Abstract
Background: Lung cancer often ranks one of the most prevalent malignancies in the world. One of the most challenging aspects of treating late-stage lung cancer patients is the development of drug resistance, from both conventional chemo- and targeted therapeutic agents. Tumor-associated microphages (TAMs) have been shown to promote the survival and distant metastasis of lung cancer cells. Methods: This study investigated the TAMs - modulating potential of cisplatin-resistant non-small cell lung cancer (NSCLC) cell lines, A549R and H460R by using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony, lung sphere formation and xenograft tumorigenecity assays. Results: In this study, we first demonstrated the elevated expression of oncogenic and stemenss markers such as Src, Notch1, macrophage inhibitory factor (MIF) and CD155 in trained cisplatin (CDDP)-resistant A549 and H460 cells (A549R and H460R cells). When co-cultured with TAMs, A549R and H460R cells promoted the M2-polarization in TAMs. In addition, A549R and H460R cells showed an increased self-renewal ability as they formed tumor spheres at higher frequency comparing to their parental counterparts. The increased MIF secretion by the A549R and H460R cells could be suppressed by a multiple kinase inhibitor, dasatinib, which resulted in the decreased of oncogenic network of Src, CD155 and MIF expression. Similarly, dasatinib treatment reduced the M2 polarization in TAMs and suppressed self-renewal ability of the A549R and H460R cells. Conclusion: In summary, cisplatin resistant lung cancer cells not only showed an increased self-renewal ability but also promoted M2 polarization of TAMs via the secretion of MIF. These findings were linked to the increased Src-associated signaling as dasatinib treatment significantly reversed these phenomena. Thus, kinase inhibitors such as dasatinib may be of potential for treating cisplatin-resistant lung cancer by targeting both tumor and the tumor microenvironment.
Original language | English |
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Article number | 180 |
Journal | Journal of Experimental and Clinical Cancer Research |
Volume | 38 |
Issue number | 1 |
DOIs | |
Publication status | Published - Apr 29 2019 |
Keywords
- Cancer stemness
- Cisplatin resistance
- Lung cancer
- M2 tumor-associated macrophages (M2-TAMs)
- Multiple kinase inhibitor
- Src signaling
ASJC Scopus subject areas
- Oncology
- Cancer Research
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Cisplatin resistant lung cancer cells promoted M2 polarization of tumor-associated macrophages via the Src/CD155/MIF functional pathway
Huang, W.-C. (Contributor), Kuo, K.-T. (Contributor), Wang, C.-H. (Creator), Yeh, C.-T. (Contributor) & Wang, Y. (Creator), Figshare, 2019
DOI: 10.6084/m9.figshare.c.4488140.v1, https://springernature.figshare.com/collections/Cisplatin_resistant_lung_cancer_cells_promoted_M2_polarization_of_tumor-associated_macrophages_via_the_Src_CD155_MIF_functional_pathway/4488140/1
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Additional file 3: of Cisplatin resistant lung cancer cells promoted M2 polarization of tumor-associated macrophages via the Src/CD155/MIF functional pathway
Huang, W.-C. (Contributor), Kuo, K.-T. (Contributor), Wang, C.-H. (Contributor), Yeh, C.-T. (Contributor) & Wang, Y. (Contributor), Unknown Publisher, Jan 1 2019
DOI: 10.6084/m9.figshare.8057546.v1, https://springernature.figshare.com/articles/Additional_file_3_of_Cisplatin_resistant_lung_cancer_cells_promoted_M2_polarization_of_tumor-associated_macrophages_via_the_Src_CD155_MIF_functional_pathway/8057546/1
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Additional file 1: of Cisplatin resistant lung cancer cells promoted M2 polarization of tumor-associated macrophages via the Src/CD155/MIF functional pathway
Huang, W.-C. (Contributor), Kuo, K.-T. (Contributor), Wang, C.-H. (Contributor), Yeh, C.-T. (Contributor) & Wang, Y. (Contributor), Unknown Publisher, Jan 1 2019
DOI: 10.6084/m9.figshare.8057528.v1, https://springernature.figshare.com/articles/Additional_file_1_of_Cisplatin_resistant_lung_cancer_cells_promoted_M2_polarization_of_tumor-associated_macrophages_via_the_Src_CD155_MIF_functional_pathway/8057528/1
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