Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

Goffart, Nicolas; Kroonen, Jérôme; Rogister, Bernard

doi:10.3390/cancers5031049

Cited by 76 publications

(71 citation statements)

References 127 publications

(156 reference statements)

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“…Of note however, we previously observed that the activity of CK2α is modulated in malignant gliomas by the expression of connexin 30, a tumor suppressor encoded by GJB6 (20). We likewise observed here that TNF-α, as well as TGF-β1, which are secreted in the microenvironment of gliomas (21)(22)(23), can induce the activity of CK2α and might thus contribute to its hyperactivity in gliomas. These results corroborate a previous report that the activation of NF-κB in response to TNF-α stimulation depends on CK2 (9).…”

Section: Discussionsupporting

confidence: 52%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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Abstract. Casein kinase II contributes to the growth and survival of malignant gliomas and attracts increasing attention as a therapeutic target in these tumors. Several reports have suggested that this strategy might be most relevant for specific subgroups of patients, namely Verhaak's classical and TP53 wild-type tumors. Using kinase assays and microarray genetic profiling in a series of 27 proprietary fresh frozen surgical glioma samples, we showed that constitutive CK2 kinase activation is not restricted to tumors that present increased copy numbers or mRNA expression of its catalytic or regulatory subunits, and can result from a functional activation by various cytokines from the glioma microenvironment. Using corresponding primary tumor and human astrocyte cell cultures as well as glioma cell lines, we confirmed that CK2 inhibition is selectively toxic to malignant glial tumors, without any restriction to tumor class or to TP53 status. We finally showed that while the contribution of CK2 to the constitutive NF-κB hyperactivation in malignant gliomas is at best moderate, a delayed activation of NF-κB may associate with the therapeutic resistance of glioma cells to CK2 inhibition. IntroductionGlioblastomas (GBMs) are the most aggressive and prevalent type of primary brain tumors and present a dismal prognosis with a median survival of less than two years (1).Casein kinase 2 is a ubiquitous serine/threonine tetrameric kinase that consists of two catalytic subunits (α and α') and two β regulatory subunits. CK2 is frequently overexpressed or overactive in aggressive forms of solid and hematological malignancies (2,3), and contributes to the dysregulation of cell growth, invasion, survival and senescence via the β-catenin, JAK/STAT, mTOR, and NF-κB pathways (4-9). As a result, CK2 inhibitors have recently entered preliminary clinical trials for advanced solid and hematological tumors (source: ClinicalTrial.gov, accessed in December 2015).In GBMs, CSNK2A1, the gene encoding the α catalytic subunit of the kinase, is amplified in one third of the tumors, and especially in those that belong to the Verhaak's 'classical' gene expression phenotype (10). CK2 has been reported to regulate tumor-initiating cell growth, tumor cell survival, DNA repair following ionizing radiation, and apoptosis in these tumors (4,5,7,8,(11)(12)(13). As a result, CK2 inhibition with drug inhibitors or siRNA technology was shown to alter the growth, survival and migration of glioma cell lines and slow down the growth of GBMs xenografts in immunodeficient mice (9,14).Prior to translating these findings to the bedside however, it remains unclear whether CK2 hyperactivity is restricted to classical GBMs presenting a CSNK2A1 amplification or not and/or whether all malignant glial tumors are evenly likely to benefit from CK2 inhibitory strategies.This report provides evidence that CK2 kinase hyperactivity occurs in vivo in all classes of GBMs as well as in glial tumors of lower grades and histology, and can be a target independently of Verhaak's ...

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Section: Discussionsupporting

confidence: 52%

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Dubois

Willems

Nguyen-Khac

et al. 2016

International Journal of Oncology

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“…23 This "seed-and-soil" relationship has also been adapted to cancer stem cell research as GSCs also rely on specific niches to maintain their stem cell properties and ability to drive tumor growth. [24][25][26] In this line, Piccirillo et al recently showed that GSCs isolated from the human SVZ are specifically resistant to supramaximal chemotherapy doses along with differential patterns of drug response. 6 Together, these findings suggest that the SVZ environment might provide GBM cells with radio/ chemoprotective inputs and could play a determinant role in malignant brain tumor recurrence.…”

Section: Discussionmentioning

confidence: 99%

CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone

et al. 2016

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). † These authors contributed equally to the present work. AbstractBackground. Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. Method. While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure.Results. Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. Conclusion. Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse. Key wordsCXCL12 | glioblastoma | mesenchymal activation | radioresistance | subventricular zone Primary brain tumors are considered as one of the nastiest scourges faced in oncology. Their most aggressive form, glioblastoma (GBM, WHO grade IV), is also regarded as the most common and lethal subtype. 1 Patients' poor survival rates are typically correlated with unsatisfactory therapeutic strategies leading to systematic GBM relapses. 2 Trying to better

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“…Bien que l'expression ectopique du facteur de transcription Gli1 ait été associée à la prolifération et à la transformation de nombreux types cellulaires, nous montrons qu'elle peut être interprétée différemment dans le contexte de l'autorenouvellement des CSN adultes. Alors que la ZSV a été proposée comme l'origine potentielle des glioblastomes -des tumeurs cérébrales parmi les plus létales chez l'adulte -nos résultats révèlent la mise en place probable d'un mécanisme de défense du tissu cérébral dans un contexte favorable à la formation de tumeurs [18]. Enfin, nous ne pouvons …”

Section: Sonic Hedgehog Contrôle Le Devenir Des Csnunclassified

Division symétrique ou division asymétrique : Sonic Hedgehog contrôle le destin des cellules souches neurales adultes

2014

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Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment

Cited by 76 publications

References 127 publications

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

Constitutive activation of casein kinase 2 in glioblastomas: Absence of class restriction and broad therapeutic potential

CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone

Division symétrique ou division asymétrique : Sonic Hedgehog contrôle le destin des cellules souches neurales adultes

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