Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas

BACKGROUND: Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a non-destructive way that suggests cooperation between glioma cells and their environment. Recent studies using an engineered rodent C6 tumor cell line have pointed to mechanisms of invasion that involved gap junctional communication (GJC), with connexin 43 as a substrate. We explored whether this concept may have clinical relevance by analyzing the participation of GJC in human glioblastoma invasion. RESULTS: Three complementary in vitro assays were used: (i) seeding on collagen IV, to analyze homocellular interactions between tumor cells (ii) co-cultures with astrocytes, to study glioblastoma/astrocytes relationships and (iii) implantation into organotypic brain slice cultures, that mimic the three-dimensional parenchymal environment. Carbenoxolone, a potent blocker of GJC, inhibited cell migration in the two latter models. It paradoxically increased it in the first one. These results showed that homocellular interaction between tumor cells supports intercellular adhesion, whereas heterocellular glioblastoma/astrocytes interactions through functional GJC conversely support tumor cell migration. As demonstrated for the rodent cell line, connexin 43 may be responsible for this heterocellular functional coupling. Its levels of expression, high in astrocytes, correlated positively with invasiveness in biopsied tumors. CONCLUSIONS: our results underscore the potential clinical relevance of the concept put forward by other authors based on experiments with a rodent cell line, that glioblastoma cells use astrocytes as a substrate for their migration by subverting communication through connexin 43-dependent gap junctions

Thérapies innovantes des glioblastomes

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Les tumeurs du tronc cérébral de l'adulte atteint de neurofibromatose de type 1

CAEN-BU Médecine pharmacie (141182102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Pseudotumoral brain lesions: MRI review

International audienceSingle or multiple space-occupying lesions on brain MRI, with or without contrast enhancement and/or perilesional oedema, evoke a neoplastic origin. However, a multitude of non-neoplastic disorders can simulate cerebral neoplasia. In this review, we will discuss the MRI characteristics of non-neoplastic disorders that can mimic cerebral neoplasia. Distinguishing MRI characteristics are discussed for each of these non-neoplastic disorders

MRI assessment of hemodynamic effects of angiopoietin-2 overexpression in a brain tumor model

Despite treatment efforts, the median survival in patients with glioblastoma multiforme, the most aggressive form of glioma, does not extend beyond 12–15 months. One of the major pathophysiological characteristics of these tumors is their ability to induce active angiogenesis. Thus, based on the lack of efficient therapies, agents that inhibit angiogenesis are particularly attractive as a therapeutic option. However, it has been recently proposed that although specifically targeting vascular endothelial growth factor, the main angiogenic factor, certainly leads to significant tumor regression, it could also be followed by tumor relapses. In this case, angiogenesis is driven by alternate pathways that include other angiogenic factors. One possible strategy to overcome this therapeutic obstacle is to overexpress antivascular factors such as angiopoietin-2 (Ang2). Here, by using MRI and histological analysis, we studied the vascular events involved in glioma growth impairment induced by Ang2 overexpression. Our results show that an increase in Ang2 expression, during the tumor growth, leads to a significant decrease in tumor growth (~86%) along with an increase in the survival median (~70%) but does not modify the tumor vascular area or cerebral blood volume. However, tumor Ang2-derived blood vessels display an abnormal, enlarged morphology. We show that the presence of Ang2 leads to an enhancement of tumor perfusion and a decrease in tumor vessel permeability. Based on our MR image evaluations of hemodynamic tumor vessel changes, we propose that Ang2-derived tumor vessels lead to an inadequate oxygenation of the tumor tissue, leading to impairment in tumor growth

Comparison between MRI-derived ADC maps and 18FLT-PET in pre-operative glioblastoma

CERVOXY/LDM TEPInternational audienc

Arrêt soudain des médicaments spécifiques de la démence au stade modéré à sévère de la maladie d’Alzheimer en institution : étude pilote longitudinale descriptive

Contexte. Les modalités d’arrêt des médicaments spécifiques de la démence (MSD) ne font pas l’objet d’un consensus. Objectifs. Les objectifs de l’étude étaient de : décrire i) les motifs et modalités d’arrêt des MSD des patients traités en Établissement Hospitalier pour Personnes âgées Dépendantes (EHPAD), ii) la sécurité d’emploi d’un arrêt brutal, iii) et l’évolution des troubles. Méthodes. Nous avons étudié des sujets atteints de la maladie d’Alzheimer à un stade modéré à sévère, vivants en institution et traités depuis au moins 1 an par rivastigmine, donépézil, galantamine et/ou mémantine. Sur décision pluridisciplinaire selon les recommandations de la Haute autorité de santé (HAS), les traitements MSD ont été arrêtés soudainement ou poursuivis. Les critères de jugement suivants ont été recueillis prospectivement sur six mois : les motifs d’arrêt, les données de sécurité, le score mini-mental state examination (MMSE), les troubles psycho-comportementaux et la prescription concomitante de psychotropes. Résultats. Trente-trois patients ont été inclus : la réévaluation du traitement a conduit à 22 arrêts et 11 poursuites. Les motivations à l’arrêt étaient une démence trop évoluée (48 %), une absence de bénéfice thérapeutique (28 %) et un traitement psychotrope associé trop lourd (24 %). La modalité d’arrêt soudain n’a entraîné aucun syndrome de sevrage. La variation du MMSE à 6 mois était de -1,8 (SD 2,2) dans le groupe arrêt (n = 14) et -2,2 (SD 2,0) dans le groupe poursuite (n = 6). Dans le groupe « arrêt », un allègement des traitements psychotropes a été observé. Conclusion. Dans cette étude pilote réalisée en institution, la réévaluation conforme aux recommandations de la HAS a conduit à 2 arrêts sur 3 du traitement MSD. La sécurité de l’arrêt soudain des MSD reste à étudier

IDH1R132H Mutation Increases U87 Glioma Cell Sensitivity to Radiation Therapy in Hypoxia

International audienceObjective. IDH1 codon 132 mutation (mostly Arg132His) is frequently found in gliomas and is associated with longer survival. However , it is still unclear whether IDH1 mutation renders the cell more vulnerable to current treatment , radio-and chemotherapy. Materials and Methods. We transduced U87 with wild type IDH1 or IDH1^R132H expressing lentivirus and analyzed the radiosensitivity (dose ranging 0 to 10 Gy) under normoxia (20% O2) and moderate hypoxia (1% O2). Results. We observed that IDH1^R132H U87 cells grow faster in hypoxia and were more sensitive to radiotherapy (in terms of cell mortality and colony formation assay) compared to nontransduced U87 and IDH1^ωt cells. This effect was not observed in normoxia. Conclusion. These data suggest that IDH1^R132H mutation increases radiosensitivity in mild hypoxic conditions

Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma

Angiogenesis inhibitors appear to be promising therapies for highly vascularized tumors such as glioblastoma multiforme (GBM). Sunitinib is an oral multitargeted tyrosine kinase inhibitor with both antiangiogenic and antitumor activities due to selective inhibition of various receptor tyrosine kinases, including those important for angiogenesis (vascular endothelial growth factor receptors and platelet-derived growth factor receptors). Here we evaluated the antitumor activities of sunitinib on orthotopic models of GBM in vitro and in vivo. Sunitinib potently inhibited angiogenesis that was stimulated by implantation of U87MG and GL15 cells into organotypic brain slices at concentrations as low as 10 nM. At high dose (10 μM), sunitinib induced direct antiproliferative and proapoptotic effects on GL15 cells and decreased invasion of these cells implanted into brain slices by 49% (p < 0.001). Treatment was associated with decreases in Src (35%) and focal adhesion kinase (44%) phosphorylation. However, anti-invasive activity was not observed in vivo at the highest dose level utilized (80 mg/kg per day). Survival experiments involving athymic mice bearing intracerebral U87MG GBM demonstrated that oral administration of 80 mg/kg sunitinib (five days on, two days off) improved median survival by 36% (p < 0.0001). Sunitinib treatment caused a 74% reduction in microvessel density (p < 0.05), an increase in tumor necrosis, and a decrease in number of GBM cells positive for MIB antibody. Sunitinib exhibited potent antiangiogenic activity that was associated with a meaningful prolongation of survival of mice bearing intracerebral GBM. These data support the potential utility of sunitinib in the treatment of GBM