Abstract
BackgroundLung 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.MethodsThis 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.ResultsIn 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.ConclusionIn 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.Graphical abstract
Highlights
Lung cancer often ranks one of the most prevalent malignancies in the world
The resistant cells were designated as H460R and A549R cells with a substantially higher IC50 values with respect to their parental counterparts for example, the IC50 value of H460R was found to be greater than 120 μM cisplatin as compared to approximately 37 μM in its parental counterpart (Additional file 3: Figure S1)
(See figure on previous page.) Fig. 3 Dasatinib treatment decreased CDDP-resistance and stemness of non-small cell lung cancer (NSCLC) cells. a Comparative MTT assay showed that when A549R and H460R cells were first treated with dasatinib (1 μM, 24 h) followed by CDDP treatment demonstrated an increased sensitivity towards CDDP. b Tumor sphere formation assay showed that dasatinib treatment (10 μM) significantly inhibited the formation of tumor spheres in both A549R and H460R cells. c Flow cytometry analysis of CD133+ cells
Summary
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. Despite the advancement in the development of targeted therapeutic agents, lung cancer patients often develop resistance against treatment and disease progression [1]. As one of the major components of TME, tumor-infiltrating or associated macrophages (TAMs) are responsible for promoting epithelial-to-mesenchymal transition (EMT) and distant metastasis [3]. The interruption of the pro-tumor signaling within this tumor-TAM communication network represent a potential area for therapeutic development. Since M2 TAMs are involved in promoting distant metastasis, we intend to examine the potential link between CD155 expression and M2 TAMs in lung cancer progression
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