Identification of CD133+ Cells in Pituitary Adenomas

Yunoue, Shunji; Arita, Kazunori; Kawano, Hiroto; Uchida, Hiroyuki; Tokimura, Hiroshi; Hirano, Hirofumi

doi:10.1159/000330625

Cited by 27 publications

(47 citation statements)

References 68 publications

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“…The endothelial-type SP cells of the pituitary tumors may represent a progenitor phenotype that drives angiogenesis during tumor expansion. The presence of endothelial progenitor cells in pituitary adenomas has indeed been suggested based on the detection of CD133, CD34, NESTIN, and VEGFR2 in non-hormonal and non-folliculostellate cells of the tumors (Yunoue et al 2011). Notably, the expression picture that was distilled from the total adenoma SP was found to be largely reconfirmed in the purified CD31 K /CD45 K SP (pSP).…”

Section: Discussionmentioning

confidence: 93%

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Mertens

Gremeaux

Chen

et al. 2015

Endocrine-Related Cancer

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Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express 'tumor stemness' markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self-renewing sphere-forming cells, considered to be a property of TSCs. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP 'main population'. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFb had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2 K/K ) mice that bear prolactinomas contain more pSP, Sox2C , and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. The present

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Section: Discussionmentioning

confidence: 93%

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Mertens

Gremeaux

Chen

et al. 2015

Endocrine-Related Cancer

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“…A subset of tumors that are non-functional or do not secrete hormones are termed null cell (NC) adenomas [2]. While the multicellular milieu and hormonal subtypes of these tumors contribute to intra- and intertumoral heterogeneity, respectively, the initiation and maintenance of human PAs remains poorly understood [3, 19, 35, 36]. …”

Section: Introductionmentioning

confidence: 99%

The identification of human pituitary adenoma-initiating cells

Manoranjan

Mahendram

Almenawer

et al. 2016

acta neuropathol commun

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Classified as benign central nervous system (CNS) tumors, pituitary adenomas account for 10% of diagnosed intracranial neoplasms. Although surgery is often curative, patients with invasive macroadenomas continue to experience significant morbidity and are prone to tumor recurrence. Given the identification of human brain tumor-initiating cells (TICs) that initiate and maintain tumor growth while promoting disease progression and relapse in multiple CNS tumors, we investigated whether TICs also drive the growth of human pituitary adenomas. Using a nanoString-based 80-gene custom codeset specific for developmental pathways, we identified a differential stem cell gene expression profile within human pituitary adenomas. Prospective functional characterization of stem cell properties in patient-derived adenomas representing all hormonal subtypes yielded a subtype-dependent self-renewal profile, which was enriched within the CD15+ cell fraction. The tumor-initiating capacity of CD15high adenoma cells was assayed in comparison to CD15low adenomas using in vivo limiting dilutions, which maintained the rare frequency of TICs. Repeated analyses using sorted cell populations for CD15+ TICs compared to CD15- adenoma cells provided further evidence of xenograft tumor formation to support CD15+ cells as putative pituitary adenoma-initiating cells (PAICs). The clinical utility of our findings was established through in silico analyses and comparative gene expression profiling of primary and recurrent pituitary adenomas. CD15 was enriched in recurrent adenomas, which was validated using routine clinical immunohistochemistry in a limited number of samples. Our work reports the first prospective identification of human PAICs using CD15. Patients with CD15high adenomas may therefore benefit from more aggressive surgical interventions and chemo/radiotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0394-4) contains supplementary material, which is available to authorized users.

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“…However, progenitor cells or even differentiated cells could give rise to cells fulfilling CSC criteria upon transformation (Valent et al 2012;Clevers 2011). Several groups have reported the presence of putative CSCs in human pituitary adenomas and from mouse pituitary tumour models Xu et al 2009;Donangelo et al 2014;Lloyd et al 2013;Mertens et al 2015;Orciani et al 2015;van Rijn et al 2013;Yunoue et al 2011;Hosoyama et al 2010). It remains unknown if CSCs arise from PSCs, although their properties can be similar; for example, both are capable of in vitro self-renewal and differentiation and PSCs are likely to be chemoresistant like CSCs, since PSCs are found within the 'side population' generated by dye efflux, utilising the same transporter properties as chemoresistance (Chen et al 2009).…”

Section: Stem Cells and Pituitary Tumoursmentioning

confidence: 99%

Pituitary Stem Cells During Normal Physiology and Disease

Andoniadou

2016

Stem Cells in Neuroendocrinology

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Summary The homeostatic maintenance and functional modification of tissues require a combination of regulated proliferation and differentiation by somatic stem cells and more committed progenitors. Of relevance to regenerative medicine approaches, the endogenous stimulation of cell types for replenishment of damaged tissues requires an understanding of the signals that promote proliferation and direct appropriate differentiation to specialised cell types. We recently showed that pituitary stem cells expressing the transcription factor SOX2 are able to contribute to the generation of new hormone-producing cells during postnatal life. The signals controlling proliferation in the anterior pituitary are poorly understood and little is known about the influences supporting the choices between proliferation and quiescence among stem cells. The WNT signalling pathway is a major regulator of proliferation and influences stem cells in multiple tissues throughout the body as well as cancer stem cells in tumorigenesis. Forced up-regulation of the WNT pathway specifically in SOX2-positive pituitary stem cells by transgenic approaches in mouse stimulates a transient burst of proliferation, maintaining their uncommitted phenotype. These mutated stem cells subsequently induce tumorigenesis in a non-cell autonomous manner, as they promote proliferation of surrounding cell types through the secretion of paracrine factors. The studies presented here aim to provide insights into pituitary stem cell behaviour and their possible roles during disease states."If there were no regeneration there could be no life. If everything regenerated there would be no death. All organisms exist between these two extremes." Richard J. Goss, Principles of Regeneration (1969).

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Identification of CD133+ Cells in Pituitary Adenomas

Cited by 27 publications

References 68 publications

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

Pituitary tumors contain a side population with tumor stem cell-associated characteristics

The identification of human pituitary adenoma-initiating cells

Pituitary Stem Cells During Normal Physiology and Disease

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