Final report of the first funding period 2013 - 2015
Prof. Dr. Glass (LMU München): "Mesenchymal stem cells modulate the Glioma progression"
Mesenchymal stem cells have been identified in previous studies by us and others as part of the GBM-stroma. The tumor stroma has in the past decade gained more and more attention and a whole range of GBM-interacting were characterized showing a virtually "organ-like" structure of these tumors. Crosstalk between tumor cells and tumor-associated non-neoplastic cells has significant influence on the resistance to treatment, expansion and invasiveness of GBM. In our current basic-science research project on the interaction of healthy brain cells (parenchymal cell) with GBM a series of in vitro experiments has demonstrated a pathological role of tumor-associated mesenchymal stem cells.
Under physiological conditions mesenchymal stem cells e.g. contribute to the coordination of immune- and regenerative-responses in peripheral organs in. The role of mesenchymal stem cells in the brain, however, is largely unknown. Our data on cultured mesenchymal stem cells and GBM cells showed that the mesenchymal stem cells release soluble factors as well as membranous vesicles (microvesicles) and thereby induce distinct physiological responses in glioblastoma cells. The soluble factors affect the viability of GBM cells and support tumor cell expansion especially under stringent (serum-free) culture-conditions. The microvesicles from the mesenchymal stem cells carry messengers such as mRNA, which lead to altered gene expression in cells taking up these vesicles. By means of this vesicle-based signal transduction the mesenchymal stem cells impact on the differentiation-state and the adhesiveness of GBM cells. To elucidate the molecular basis of these two signaling pathways (mediated by soluble factors and microvesicles from mesenchymal stem cells) we have collected gene expression profiles of GBM cells after stimulation with the respective components from the cell culture medium of mesenchymal stem cells. We identified a number of genes and epigenetic modulators in glioblastoma cells and in mesenchymal stem cell-derived microvesicles that can explain the pathological effects of mesenchymal stem cell and GBM interactions. These newly-identified candidate genes were directly manipulated (using molecular biology techniques) and proved to be responsible for distinct tumor traits in GBM. Through these experiments, we now have a much clearer picture of the molecular basis of the tumor-modulating properties of mesenchymal stem cells and commence to generate strategies for pharmacological inhibition of pro-tumorigenic properties of mesenchymal stem cells in brain tumors. All in all, our in vitro studies lay the foundations for new mesenchymal stem cell-targeting adjuvant therapies in glioblastomas. With our current funding by the Anni-Hofmann Foundation we have the opportunity to extent our studies to in vivo models and to define new treatments against the pro-tumorigenic mesenchymal stem cells in GBM.