Abstract
BackgroundGliomas 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.ResultsThree 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.Conclusionsour 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.
Highlights
Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a nondestructive way that suggests cooperation between glioma cells and their environment
Building up upon the concepts defined by Zhang et al (1999) and Lin et al (2002), we have explored their clinical relevance by looking at the ability of human glioblastoma cells to establish functional gap junctions with astrocytes, and at the role that such functional interaction may play in their migratory behavior
Heterocellular coupling and migration of human glioblastoma cell lines Heterocellular coupling was assessed in glioma-astrocytes co-cultures, using the dual-label technique, in which glioma cells were pre-labeled donors cells and astrocytes potential recipient cells labeled through gap-junctional diffusion of the dye
Summary
Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a nondestructive 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. Glioblastoma, the most aggressive primary brain tumor, is invariably associated with profuse and long-distance invasion of the brain parenchyma. This tumor has been defined as "intraparenchymally metastatic" [1]. Less is known about the mechanisms that underlie the migration of glioma cells among neural cells, in the brain parenchyma, despite its profuseness in the area that surrounds the tumor mass, and its major role in recurrence
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