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73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)
Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie

Deutsche Gesellschaft für Neurochirurgie (DGNC) e. V.

29.05. - 01.06.2022, Köln

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Influence of the tumour microenvironment on the therapeutic response of residual tumour cells after GBM resection

Einfluss der Tumor-Mikroumgebung auf die Therapieresponsivität von residuellen Tumorzellen nach einer GBM-Resektion

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  • presenting/speaker Dana Hellmold - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
  • Carolin Kubelt - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
  • Tina Daunke - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institute of Experimental Cancer Research, Kiel, Deutschland
  • Silje Beckinger - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institute of Experimental Cancer Research, Kiel, Deutschland
  • Ottmar Janssen - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institute for Immunology, Kiel, Deutschland
  • Margarethe Hauck - Christian-Albrechts-Universität zu Kiel, Institute for Materials Science, Chair for Functional Nanomaterials, Kiel, Deutschland
  • Fabian Schütt - Christian-Albrechts-Universität zu Kiel, Institute for Materials Science, Chair for Functional Nanomaterials, Kiel, Deutschland
  • Rainer Adelung - Christian-Albrechts-Universität zu Kiel, Institute for Materials Science, Chair for Functional Nanomaterials, Kiel, Deutschland
  • Susanne Sebens - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Institute of Experimental Cancer Research, Kiel, Deutschland
  • Michael Synowitz - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland
  • Janka Held-Feindt - Universitätsklinikum Schleswig-Holstein, Campus Kiel, Klinik für Neurochirurgie, Kiel, Deutschland

Deutsche Gesellschaft für Neurochirurgie. 73. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Griechischen Gesellschaft für Neurochirurgie. Köln, 29.05.-01.06.2022. Düsseldorf: German Medical Science GMS Publishing House; 2022. DocP150

doi: 10.3205/22dgnc463, urn:nbn:de:0183-22dgnc4639

Published: May 25, 2022

© 2022 Hellmold et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.

Outline

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Objective: Glioblastoma (GBM) is the most malignant brain tumor in adults. Despite the standard therapy including surgical resection and adjuvant combined radio/chemotherapy, the average survival of GBM patients is still poor. Since the crosstalk between residual tumor cells and the surrounding healthy brain cells is having a strong influence on the therapeutic outcome after surgical resection of the solid tumor mass, the present study evaluates the intra- and intercellular effects of a sequential therapy with TMZ combined with the alternative compound AT101 on two GBM primary cultures in an in vitro co-culture model mimicking an incomplete GBM resection.

Methods: The analyses comprised cytotoxicity assays, a fluorescence real-time apoptosis detection assay, the investigation of changes in signaling pathways and on the gene expression level, as well as the role of extracellular vesicles (EVs) using nanoparticle-tracking analysis (NTA) and western blotting. The analysis for both the intra- and intercellular effects of the sequential therapy were compared between mono- and co-culture of two GBM primary cultures.

Results: GBM cells were found to exhibit different apoptotic states over time upon sequential treatment when comparing mono- vs. co-culture conditions. Co-culture conditions were protectively influencing the death rates of GBM cells and were characterized by an increase of early-apoptotic cells (reversible event) with only little numbers of dead cells, whereas the mono-culture showed the opposite behavior, indicating a regulatory effect of healthy brain cells on the apoptotic cell death mechanisms. In addition, the MAP-kinases ERK1/2, GSK3β, mTOR, as well as β-Catenin were found to be activated upon treatment and the activation appeared to be differentially regulated in mono- vs. co-cultured GBM cells. Moreover, genes associated with dormancy and stemness were found to be upregulated under co-culture conditions upon treatment. Furthermore, NTA of isolated EVs revealed a shift in the size distribution of particles towards smaller sizes and a change in the total number of EVs in the samples that underwent the sequential treatment.

Conclusion: Our results indicate a complex role of the tumor microenvironment for the therapeutic outcome of GBMs. Understanding the mechanisms how healthy brain cells influence the response of residual GBM cells to a treatment and how the cellular crosstalk via EVs is involved might help to develop a more effective treatment strategy.