APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization
Background: Tumor-associated macrophages (TAMs) are pivotal in shaping the tumor microenvironment (TME) during cancer progression. Emerging evidence indicates that dysregulation of key signaling pathways in cancer cells drives the secretion of various cytokines, modulating TAMs function. This study...
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Elsevier
2025-05-01
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| Series: | Immunobiology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0171298525000294 |
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| author | Wei Huang Weimin Li Xingyu Chen Chengwei Xiang Ke Luo |
| author_facet | Wei Huang Weimin Li Xingyu Chen Chengwei Xiang Ke Luo |
| author_sort | Wei Huang |
| collection | DOAJ |
| description | Background: Tumor-associated macrophages (TAMs) are pivotal in shaping the tumor microenvironment (TME) during cancer progression. Emerging evidence indicates that dysregulation of key signaling pathways in cancer cells drives the secretion of various cytokines, modulating TAMs function. This study aimed to explore how glioblastoma cells regulate macrophages and establish a TME conducive to tumor immune escape. Methods: In previous bioinformatics studies, we identified abnormally expressed genes in glioblastoma patients. Among them, the metabolism-related protein APOE garnered particular attention. We generated U87 and U251 cell lines with altered APOE expression to evaluate cancer cell invasion, migration, and inflammatory cytokine secretion through scratch assays, Transwell assays, and ELISA, respectively. Additionally, we established a co-culture system of cancer cells and monocytes THP-1 to assess the impact of shAPOE tumor cells on macrophage polarization using flow cytometry, Western blot, and immunofluorescence techniques. Result: Knockdown of APOE significantly reduced the viability, invasion, and migration capabilities of U87 and U251 cells. ELISA results also showed that APOE knockdown cells secreted higher levels of IL-6, IL-12, and TNF-α, while CCL5 and TGF-β secretion was markedly reduced. In macrophage studies, we observed that APOE knockdown altered the M1/M2 polarization ratio in THP-1 monocytes, with CCR5 inhibition further decreasing M2 macrophage proportions. Immunofluorescence analysis revealed that the reduction of M2 macrophages was dependent on APOE and CCL5. Conclusion: Our findings indicate that APOE knockdown suppresses glioblastoma cell migration, invasion, and CCL5 secretion, while enhancing the production of tumor-suppressive cytokines. |
| format | Article |
| id | doaj-art-a7fc3d55ff2746bfb54ad39a446b463e |
| institution | OA Journals |
| issn | 0171-2985 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
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| series | Immunobiology |
| spelling | doaj-art-a7fc3d55ff2746bfb54ad39a446b463e2025-08-20T02:32:33ZengElsevierImmunobiology0171-29852025-05-01230315289510.1016/j.imbio.2025.152895APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage PolarizationWei Huang0Weimin Li1Xingyu Chen2Chengwei Xiang3Ke Luo4Department of Neurosurgery, Suining Central Hospital, Suining city, Sichuan Province, ChinaDepartment of Neurosurgery, Suining Central Hospital, Suining city, Sichuan Province, ChinaDepartment of Neurosurgery, Suining Central Hospital, Suining city, Sichuan Province, ChinaDepartment of Neurosurgery, Suining Central Hospital, Suining city, Sichuan Province, ChinaDepartment of Neurosurgery, Suining Central Hospital, Suining city, Sichuan Province, China; Corresponding author at: Department of Neurosurgery, Suining Central Hospital, 27 Dongping North Road, Hedong New District, Chuanshan District, Suining City, Sichuan Province, China.Background: Tumor-associated macrophages (TAMs) are pivotal in shaping the tumor microenvironment (TME) during cancer progression. Emerging evidence indicates that dysregulation of key signaling pathways in cancer cells drives the secretion of various cytokines, modulating TAMs function. This study aimed to explore how glioblastoma cells regulate macrophages and establish a TME conducive to tumor immune escape. Methods: In previous bioinformatics studies, we identified abnormally expressed genes in glioblastoma patients. Among them, the metabolism-related protein APOE garnered particular attention. We generated U87 and U251 cell lines with altered APOE expression to evaluate cancer cell invasion, migration, and inflammatory cytokine secretion through scratch assays, Transwell assays, and ELISA, respectively. Additionally, we established a co-culture system of cancer cells and monocytes THP-1 to assess the impact of shAPOE tumor cells on macrophage polarization using flow cytometry, Western blot, and immunofluorescence techniques. Result: Knockdown of APOE significantly reduced the viability, invasion, and migration capabilities of U87 and U251 cells. ELISA results also showed that APOE knockdown cells secreted higher levels of IL-6, IL-12, and TNF-α, while CCL5 and TGF-β secretion was markedly reduced. In macrophage studies, we observed that APOE knockdown altered the M1/M2 polarization ratio in THP-1 monocytes, with CCR5 inhibition further decreasing M2 macrophage proportions. Immunofluorescence analysis revealed that the reduction of M2 macrophages was dependent on APOE and CCL5. Conclusion: Our findings indicate that APOE knockdown suppresses glioblastoma cell migration, invasion, and CCL5 secretion, while enhancing the production of tumor-suppressive cytokines.http://www.sciencedirect.com/science/article/pii/S0171298525000294GlioblastomaTumor microenvironmentAPOETumor-associated MacrophagesCCL5-CCR5 signaling pathwayImmunosuppressive Mechanisms |
| spellingShingle | Wei Huang Weimin Li Xingyu Chen Chengwei Xiang Ke Luo APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization Immunobiology Glioblastoma Tumor microenvironment APOE Tumor-associated Macrophages CCL5-CCR5 signaling pathway Immunosuppressive Mechanisms |
| title | APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization |
| title_full | APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization |
| title_fullStr | APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization |
| title_full_unstemmed | APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization |
| title_short | APOE Drives Glioma Progression by Modulating CCL5/CCR5 Signaling in the Tumor Microenvironment and Inducing M2 Macrophage Polarization |
| title_sort | apoe drives glioma progression by modulating ccl5 ccr5 signaling in the tumor microenvironment and inducing m2 macrophage polarization |
| topic | Glioblastoma Tumor microenvironment APOE Tumor-associated Macrophages CCL5-CCR5 signaling pathway Immunosuppressive Mechanisms |
| url | http://www.sciencedirect.com/science/article/pii/S0171298525000294 |
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