Craniopharyngiomas Express Embryonic Stem Cell Markers (SOX2, OCT4, KLF4, and SOX9) as Pituitary Stem Cells but Do Not Coexpress RET/GFRA3 Receptors

García-Lavandeira, Montserrat; Sáez, Carmen; Díaz‐Rodriguez, Esther; Pérez-Romero, Sihara; Senra, Ana; Diéguez, Carlos; Japón, Miguel Á.; Álvarez, Clara V.

doi:10.1210/jc.2011-2187

Cited by 64 publications

(78 citation statements)

References 21 publications

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“…LEF1, AXIN2, PITX2) when compared to normal pituitary (Gaston-Massuet et al 2011, Gump et al 2015. In contrast, no upregulation of WNT pathway components was found in papillary craniopharyngioma (Garcia-Lavandeira et al 2012, Esheba & Hassan 2015, Goschzik et al 2017, but interestingly, expression of the stemness markers SOX2, SOX9, OCT4 and KLF4 was observed (Garcia-Lavandeira et al 2012). In a mouse model of ACP, activation of the WNT pathway by targeted expression of degradation-resistant β-catenin in SOX2 + pituitary stem cells triggered a (transient) proliferation of the latter cell population (Gaston-Massuet et al 2011, Andoniadou et al 2013.…”

Section: Dysregulation Of Wnt In Pituitary Tumorigenesismentioning

confidence: 97%

“…Pituitary tumors are classified as hormone-producing adenomas (prolactinomas, somatotropinomas, corticotropinomas, thyrotropinomas and plurihormonal adenomas) and non-functional pituitary adenomas (NFPA), which do not measurably secrete hormones (Melmed 2011). In addition, craniopharyngiomas occur in the pituitary (sellar/ parasellar) region, representing rare epithelial tumors and categorized as adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (GastonMassuet et al 2011, Garcia-Lavandeira et al 2012. Whereas ACP represents the most common pediatric tumor of the pituitary, most probably originating from (ectopic) RP remnants, papillary craniopharyngiomas occur in adults (Esheba & Hassan 2015).…”

Section: Pituitary Tumorigenesis: Stem Cell Regulation Going Awry?mentioning

confidence: 99%

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Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.

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Section: Dysregulation Of Wnt In Pituitary Tumorigenesismentioning

confidence: 97%

Section: Pituitary Tumorigenesis: Stem Cell Regulation Going Awry?mentioning

confidence: 99%

Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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“…The diagnosis considered clinical, hormonal, ophthalmological, and neural system imaging findings, as previously described (8), and it was confirmed by histopathology after surgery. Normal anterior pituitaries (nZ7), which were obtained from adults who died from natural causes and underwent routine autopsy, were chosen as control tissue considering the probable embryonic common origin of aCPs (17).…”

Section: Patientsmentioning

confidence: 99%

“…Moreover, the SHH pathway plays an important role in adult stem cell maintenance, and GLI1 expression is considered as a marker of SHH-responsive cells and as a marker of progenitor/stem cells (16). The expression of the stem cell markers, SOX2 and OCT4, has been observed in human aCPs (17).…”

Section: Introductionmentioning

confidence: 99%

Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas

Gomes

Jamra

Leal

et al. 2015

European Journal of Endocrinology

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Objectives: Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/b-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs. Design: To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/b-catenin mutations and patients outcomes. Patients and methods: In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, b-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed. Results: The aCPs presented higher mRNA expression of SHH (C400-fold change (FC); P!0.01), GLI1 (C102-FC; P!0.001), and GLI3 (C5.1-FC; P!0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P!0.01 and PZ0.02 respectively). CTNNB1/b-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (C4.3-FC; PZ0.02 and C10.2-FC; PZ0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation. Conclusions: The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/b-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.

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“…Such assumption is strengthened by the detection of a side population in human pituitary adenomas that could represent tumor-initiating cells due to the expression of multidrug transporters, oncogenes and components of several stem cell pathways (Vankelecom & Gremeaux 2010). Moreover, craniopharyngiomas arising from embryonic pituitary tissue were found to express the stem cell markers SOX2, SOX9, OCT4, KLF4 and b-catenin (Gaston-Massuet et al 2011, Andoniadou et al 2012, Garcia-Lavandeira et al 2012.…”

Section: Introductionmentioning

confidence: 99%

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Lampichler¹,

Ferrer²,

Vila³

et al. 2015

Endocrine-Related Cancer

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The Hedgehog (Hh) pathway is an important regulator of early tissue patterning and stem cell propagation. It was found to be aberrantly activated in numerous types of human cancer and might be relevant in cancer stem cells. The identification of adult stem cells in the pituitary raised the question if tumor-initiating cells and Hh signaling are involved in pituitary adenoma formation. The present study aimed at the evaluation of Hh signaling in relation to stem cell and cell cycle markers in 30 human pituitary adenomas and in cultured murine adenoma cells. Therefore, expression levels of components of the Hh pathway, stem cell marker SOX2, cell cycle regulator tumor-protein 53 (TP53), proliferation marker Ki67 (MKI67) and superoxide dismutase 1 (SOD1) were evaluated in 30 human pituitary adenomas in comparison to control tissue. Modulation of cell function and target gene expression by the inhibition and activation of the Hh pathway were studied in murine adenoma cells. We show that transcription factor glioma-associated oncogene 1 (GLI1) is overexpressed in 87% of all pituitary adenomas. The expression of GLI1 significantly correlated with that of SOX2, TP53, MKI67 and SOD1. Inhibition of GLI1 resulted in the downregulation of the above genes and severe cell death in mouse adenoma cells. On the other hand, activation of the Hh pathway increased cell viability and target gene expression. In conclusion, our findings point toward an alternative, ligand-independent Hh pathway activation with GLI1 playing a major role in the cell survival of pituitary adenoma cells.

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Craniopharyngiomas Express Embryonic Stem Cell Markers (SOX2, OCT4, KLF4, and SOX9) as Pituitary Stem Cells but Do Not Coexpress RET/GFRA3 Receptors

Cited by 64 publications

References 21 publications

Pituitary stem cell regulation: who is pulling the strings?

Pituitary stem cell regulation: who is pulling the strings?

Sonic Hedgehog pathway is upregulated in adamantinomatous craniopharyngiomas

The role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

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