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

Invasion, angiogenèse et thérapies anti-angiogéniques des glioblastomes

PARIS12-CRETEIL BU Multidisc. (940282102) / SudocSudocFranceF

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

TL-dating applied to building archaeology: The case of the medieval church Notre-Dame-Sous-Terre (Mont-Saint-Michel, France)

The recent application of thermoluminescence (TL) dating to young building materials is being increasingly developed for use in the field of buildings archaeology. Ensuring the accuracy of the dating method is of the utmost importance in order to achieve results which are pertinent enough to have archaeological significance. This paper deals with an archaeological building study of the first church built on the Mont-Saint-Michel (France) and improvements made to the TL-protocol in Bordeaux. The aim is to achieve precise dates for the material under analysis and therefore, a better understanding of the evolution of the building. For this study, 14 bricks have been sampled from eight different masonries and submitted for TL dating analysis. With the exception of one sample which appears to be non-contemporaneous to the others, the date results range from 900 ± 80 to 1020 ± 60 AD. The results were then averaged according to the two phases established by the archaeological building study. The first two stages of the primitive church both date from the 10th century