gms | German Medical Science

Objective: In spite of improved knowledge and advanced treatments of gliomas, the overall survival rate for glioma patients remains low. Gliomas comprise significant cell heterogeneity and contain a large number of multidrug resistant phenotypes and cancer stem cells. An understanding of the molecular mechanisms of stem cell migration towards gliomas could offer new therapeutic options that are strongly needed. Therefore, we investigated the signals underlying the crosstalk between various stem cells and glioma cells and glioma tissue in vitro.

Methods: Migration of unrestricted somatic stem cells from human umbilical cord blood, murine neural stem cells and human mesenchymal stem cells from bone marrow towards glioma cells and tissue extract of gliomas was investigated in vitro using an agarose invasion assay. Antibodies and inhibitors of different cytokines and enzymes were tested for their ability to block stem cell migration. Moreover, the expression of cytokines in glioma cells and tissue extract of gliomas and of cytokine receptors in stem cells were determined.

Results: Analyzing the migrational potential of stem cells by an agarose invasion assay we found that various rat and human glioma cell lines as well as tissue extracts from human gliomas are able to attract unrestricted somatic stem cells from human umbilical cord blood, murine neural stem cells and human mesenchymal stem cells from bone marrow. An antibody specifically interfering with the bioactivity of hepatocyte growth factor (HGF) was able to reduce migration of stem cells towards glioma cells and extract from human glioblastomas significantly. Moreover, an inhibitor of Rho-kinases significantly inhibited stem cell migration. Determination of the expression of HGF in glioma cells and glioma tissue and of the HGF receptor cMet in the stem cells resulted in a good correlation between stem cell migration and HGF expression of the target and cMet expression of the migrating cell.

Conclusions: Our results demonstrate that the HGF/cMet axis plays a predominant role in attracting stem cells from various sources towards glioma cells and glioma tissue turning it into a promising target for therapeutical intervention. Moreover, we show that stem cell migration is dependent on Rho-kinase activity.