Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2
Abstract Background Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance pos...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-03-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-023-04063-0 |
| _version_ | 1797859820648267776 |
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| author | Yu Zhao Zuyi Weng Xuan Zhou Zhi Xu Bei Cao Bin Wang Juan Li |
| author_facet | Yu Zhao Zuyi Weng Xuan Zhou Zhi Xu Bei Cao Bin Wang Juan Li |
| author_sort | Yu Zhao |
| collection | DOAJ |
| description | Abstract Background Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism. Methods Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-β2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST. Results Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-β2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance. Conclusions Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy. |
| first_indexed | 2024-04-09T21:36:48Z |
| format | Article |
| id | doaj.art-6454f7021d2b4de3a0d597d825cb9ae8 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-09T21:36:48Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-6454f7021d2b4de3a0d597d825cb9ae82023-03-26T11:16:45ZengBMCJournal of Translational Medicine1479-58762023-03-0121111710.1186/s12967-023-04063-0Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2Yu Zhao0Zuyi Weng1Xuan Zhou2Zhi Xu3Bei Cao4Bin Wang5Juan Li6Phase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolClinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolPhase I Clinical Trials Unit, The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolAbstract Background Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism. Methods Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-β2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST. Results Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-β2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance. Conclusions Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy.https://doi.org/10.1186/s12967-023-04063-0Mesenchymal stromal cellsTumor microenvironmentGastrointestinal stromal tumorsTGF-βPI3K-AKTImatinib mesylate |
| spellingShingle | Yu Zhao Zuyi Weng Xuan Zhou Zhi Xu Bei Cao Bin Wang Juan Li Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 Journal of Translational Medicine Mesenchymal stromal cells Tumor microenvironment Gastrointestinal stromal tumors TGF-β PI3K-AKT Imatinib mesylate |
| title | Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 |
| title_full | Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 |
| title_fullStr | Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 |
| title_full_unstemmed | Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 |
| title_short | Mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the PI3K-AKT pathway via TGF-β2 |
| title_sort | mesenchymal stromal cells promote the drug resistance of gastrointestinal stromal tumors by activating the pi3k akt pathway via tgf β2 |
| topic | Mesenchymal stromal cells Tumor microenvironment Gastrointestinal stromal tumors TGF-β PI3K-AKT Imatinib mesylate |
| url | https://doi.org/10.1186/s12967-023-04063-0 |
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