Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival

Zhu, Zhe; Khan, Muhammad Amir; Weiler, Markus; Blaes, Jonas; Jestaedt, Leonie; Geibert, Madeleine; Zou, Peng; Gronych, Jan; Bernhardt, Olga; Korshunov, Andrey; Bugner, Verena; Lichter, Peter; Radlwimmer, Bernhard; Heiland, Sabine; Bendszus, Martin; Wick, Wolfgang; Liu, Hai-Kun

doi:10.1016/j.stem.2014.04.007

Cited by 112 publications

(134 citation statements)

References 37 publications

(51 reference statements)

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“…The fact that cell numbers and increments are not identical among the three populations (pSP, Sox2 C , and colonyforming) indicates that they do not fully overlap, as has also been observed previously (Chen et al 2009. Moreover, more than one (cancer) stem cell population has also been detected in other tissues and tumors (see, e.g., Zhu et al 2014). The finding that these populations expand in number may indicate that the stem cells react during tumorigenesis and that they might play a role in the pathogenic process.…”

Section: Discussionmentioning

confidence: 52%

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: 52%

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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“…Some of these targets can potentially explain the physiological effects of miR‐9. For example, the ability of miR‐9 to inhibit cell proliferation has been linked to downregulation of MTHFD2 expression in cancer cells (Selcuklu et al ., 2012) or TLX/NR2E1 in neural stem cells (Liu et al ., 2010; Zhu et al ., 2014). The regulation of CXCR4 by miR‐9 has also been invoked to explain the effect of miR‐9 on cell growth (Yu et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Several miR‐9 target genes have been described that might play a role in this context. One of the most prominent is the nuclear receptor NR2E1 (also called TLX), which is essential for the proliferation and self‐renewal of neural stem cells (NSC) and brain tumour stem cells (BTSC) (Liu et al ., 2010; Zhu et al ., 2014). Besides its role in the brain, miR‐9 also influences normal physiology and tumour development in other tissues.…”

Section: Introductionmentioning

confidence: 99%

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

et al. 2015

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SummaryPolycomb repressive complexes (PRC1 and PRC2) are epigenetic regulators that act in coordination to influence multiple cellular processes including pluripotency, differentiation, cancer and senescence. The role of PRCs in senescence can be mostly explained by their ability to repress the INK4/ARF locus. CBX7 is one of five mammalian orthologues of Drosophila Polycomb that forms part of PRC1. Despite the relevance of CBX7 for regulating senescence and pluripotency, we have a limited understanding of how the expression of CBX7 is regulated. Here we report that the miR‐9 family of microRNAs (miRNAS) downregulates the expression of CBX7. In turn, CBX7 represses miR‐9‐1 and miR‐9‐2 as part of a regulatory negative feedback loop. The miR‐9/CBX7 feedback loop is a regulatory module contributing to induction of the cyclin‐dependent kinase inhibitor (CDKI) p16INK 4a during senescence. The ability of the miR‐9 family to regulate senescence could have implications for understanding the role of miR‐9 in cancer and aging.

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“…The cytotoxicity of TMZ is related to DNA methylation and the subsequent formation of O6-methylguanine (O6-MeG), followed by cell cycle arrest at the G2/M phase [7,8]. Glioma stem cells (GSCs) have been considered to be the less differentiated populations in malignant tissues, and considered as cells responsible for the maintenance of tumor tissues, as well as for the relapse of tumors after conventional treatment [9]. GBM are among the first solid cancers, in which tumor cells with stem celllike features, such as the so-called CSCs, were identified.…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

Yang¹,

Bu²,

Xue³

et al. 2018

Oncotarget

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This study aims to investigate the efficacy and safety of intranasal granulocytemacrophage colony stimulating factor (GM-CSF) treatment rendezvousing with chemoradiotherapy for post-operative glioblastoma patients. A total of ninety-two patients were randomized into two groups: control group (n = 46), patients who received radiotherapy with concomitant and adjuvant local delivery of nimustine hydrochloride (ACNU) rendezvousing with systemic administration of temozolomide (TMZ); observation group (n = 46), patients who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy based on the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS) and adverse effects were compared between these two groups. Two patients in the control group were excluded due to grade 3 hematologic toxicity. Furthermore, the observation group was superior to the control group with regard to PFS (7.8 months vs. 6.9 months, P = 0.016) and OS (19.2 months vs. 17.1 months, P = 0.045 without adjustment for interim analyses). KPS scores was higher in the observation group than in the control group after six months (84.35 ± 8.86, 80.65 ± 7.72; t = 4.552, P = 0.036). Neutropenia and thrombocytopenia decreased in the observation group, with incidences of 8.7% and 8.7%, respectively, when compared with the control group (29.5% and 18.2%, respectively; P = 0.012); while other adverse events were similar in both groups. Most adverse events were grade I-II and resolved spontaneously. Intranasal GM-CSF enhances the efficacy of the local delivery of ACNU rendezvousing with oral TMZ chemotherapy associated with significantly improved survival and quality of life in glioblastoma patients after surgery. This therapy could relieve chemotherapy related neutropenia, and does not increase the adverse events of other aspects.www.impactjournals.com/oncotarget/

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Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival

Cited by 112 publications

References 37 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

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

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Targeting Self-Renewal in High-Grade Brain Tumors Leads to Loss of Brain Tumor Stem Cells and Prolonged Survival

Cited by 112 publications

References 37 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

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

WITHDRAWN: Intranasal GM-CSF enhances efficacy of local ACNU delivery rendezvousing with TMZ plus irradiation in glioblastoma

Contact Info

Product

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About

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16^INK^4a