Isolation of tumour stem-like cells from benign tumours

Xu, Qijin; Yuan, Xiangpeng; Tunici, Patrizia; Liu, G; Fan, Xuemo; Xu, Minlin; Hu, Jinwei; Hwang, Joonsung; Farkas, Daniel L.; Black, Keith L.; Yu, John S.

doi:10.1038/sj.bjc.6605142

Cited by 108 publications

(134 citation statements)

References 45 publications

(60 reference statements)

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“…In the present study, only NOTCH4, DLL1, and NESTIN were found to be overexpressed, with NOTCH4 and DLL1 being upregulated only in the total SP and not in the pSP. Moreover, expression levels of the multidrug transporter genes BCRP1 (ABCG2) and MDR1 (ABCB1) have been reported not to be upregulated in the PASCs (Xu et al 2009b). These divergent results could be mainly explained by the use of cultured cells (Xu et al 2009b) versus cells that were obtained directly from the tumor (the present study; further commented on in Vankelecom (2012) and Vankelecom & Chen (2014)).…”

Section: Discussioncontrasting

confidence: 41%

“…Moreover, CXCR4 and PI3K/Akt are interconnected; it has been shown that the paracrine/autocrine activation of CXCR4 signaling provokes the Akt-mediated improvement in survival of glioblastoma CSCs (Rubin et al 2003, Gatti et al 2013. It should be noted that the expression pattern in the pSP only minimally overlaps with the set of genes (CD133, NESTIN, CD90/THY1, OCT4, MSI, JAG2, NOTCH4, and DLL1) that have recently been identified as being upregulated in candidate pituitary TSCs (so-called 'pituitary adenoma stem-like cells' (PASCs)), which were obtained by culture of sphere-like bodies (Xu et al 2009b). In the present study, only NOTCH4, DLL1, and NESTIN were found to be overexpressed, with NOTCH4 and DLL1 being upregulated only in the total SP and not in the pSP.…”

Section: Discussionmentioning

confidence: 99%

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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: Discussioncontrasting

confidence: 41%

Section: Discussionmentioning

confidence: 99%

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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“…Xu et al (2009) reported the isolation of putative tumor-initiating cells from human pituitary adenomas. These clones were able to self-renew, had a differentiation potential for multiple pituitary cell lineages, expressed several stem/ progenitor-associated marker genes and initiated pituitary tumor formation after transplantation into immunodeficient mice.…”

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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“…TICs were initially identified in acute myeloid leukaemia (AML), and were found capable of inducing AML in immunodeficient mice (Lapidot et al, 1994;Bonnet and Dick, 1997). TICs have since been identified in numerous other tumours, including melanoma, lung, head, neck, pancreatic, prostate, colon, squamous cell cancers, and benign tumours (Collins et al, 2005;Fang et al, 2005;Kim et al, 2005;Dalerba et al, 2007;Prince et al, 2007;Loebinger et al, 2008;Xu et al, 2009). Although the AML TICs resemble and probably originate from the transformation of a stem cell, it is possible that other TICs originate from transformation of early or late progenitor cells.…”

mentioning

confidence: 99%

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

et al. 2009

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BACKGROUND: The hypothesis that malignant tumours are generated by rare populations of cancer stem cells that are more tumourigenic than other cancer cells has gained increasing credence. The objective of this study was to identify and characterise a subpopulation of human sarcoma-initiating cells. METHODS: We examined established rhabdomyosarcoma cell lines by flow cytometry. Tumourigenesis was examined by xenograft models. Real-time PCR and immunohistochemistry were performed to examine the gene expression using cell lines and biopsy specimens. RESULTS: Rhabdomyosarcoma cell lines included small populations of fibroblast growth factor receptor 3 (FGFR3)-positive cells. FGFR3-positive KYM-1 and RD cells were more strongly tumourigenic than FGFR3-negative cells. In addition, xenoengraftment of 33% of single FGFR3-positive KYM-1 cells yielded tumour formation. Stem cell properties of FGFR3-positive cells were further established by real-time PCR, which demonstrated upregulation of undifferentiated cell markers and downregulation of differentiation markers. We showed that in the absence of serum, addition of basic fibroblast growth factor maintained and enriched FGFR3-positive cells. On the other hand, ciliary neurotrophic factor reduced the proportion of FGFR3-positive cells. Real-time PCR and immunohistochemical examination revealed that embryonal rhabdomyosarcoma patient biopsy specimens were found to overexpress FGFR3. CONCLUSIONS: Our findings suggest that rhabdomyosarcoma cell lines include a minor subpopulation of FGFR3-positive sarcomainitiating cells, which can be maintained indefinitely in culture and which is crucial for their malignancy.

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Isolation of tumour stem-like cells from benign tumours

Cited by 108 publications

References 45 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 role of proto-oncogene GLI1 in pituitary adenoma formation and cell survival regulation

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

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