Molecular Mechanism of the Effect of Bone Marrow Mesenchymal Stem Cells on Human Glioblastoma Cells upon an Indirect and Direct Cellular Contact

An important components of tumour microenvironment are endogenous normal stem cells, i.e. neural stem cells, haematopoietic and mesenchymal stem cells (MSC), the latter being mostly investigated in cancer, including glioblastoma (GBM). Tropism of MSC to GBM has been demonstrated in animal and human brains in vivo. However, the molecular mechanisms can only be revealed by using the in vitro cell co-cultures (1). We studied indirect co-cultures and direct co-cultures, using bone marrow derived BM-MSC with U87 and U373 GBM cells, as well as umbilical cord derived UC-MSC with GBM stem–like cells (GSLC) NCH421K and NCH644. We found that BM-MSC in indirect cultures impair proliferation and invasion, and induce senescence of U87 cells, most effectively via cytokine CCL2/MCP1 paracrine effects on GBM cell survival, senescence and adhesion related genes, as revealed by transcriptomics analyses. Similarly, senescence was induced also in GSLC cells by UC-MSC condition medium via p53-p21-pRb TSG pathway (2).

In direct co-cultures GBM observed gap junction and cell fusion events enhanced U87 and U373 GBM cells invasion. The mechanism may involve activation of bradykinin (BK) receptors BDKBR1/B1R and BDKBR2/B2R in U87 cells, followed by observed Ca++ signaling, known to affect PI3K/Akt pathway ad/or cell cytoskeleton, as well as possibly COX2, resulting in the metalloprotease MMP9 induction.

In conclusion, MSC approaching GBM secrete factors affecting GBM cell invasion and inducing senescence, whereas upon direct contact, MSC enhance GBM migration, thus promoting tumour aggressiveness. This reflects a general notion on highly relevant role of MSC in tumour microenvironment.

1) Motaln and Lah, Proteins and Peptide Letters 2015

2) Kološa et al., Cell Transplantaion 2015