remain of unclear pathogenetic mechanism. Germline genetic defects account for a small percentage of all patients and may present in the context of relevant family history. Defects in AIP (mutated in Familial Isolated Pituitary Adenoma syndrome or FIPA), MEN1 (coding for menin, mutated in Multiple Endocrine Neoplasia type 1 or MEN 1), PRKAR1A (mutated in Carney complex), GPR101 (involved in X-Linked Acrogigantism or X-LAG), and SDHx (mutated in the so called "3 P association" of PAs with pheochromocytomas and paragangliomas or 3PAs) account for the most common familial syndromes associated with PAs. Tumor genetic defects in USP8, GNAS, USP48 and BRAF are some of the commonly encountered tissue-specific changes and may explain a larger percentage of the developed tumors. Somatic (at the tumor level) genomic changes, copy number variations (CNVs), epigenetic modifications, and differential expression of miRNAs, add to the variable genetic background of PAs.
| S-EPMC7019860 | biostudies-literature
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.
| S-EPMC10526513 | biostudies-literature
Project description:ObjectivePituitary adenoma surgery has evolved rapidly in recent decades. This study aims to determine current practice across a wide range of European neurosurgical centers.MethodsA list of eligible departments performing pituitary adenoma surgery was created. The survey consisted of 58 questions. For analysis, the departments were divided into four subgroups: academic/nonacademic, high-volume/low-volume, "mainly endoscopic/mainly microscopic practice," and geographical regions.ResultsData from 254 departments from 34 countries were obtained. In 108 centers (42.5%), <30 pituitary adenomas were operated per year. Twenty (7.9%) centers performed >100 adenoma surgeries per year. Number of neurosurgeons performing endonasal surgeries are as follows: 1 in 24.9% of centers and 2 in 49.8% of centers. All residents assisted endonasal surgeries in 126 centers (49.8%). In 28 centers (21.1%), all residents performed endonasal surgery under supervision during residency. In 141 centers (56.8%), the endoscopic approach was used in >90% of the surgeries. Regular pituitary board (either weekly or once a month) meetings were held in 147 centers (56.3%). Nonfunctioning adenomas represent >70% of pituitary caseload in 149 centers (58.7%).ConclusionsIn our survey, most centers perform less than 100 surgeries for pituitary adenomas. In most centers, pituitary surgeries are performed by one or two neurosurgeons. Residents have a limited exposure to this type of surgery, and the formal pituitary board is not a standard. Nonfunctioning adenomas make up most of surgically treated adenomas. This study can serve as a benchmark for further analyses of pituitary adenoma centers in Europe.
| S-EPMC9017568 | biostudies-literature
Project description:IntroductionAngiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.Materials and methods219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice.Results71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice.ConclusionHuman pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.
| S-EPMC9117625 | biostudies-literature
Project description:Background Pituitary apoplexy after resection of giant pituitary adenomas is a rare but often cited morbidity associated with devastating outcomes. It presents as hemorrhage and/or infarction of residual tumor in the postoperative period. Because of its rarity, its incidence and consequences remain ill defined. Objective The aim of this study is to estimate the rate of postoperative pituitary apoplexy after resection of giant pituitary adenomas and assess the morbidity and mortality associated with apoplexy. Methods A systematic review of literature was performed to examine extent of resection in giant pituitary adenomas based on surgical approach, rate of postoperative apoplexy, morbidities, and mortality. Advantages and disadvantages of each approach were compared. Results Seventeen studies were included in quantitative analysis describing 1,031 cases of resection of giant pituitary adenomas. The overall rate of subtotal resection (<90%) for all surgical approaches combined was 35.6% (95% confidence interval: 28.0-43.1). Postoperative pituitary apoplexy developed in 5.65% ( n = 19) of subtotal resections, often within 24 hours and with a mortality of 42.1% ( n = 8). Resulting morbidities included visual deficits, altered consciousness, cranial nerve palsies, and convulsions. Conclusion Postoperative pituitary apoplexy is uncommon but is associated with high rates of morbidity and mortality in subtotal resection cases. These findings highlight the importance in achieving a maximal resection in a time sensitive fashion to mitigate the severe consequences of postoperative apoplexy.
| S-EPMC9272256 | biostudies-literature
Project description: Not available
| S-EPMC7761748 | biostudies-literature