Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer
Objective: The aim of this study was to understand the interactions between tumor-associated mesenchymal stemcells (TA-MSCs) and triple-negative breast cancer (TNBC) cells, which appear to be necessary for developing effectivetherapies.Materials and Methods: In this experimental study, MDA-MB-231 an...
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Royan Institute (ACECR), Tehran
2024-09-01
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| Online Access: | https://www.celljournal.org/article_715803_992a1849a1bcd87351c744f0fc3ba0fa.pdf |
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| author | Babak Jahangiri Zahra-Soheila Soheili Elahe Asadollahi Mehdi Shamsara Vahid Shariati Alireza Zomorodipour |
| author_facet | Babak Jahangiri Zahra-Soheila Soheili Elahe Asadollahi Mehdi Shamsara Vahid Shariati Alireza Zomorodipour |
| author_sort | Babak Jahangiri |
| collection | DOAJ |
| description | Objective: The aim of this study was to understand the interactions between tumor-associated mesenchymal stemcells (TA-MSCs) and triple-negative breast cancer (TNBC) cells, which appear to be necessary for developing effectivetherapies.Materials and Methods: In this experimental study, MDA-MB-231 and 4T1 TNBC cells were co-cultured with bonemarrow-derived MSCs, and TA-MSCs conditioned media (CM) were collected. TA-MSC CM-treated TNBC cells weresubjected to migration and invasion assays. Epithelial-mesenchymal transition (EMT) marker expression was quantifiedby real-time polymerase chain reaction (RT-PCR). Cell proliferation was measured using trypan blue exclusiontechnique, while cell cycle distribution and apoptosis were assessed by flow cytometry. The effects of TA-MSCs ontumor volume, survival rate, and lung metastasis were evaluated by subcutaneous co-injection of MSCs with 4T1 cellsin the right flanks of BALB/c mice (n=5 per group). Intratumoral interleukin-12 (IL-12) immunotherapy was performedusing lentiviral particles as a rescue experiment. The TA-MSCs RNA-seq dataset (PRJEB27694) was analyzed todetect elevated metastasis-associated oncogenes, downloaded from the European Nucleotide Archive database. Forvalidation of the RNA-seq data analysis, the expression levels of candidate oncogenes were evaluated in TA-MSCs,TNBC cells, and tumor tissue using RT-PCR.Results: TA-MSCs enhanced migration, invasion, and EMT of TNBC cells in vitro without affecting cell proliferation orapoptosis. In vivo, TA-MSCs increased tumor growth and lung metastasis, while decreasing survival rates. IL-12 therapyelevated serum IL-12 and interferon-gamma (IFN-γ) expression, suppressed tumor volume and lung metastasis, andimproved overall survival in the TA-MSC group. RNA-seq data analysis identified upregulated oncogenes in TA-MSCs,among which MMP3, CXCL2, CXCL5, and ICAM1 were selected as the most relevant to metastasis. These genesshowed increased expression in TA-MSCs, TNBC cells, and tumor tissues.Conclusion: The findings of the present study revealed a complex interplay between TA-MSCs and TNBC cells thataffects tumor growth and metastasis. Preclinical results indicate that intratumoral IL-12 immunotherapy shows promisein overcoming TA-MSC-promoted tumor growth and metastasis. |
| format | Article |
| id | doaj-art-f7638cf155ae46c1add82f22278d547c |
| institution | Kabale University |
| issn | 2228-5806 2228-5814 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Royan Institute (ACECR), Tehran |
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| series | Cell Journal |
| spelling | doaj-art-f7638cf155ae46c1add82f22278d547c2025-01-19T09:34:57ZengRoyan Institute (ACECR), TehranCell Journal2228-58062228-58142024-09-0126954355810.22074/cellj.2024.2036513.1634715803Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast CancerBabak Jahangiri0Zahra-Soheila Soheili1Elahe Asadollahi2Mehdi Shamsara3Vahid Shariati4Alireza Zomorodipour5Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, IranDepartment of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, IranDepartment of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IranDepartment of Animal Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, IranNational Institute of Genetic Engineering and Biotechnology, Tehran, IranDepartment of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, IranObjective: The aim of this study was to understand the interactions between tumor-associated mesenchymal stemcells (TA-MSCs) and triple-negative breast cancer (TNBC) cells, which appear to be necessary for developing effectivetherapies.Materials and Methods: In this experimental study, MDA-MB-231 and 4T1 TNBC cells were co-cultured with bonemarrow-derived MSCs, and TA-MSCs conditioned media (CM) were collected. TA-MSC CM-treated TNBC cells weresubjected to migration and invasion assays. Epithelial-mesenchymal transition (EMT) marker expression was quantifiedby real-time polymerase chain reaction (RT-PCR). Cell proliferation was measured using trypan blue exclusiontechnique, while cell cycle distribution and apoptosis were assessed by flow cytometry. The effects of TA-MSCs ontumor volume, survival rate, and lung metastasis were evaluated by subcutaneous co-injection of MSCs with 4T1 cellsin the right flanks of BALB/c mice (n=5 per group). Intratumoral interleukin-12 (IL-12) immunotherapy was performedusing lentiviral particles as a rescue experiment. The TA-MSCs RNA-seq dataset (PRJEB27694) was analyzed todetect elevated metastasis-associated oncogenes, downloaded from the European Nucleotide Archive database. Forvalidation of the RNA-seq data analysis, the expression levels of candidate oncogenes were evaluated in TA-MSCs,TNBC cells, and tumor tissue using RT-PCR.Results: TA-MSCs enhanced migration, invasion, and EMT of TNBC cells in vitro without affecting cell proliferation orapoptosis. In vivo, TA-MSCs increased tumor growth and lung metastasis, while decreasing survival rates. IL-12 therapyelevated serum IL-12 and interferon-gamma (IFN-γ) expression, suppressed tumor volume and lung metastasis, andimproved overall survival in the TA-MSC group. RNA-seq data analysis identified upregulated oncogenes in TA-MSCs,among which MMP3, CXCL2, CXCL5, and ICAM1 were selected as the most relevant to metastasis. These genesshowed increased expression in TA-MSCs, TNBC cells, and tumor tissues.Conclusion: The findings of the present study revealed a complex interplay between TA-MSCs and TNBC cells thataffects tumor growth and metastasis. Preclinical results indicate that intratumoral IL-12 immunotherapy shows promisein overcoming TA-MSC-promoted tumor growth and metastasis.https://www.celljournal.org/article_715803_992a1849a1bcd87351c744f0fc3ba0fa.pdfimmunotherapyinterleukin-12metastasisrna-seqtriple-negative breast cancer |
| spellingShingle | Babak Jahangiri Zahra-Soheila Soheili Elahe Asadollahi Mehdi Shamsara Vahid Shariati Alireza Zomorodipour Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer Cell Journal immunotherapy interleukin-12 metastasis rna-seq triple-negative breast cancer |
| title | Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer |
| title_full | Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer |
| title_fullStr | Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer |
| title_full_unstemmed | Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer |
| title_short | Interleukin-12 Inhibits Tumor Growth and Metastasis Promoted by Tumor-Associated Mesenchymal Stem Cells in Triple-Negative Breast Cancer |
| title_sort | interleukin 12 inhibits tumor growth and metastasis promoted by tumor associated mesenchymal stem cells in triple negative breast cancer |
| topic | immunotherapy interleukin-12 metastasis rna-seq triple-negative breast cancer |
| url | https://www.celljournal.org/article_715803_992a1849a1bcd87351c744f0fc3ba0fa.pdf |
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