Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling.
; KROONEN, Jérôme ; Di Valentin, Emmanuel et al
in Neuro-oncology (2014)
BACKGROUND: Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from ... [more ▼]
BACKGROUND: Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. METHOD: In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. RESULTS: We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results. CONCLUSION: Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion. [less ▲]Detailed reference viewed: 22 (5 ULg)
Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocampal sclerosis
CREVECOEUR, Julie ; ; Rogister, Bernard et al
in Neuropathology & Applied Neurobiology (2014), 40(2), 191-204Detailed reference viewed: 39 (26 ULg)
Glioblastoma-Initiating Cells: Relationship with Neural Stem Cells and the Micro-Environment
Goffart, Nicolas ; KROONEN, Jérôme
in Cancers (2013)
Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a ... [more ▼]
Glioblastoma multiforme (GBM, WHO grade IV) is the most common and lethal subtype of primary brain tumor with a median overall survival of 15 months from the time of diagnosis. The presence in GBM of a cancer population displaying neural stem cell (NSC) properties as well as tumor-initiating abilities and resistance to current therapies suggests that these glioblastoma-initiating cells (GICs) play a central role in tumor development and are closely related to NSCs. However, it is nowadays still unclear whether GICs derive from NSCs, neural progenitor cells or differentiated cells such as astrocytes or oligodendrocytes. On the other hand, NSCs are located in specific regions of the adult brain called neurogenic niches that have been shown to control critical stem cell properties, to nourish NSCs and to support their self-renewal. This “seed-and-soil” relationship has also been adapted to cancer stem cell research as GICs also require a specific micro-environment to maintain their “stem cell” properties. In this review, we will discuss the controversies surrounding the origin and the identification of GBM stem cells and highlight the micro-environment impact on their biology. [less ▲]Detailed reference viewed: 11 (0 ULg)
Glioblastoma-initiating cells: relationship with neural stem cells and the micro-environement
Goffart, Nicolas ; KROONEN, Jérôme ; Rogister, Bernard
in Cancers (2013), 5(3), 1049-1071Detailed reference viewed: 16 (3 ULg)
Casein kinase 2 inhibition modulates the DNA damage response but fails to radiosensitize malignant glioma cells.
KROONEN, Jérôme ; Artesi, Maria ; CAPRARO, Valérie et al
in International Journal of Oncology (2012), 41(2), 776-82
Inhibitors of casein kinase 2 (CK2), a regulator of cell proliferation and mediator of the DNA damage response, are being evaluated in clinical trials for the treatment of cancers. Apigenin was capable of ... [more ▼]
Inhibitors of casein kinase 2 (CK2), a regulator of cell proliferation and mediator of the DNA damage response, are being evaluated in clinical trials for the treatment of cancers. Apigenin was capable of inhibiting the activation of CK2 following gamma irradiation in LN18 and U87 malignant glioma cells. Apigenin and siRNA-mediated CK2 protein depletion further inhibited NF-kappaB activation and altered the Tyr68 phosphorylation of Chk2 kinase, a DNA damage response checkpoint kinase, following irradiation. However, CK2 inhibition did not decrease the ability of these glioma cells to repair double-strand DNA breaks, as assessed by COMET assays and gamma-H2Ax staining. Likewise, apigenin and siRNA-induced depletion of CK2 failed to sensitize glioma cells to the cytotoxic effect of 2 to 10 G-rays of gamma irradiation, as assessed by clonogenic assays. These results contrast with those found in other cancer types, and urge to prudence regarding the inclusion of malignant glioma patients in clinical trials that assess the radiosensitizing role of CK2 inhibitors in solid cancers. [less ▲]Detailed reference viewed: 15 (5 ULg)
Multifocal choroid plexus papilloma: a case report.
; Scholtes, Félix ; Robe, Pierre et al
in Clinical neuropathology (2012), 31(6), 430-4
BACKGROUND: Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been ... [more ▼]
BACKGROUND: Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been reported as synchronous tumors. CASE REPORT: Three synchronous CPPs were resected in a 59-year-old female 6 years after their first imaging description. Pathology showed mucus-producing CPP in all 3, 1 of the 3 presenting some signs of atypia. No p53 or hSNF5/INI1 mutation, or signs of polyoma viruses infection were found. CONCLUSION: Although no clear cause for the multifocality was found, the simultaneous presence of the three tumors and their benign histology suggest that they were synchronous and not metastatic. The issue of differentiating synchronous CPPs from metastatic CPP is discussed. [less ▲]Detailed reference viewed: 24 (4 ULg)
Les cellules initiatrices de glioblastome: étude de leur caractère "souche" et de leur relations avec les zones neurogéniques adultes
Doctoral thesis (2011)Detailed reference viewed: 9 (0 ULg)
Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection.
Kroonen, Jérôme ; Nassen, Jessica ; et al
in International Journal of Cancer = Journal International du Cancer (2011), 129(3), 574-585
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs ... [more ▼]
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs following xenograft in the caudate putamen of immunodeficient mice.In patients with glioblastoma multiforme, recurrence is the rule despite continuous advances in surgery, radiotherapy and chemotherapy. Within these malignant gliomas, glioblastoma stem cells or initiating cells have been recently described and they were shown to be specifically involved in experimental tumorigenesis. In this study, we show that some human glioblastoma cells injected into the striatum of immunodeficient nude mice exhibit a tropism for the subventricular zones. There and similarily to neurogenic stem cells, these subventricular glioblastoma cells were then able to migrate towards the olfactory bulbs. Finally, the glioblastoma cells isolated from the adult mouse subventricular zones and olfactory bulbs display high tumorigenicity when secondary injected in a new mouse brain. Together, these data suggest that neurogenic zones could be a reservoir for particular cancer-initiating cells. [less ▲]Detailed reference viewed: 70 (28 ULg)
Les glioblastomes, un exemple de recherche translationnelle?
Kroonen, Jérôme ; Nguyen-Khac, Minh-Tuan ; Deprez, Manuel et al
in Revue Médicale de Liège (2008), 63(5-6), 251-6
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most ... [more ▼]
Among patients which develop glioblastoma multiform (GBM), recurrence is the rule despite continuous progress in surgery, radiotherapy and chemotherapy. In the adult, GBM is the most frequent and most aggressive tumour of the Central Nervous System. A better understanding of the mechanisms by which these tumours relapse could promote the use of preventive therapy and could increase patients' survival. GBM stem cells have been recently described and it was demonstrated that they are specifically implied in the experimental tumorigenesis. It is thus very attractive to speculate on a possible relationship between these GBM stem cells and the neural stem cells which are persisting in the neurogenic zones of the adult brain. In this review, we formulate and discuss the hypothesis by which, in a patient with GBM, malignant stem cells might be present in the neurogenic zones, away from the tumour mass. This hypothesis could explain the tumour relapse observed after the first treatments. [less ▲]Detailed reference viewed: 146 (49 ULg)