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Glioma-associated mesenchymal stem cells have profound effects on brain tumors
Glioma-associated mesenchymal stem cells have profound effects on brain tumors
GBMs have proven to be a major pathology with vast infiltration potential and extreme chemo- and radio-resistance leading to devastating outcomes. The GBMs, however, are not only detrimental on the host alone but also they interact with the microenvironment to manifest some of their pathological hallmarks. Within the tumor microenvironment, MSCs have gained a strong attention in the recent years. The role of MSCs within the brain tumor niche has been partially explained including pro- and anti-tumorigenic effects. It was, however, a controversial issue as to what makes MSCs pro- or anti-tumorigenic. Moreover, the contribution of MSCs in the brain tumor histopathology was not yet fully uncovered. Here I investigated the role of MSCs in the brain tumor pathology and the signaling mechanisms. It was shown earlier in our lab that MSCs act as anti-tumorigenic in the presence of serum and anti-tumorigenic in serum-free conditions. Which condition is more relevant to the pathological situation was an open question. When I co-inoculated MSCs with GBMs, they homed the tumor satellites, where they are probably not in contact with blood-borne factors. Therefore, I concluded that serum-free conditions are more relevant to in vivo pathological situation. MSCs promoted viability of many primary GSC lines under serum-free conditions. The induction of survival and proliferation was mediated by the increase in the levels of QKIs in GBMs upon exposure to MSC-derived soluble factors. In turn, QKIs increase the levels of EGFR causing an overresponse to growth factors. Moreover, increased QKI-levels in GBMs mediate the chemoresistance against TMZ. In addition to soluble factors, MSCs signal via exosomes. Those exosomes carry EFNA3 mRNA from MSCs to GBMs. EFNA3 expression in turn induces cellular migration. The inhibition of EFNA3 transfer via genetically engineered antibodies against exosome docking sites on the recipient GBM cells or against EFNA3 (if it is translated and integrated on the surface) as well as EGFR-blockade might prove useful for future therapeutic approaches against GBMs. There are no well-established mouse models to study the interaction between MSCs and GBMs at the tumor satellite. Therefore, I sought to establish such a model by expressing HSV-TK in GBMs and inducing cell death via GCV administration either by osmotic pumps or via systemic injection and established a model where one can study tumor satellites. Additionally, I established a model to study the mRNA transfer from MSCs to GBMs. For this, I expressed Cre-recombinase in MSCs, and flipped- and floxed-GFP in GBMs. The Cre-recombinase mRNA is packed into exosomes and delivered to GBMs, labelling GBMs with GFP for the rest of their lives. This enables us to demonstrate the transfer of mRNA as well as to track individual GBM cells, contacted by the MSCs, in terms of their migratory behaviors in vivo. All in all, I uncovered a previously unknown action of MSCs in GBM pathology defining two targetable systems (EGFR and EFNA3) and established two models to study in vivo interaction of MSCs with GBMs.
GBM, glioma, brain tumors, MSC, mesenchymal stem cells, exosomes, invasion
Uyar, Ramazan
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Uyar, Ramazan (2019): Glioma-associated mesenchymal stem cells have profound effects on brain tumors. Dissertation, LMU München: Faculty of Medicine
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Abstract

GBMs have proven to be a major pathology with vast infiltration potential and extreme chemo- and radio-resistance leading to devastating outcomes. The GBMs, however, are not only detrimental on the host alone but also they interact with the microenvironment to manifest some of their pathological hallmarks. Within the tumor microenvironment, MSCs have gained a strong attention in the recent years. The role of MSCs within the brain tumor niche has been partially explained including pro- and anti-tumorigenic effects. It was, however, a controversial issue as to what makes MSCs pro- or anti-tumorigenic. Moreover, the contribution of MSCs in the brain tumor histopathology was not yet fully uncovered. Here I investigated the role of MSCs in the brain tumor pathology and the signaling mechanisms. It was shown earlier in our lab that MSCs act as anti-tumorigenic in the presence of serum and anti-tumorigenic in serum-free conditions. Which condition is more relevant to the pathological situation was an open question. When I co-inoculated MSCs with GBMs, they homed the tumor satellites, where they are probably not in contact with blood-borne factors. Therefore, I concluded that serum-free conditions are more relevant to in vivo pathological situation. MSCs promoted viability of many primary GSC lines under serum-free conditions. The induction of survival and proliferation was mediated by the increase in the levels of QKIs in GBMs upon exposure to MSC-derived soluble factors. In turn, QKIs increase the levels of EGFR causing an overresponse to growth factors. Moreover, increased QKI-levels in GBMs mediate the chemoresistance against TMZ. In addition to soluble factors, MSCs signal via exosomes. Those exosomes carry EFNA3 mRNA from MSCs to GBMs. EFNA3 expression in turn induces cellular migration. The inhibition of EFNA3 transfer via genetically engineered antibodies against exosome docking sites on the recipient GBM cells or against EFNA3 (if it is translated and integrated on the surface) as well as EGFR-blockade might prove useful for future therapeutic approaches against GBMs. There are no well-established mouse models to study the interaction between MSCs and GBMs at the tumor satellite. Therefore, I sought to establish such a model by expressing HSV-TK in GBMs and inducing cell death via GCV administration either by osmotic pumps or via systemic injection and established a model where one can study tumor satellites. Additionally, I established a model to study the mRNA transfer from MSCs to GBMs. For this, I expressed Cre-recombinase in MSCs, and flipped- and floxed-GFP in GBMs. The Cre-recombinase mRNA is packed into exosomes and delivered to GBMs, labelling GBMs with GFP for the rest of their lives. This enables us to demonstrate the transfer of mRNA as well as to track individual GBM cells, contacted by the MSCs, in terms of their migratory behaviors in vivo. All in all, I uncovered a previously unknown action of MSCs in GBM pathology defining two targetable systems (EGFR and EFNA3) and established two models to study in vivo interaction of MSCs with GBMs.