Locoregional heterogeneity of glioblastoma entails pro- or antitumorigenic effects of tumor associated mesenchymal stem cells

Waechter, Robin (2023): Locoregional heterogeneity of glioblastoma entails pro- or antitumorigenic effects of tumor associated mesenchymal stem cells. Dissertation, LMU München: Medizinische Fakultät

Abstract

Among other cell lines of the tumor microenvironment, mesenchymal stem cells play an important role in glioma progression. However, many diverging aspects were shown throughout the complex interaction between mesenchymal stem cells and tumor cells. The first part of this work investigated in the migration of injected mesenchymal stem cells in glioblastoma. Furthermore, this study aimed to model one pathologically relevant aspect of the in vivo interaction between mesenchymal stem cells and glioma cells under simplified in vitro conditions in order to analyze a potential effect on the viability of glioma cells. First, mice were intracranially inoculated with glioma cells. Once the tumor had grown for 58 days, mesenchymal stem cells were injected into the brain into the main tumor mass. After sacrificing the mice, brain sections were analyzed with regards to the mesenchymal stem cells location and blood-brain barrier integrity in glioma. Furthermore, an in vitro proliferation assay was performed studying glioma cells viability under serum-free mesenchymal stem cell conditioned medium. The in vivo experiment shows migration of mesenchymal stem cells to invasive parts of the tumor. It was demonstrated that in these regions the blood-brain barrier is widely intact. Hence, serum-derived factors larger than the size of 70 kDa do not reach the structures where mesenchymal stem cells reside. Consequently, this serum-free situation was modeled in an in vitro proliferation assay. Serum-free medium, which was conditioned by mesenchymal stem cells, enhances viability in two lines of glioma stem cells even under conditions of chemotherapy. This paper adds to our understanding of the complex interaction between mesenchymal stem cells and glioma cells. The results of the study provide evidence for mesenchymal stem cells tropism for invasive regions of glioblastoma. These invasive regions remain in the brain after neurosurgery, representing the source of tumor relapse. Taken together, these encouraging results suggest that mesenchymal stem cells are able to support tumor relapse formation by improving viability of glioma cells even under conditions of chemotherapy. This makes mesenchymal stem cells and their interaction with glioblastoma promising potential therapeutical targets to evaluate in glioblastoma therapy in the future.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Keywords: Glioblastoma multiforme, GBM, mesenchymal stem cell, MSC
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 17. Januar 2023
• 1. Bericht­erstatter:in: Glaß, Rainer