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Bioactive glass selectively promotes cytotoxicity towards giant cell tumor of bone derived neoplastic stromal cells and induces MAPK signalling dependent autophagy.

ABSTRACT: Giant cell tumors of bone (GCTB) are associated with massive bone destructions and high recurrence rates. In a previous study, we observed cytotoxic effects of three different compositions of bioactive glasses (BGs) towards GCTSC but not bone marrow derived stromal cells (BMSC) indicating that BGs represent promising candidates for the development of new therapeutic approaches. In the current study we aimed to investigate the molecular mechanisms that are involved in BG induced cytotoxicity. We observed, that BG treatment was not associated with any signs of apoptosis, but rather led to a strong induction of mitogen activated protein kinases (MAPK) and, as a consequence, upregulation of several transcription factors specifically in GCTSC. Genome wide gene expression profiling further revealed a set of fifteen genes that were exclusively induced in GCTSC or induced significantly stronger in GCTSC compared to BMSC. BG treatment further induced autophagy that was significantly more pronounced in GCTSC compared to BMSC and could be inhibited by MAPK inhibitors. Together with the known osteogenic properties of BGs our findings support the suitability of BGs as therapeutic agents for the treatment of GCTB. However, these data have to be verified under in vivo conditions.

SUBMITTER: Fellenberg J

PROVIDER: S-EPMC8958388 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Bioactive glass selectively promotes cytotoxicity towards giant cell tumor of bone derived neoplastic stromal cells and induces MAPK signalling dependent autophagy.

Fellenberg Joerg J Losch Sarina S Lehner Burkhard B Arango-Ospina Marcela M Boccaccini Aldo R AR Westhauser Fabian F

Bioactive materials 20220228

Giant cell tumors of bone (GCTB) are associated with massive bone destructions and high recurrence rates. In a previous study, we observed cytotoxic effects of three different compositions of bioactive glasses (BGs) towards GCTSC but not bone marrow derived stromal cells (BMSC) indicating that BGs represent promising candidates for the development of new therapeutic approaches. In the current study we aimed to investigate the molecular mechanisms that are involved in BG induced cytotoxicity. We ...[more]

PMID: 35386334

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Project description:The interaction between neoplastic and stromal cells within a tumor mass plays an important role in cancer biology. However, it is challenging to distinguish between tumor and stromal cells in mesenchymal tumors because lineage-specific cell surface markers typically used in other cancers do not distinguish between the different cell subpopulations. Desmoid tumors consist of mesenchymal fibroblast-like cells driven by mutations stabilizing beta-catenin. Here we aimed to identify surface markers that can distinguish mutant cells from stromal cells to study tumor-stroma interactions. We analyzed colonies derived from single cells from human desmoid tumors using a high-throughput surface antigen screen, to characterize the mutant and nonmutant cells. We found that CD142 is highly expressed by the mutant cell populations and correlates with beta-catenin activity. CD142-based cell sorting isolated the mutant population from heterogeneous samples, including one where no mutation was previously detected by traditional Sanger sequencing. We then studied the secretome of mutant and nonmutant fibroblastic cells. PTX3 is one stroma-derived secreted factor that increases mutant cell proliferation via STAT6 activation. These data demonstrate a sensitive method to quantify and distinguish neoplastic from stromal cells in mesenchymal tumors. It identifies proteins secreted by nonmutant cells that regulate mutant cell proliferation that could be therapeutically.SignificanceDistinguishing between neoplastic (tumor) and non-neoplastic (stromal) cells within mesenchymal tumors is particularly challenging, because lineage-specific cell surface markers typically used in other cancers do not differentiate between the different cell subpopulations. Here, we developed a strategy combining clonal expansion with surface proteome profiling to identify markers for quantifying and isolating mutant and nonmutant cell subpopulations in desmoid tumors, and to study their interactions via soluble factors.

Dataset Information

Bioactive glass selectively promotes cytotoxicity towards giant cell tumor of bone derived neoplastic stromal cells and induces MAPK signalling dependent autophagy.

Publications

Bioactive glass selectively promotes cytotoxicity towards giant cell tumor of bone derived neoplastic stromal cells and induces MAPK signalling dependent autophagy.

Similar Datasets

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