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Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways

  • Authors:
    • Shiyang Yuan
    • Wenjun Chen
    • Jian Yang
    • Yuanhai Zheng
    • Wen Ye
    • Hui Xie
    • Lie Dong
    • Junping Xie
  • View Affiliations / Copyright

    Affiliations: Department of Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Respiratory and Critical Care Medicine, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, Fujian 353000, P.R. China
    Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 356
    |
    Published online on: August 24, 2022
       https://doi.org/10.3892/ol.2022.13476
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Abstract

The evolutionary properties of organisms lead to the issue of targeted drug resistance. Numerous clinical trials have shown that tumor‑associated macrophages (TAMs) in patients with lung cancer adversely affect the clinical efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanism by which TAMs influence the tumor cell response to TKIs remains unclear. The aim of the present study was to investigate the influence of TAM‑derived exosomes on the sensitivity of PC9 and HCC827 lung adenocarcinoma cells to the EGFR inhibitor gefitinib. Multiple cytokines were used to induce the differentiation of THP‑1 human leukemia monocytes into macrophages in vitro. The obtained cells were identified as TAMs by cytomorphology and flow cytometry. Exosomes were extracted from the TAM culture supernatants and identified using electron microscopy and nanoparticle tracking analysis. Flow cytometry was used to examine the apoptosis of lung adenocarcinoma cells when treated with gefitinib and/or TAM‑derived exosomes. In addition, western blotting was used to detect the expression of the key proteins of the AKT, ERK1/2 and STAT3 signaling pathways. TAM‑derived exosomes were successfully obtained. The TAM‑derived exosomes were shown to affect the proliferation and apoptosis of lung adenocarcinoma cells. Furthermore, the killing effect of gefitinib on the tumor cells was attenuated. The mechanism underlying the effects of the TAM‑derived exosomes may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. In conclusion, the findings indicate that TAM‑derived exosomes promote resistance to gefitinib in non‑small cell lung cancer (NSCLC), and the mechanism may be associated with reactivation of the AKT, ERK1/2 and STAT3 signaling pathways. This study may serve as a reference in the exploration of alternative strategies for NSCLC following the development of resistance to EGFR‑targeted drugs.
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1 

Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N and Chen W: Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin Med J (Engl). 135:584–590. 2022. View Article : Google Scholar : PubMed/NCBI

2 

Daly ME, Singh N, Ismaila N, Antonoff MB, Arenberg DA, Bradley J, David E, Detterbeck F, Fruh M, Gubens MA, et al: Management of stage III Non-small-cell lung cancer: ASCO guideline. J Clin Oncol. 40:1356–1384. 2022. View Article : Google Scholar : PubMed/NCBI

3 

Lin JJ, Zhu VW, Schoenfeld AJ, Yeap BY, Saxena A, Ferris LA, Dagogo-Jack I, Farago AF, Taber A, Traynor A, et al: Brigatinib in patients with alectinib-refractory ALK-positive NSCLC. J Thorac Oncol. 13:1530–1538. 2018. View Article : Google Scholar : PubMed/NCBI

4 

Peled N, Gillis R, Kilickap S, Froesch P, Orlov S, Filippova E, Demirci U, Christopoulos P, Cicin I, Basal FB, et al: GLASS: Global Lorlatinib for ALK(+) and ROS1(+) retrospective Study: Real world data of 123 NSCLC patients. Lung Cancer. 148:48–54. 2020. View Article : Google Scholar : PubMed/NCBI

5 

Seto T, Ohashi K, Sugawara S, Nishio M, Takeda M, Aoe K, Moizumi S, Nomura S, Tajima T and Hida T: Capmatinib in Japanese patients with MET exon 14 skipping-mutated or MET-amplified advanced NSCLC: GEOMETRY mono-1 study. Cancer Sci. 112:1556–1566. 2021. View Article : Google Scholar : PubMed/NCBI

6 

Schmid S, Li J and Leighl NB: Mechanisms of osimertinib resistance and emerging treatment options. Lung Cancer. 147:123–129. 2020. View Article : Google Scholar : PubMed/NCBI

7 

Shaikh M, Shinde Y, Pawara R, Noolvi M, Surana S, Ahmad I and Patel H: Emerging approaches to overcome acquired drug resistance obstacles to osimertinib in non-small-cell lung cancer. J Med Chem. 65:1008–1046. 2022. View Article : Google Scholar : PubMed/NCBI

8 

Ostrand-Rosenberg S: Tolerance and immune suppression in the tumor microenvironment. Cell Immunol. 299:23–29. 2016. View Article : Google Scholar : PubMed/NCBI

9 

Ruffell B and Coussens LM: Macrophages and therapeutic resistance in cancer. Cancer Cell. 27:462–472. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Kerkar SP and Restifo NP: Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 72:3125–3130. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Mantovani A, Sozzani S, Locati M, Allavena P and Sica A: Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 23:549–555. 2002. View Article : Google Scholar : PubMed/NCBI

12 

Solinas G, Germano G, Mantovani A and Allavena P: Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 86:1065–1073. 2009. View Article : Google Scholar : PubMed/NCBI

13 

Chung FT, Lee KY, Wang CW, Heh CC, Chan YF, Chen HW, Kuo CH, Feng PH, Lin TY, Wang CH, et al: Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer. 131:E227–E235. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Zhang B, Zhang Y, Zhao J, Wang Z, Wu T, Ou W, Wang J, Yang B, Zhao Y, Rao Z and Gao J: M2-polarized macrophages contribute to the decreased sensitivity of EGFR-TKIs treatment in patients with advanced lung adenocarcinoma. Med Oncol. 31:1272014. View Article : Google Scholar : PubMed/NCBI

15 

Yuan S, Dong Y, Peng L, Yang M, Niu L, Liu Z and Xie J: Tumor-associated macrophages affect the biological behavior of lung adenocarcinoma A549 cells through the PI3K/AKT signaling pathway. Oncol Lett. 18:1840–1846. 2019.PubMed/NCBI

16 

Wendler F, Favicchio R, Simon T, Alifrangis C, Stebbing J and Giamas G: Extracellular vesicles swarm the cancer microenvironment: From tumor-stroma communication to drug intervention. Oncogene. 36:877–884. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Robbins PD and Morelli AE: Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 14:195–208. 2014. View Article : Google Scholar : PubMed/NCBI

18 

Lee JK, Park SR, Jung BK, Jeon YK, Lee YS, Kim MK, Kim YG, Jang JY and Kim CW: Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS One. 8:e842562013. View Article : Google Scholar : PubMed/NCBI

19 

Looze C, Yui D, Leung L, Ingham M, Kaler M, Yao X, Wu WW, Shen RF, Daniels MP and Levine SJ: Proteomic profiling of human plasma exosomes identifies PPARgamma as an exosome-associated protein. Biochem Biophys Res Commun. 378:433–438. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Wu Z, Zhou J, Chen F, Yu J, Li H, Li Q and Li W: 13-Methyl-palmatrubine shows an anti-tumor role in non-small cell lung cancer via shifting M2 to M1 polarization of tumor macrophages. Int Immunopharmacol. 104:1084682022. View Article : Google Scholar : PubMed/NCBI

21 

Sun D, Luo T, Dong P, Zhang N, Chen J and Zhang S, Dong L, Janssen H and Zhang S: M2-polarized tumor-associated macrophages promote epithelial-mesenchymal transition via activation of the AKT3/PRAS40 signaling pathway in intrahepatic cholangiocarcinoma. J Cell Biochem. 121:2828–2838. 2020. View Article : Google Scholar : PubMed/NCBI

22 

Wang J, Li D, Cang H and Guo B: Crosstalk between cancer and immune cells: Role of tumor-associated macrophages in the tumor microenvironment. Cancer Med. 8:4709–4721. 2019. View Article : Google Scholar : PubMed/NCBI

23 

de Goede KE, Driessen A and Van den Bossche J: Metabolic cancer-macrophage crosstalk in the tumor microenvironment. Biology (Basel). 9:3802020.PubMed/NCBI

24 

Ruivo CF, Adem B, Silva M and Melo SA: The biology of cancer exosomes: Insights and new perspectives. Cancer Res. 77:6480–6488. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Pashazadeh M: The role of tumor-isolated exosomes on suppression of immune reactions and cancer progression: A systematic review. Med J Islam Repub Iran. 34:912020.PubMed/NCBI

26 

Wei K, Ma Z, Yang F, Zhao X, Jiang W, Pan C, Li Z, Pan X, He Z, Xu J, et al: M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett. 526:205–216. 2022. View Article : Google Scholar : PubMed/NCBI

27 

Li X, Chen Z, Ni Y, Bian C, Huang J, Chen L, Xie X and Wang J: Tumor-associated macrophages secret exosomal miR-155 and miR-196a-5p to promote metastasis of non-small-cell lung cancer. Transl Lung Cancer Res. 10:1338–1354. 2021. View Article : Google Scholar : PubMed/NCBI

28 

Wang H, Wang L, Pan H, Wang Y, Shi M, Yu H, Wang C, Pan X and Chen Z: Exosomes derived from macrophages enhance aerobic glycolysis and Chemoresistance in lung cancer by stabilizing c-Myc via the inhibition of NEDD4L. Front Cell Dev Biol. 8:6206032020. View Article : Google Scholar : PubMed/NCBI

29 

Zhou D, Xia Z, Xie M, Gao Y, Yu Q and He B: Exosomal long non-coding RNA SOX2 overlapping transcript enhances the resistance to EGFR-TKIs in non-small cell lung cancer cell line H1975. Hum Cell. 34:1478–1489. 2021. View Article : Google Scholar : PubMed/NCBI

30 

Wang J, Li D, Cang H and Guo B: Crosstalk between cancer and immune cells: Role of tumor-associated macrophages in the tumor microenvironment. Cancer Med. 8:4709–4721. 2019. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yuan S, Chen W, Yang J, Zheng Y, Ye W, Xie H, Dong L and Xie J: Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways. Oncol Lett 24: 356, 2022.
APA
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H. ... Xie, J. (2022). Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways. Oncology Letters, 24, 356. https://doi.org/10.3892/ol.2022.13476
MLA
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H., Dong, L., Xie, J."Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways". Oncology Letters 24.4 (2022): 356.
Chicago
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H., Dong, L., Xie, J."Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways". Oncology Letters 24, no. 4 (2022): 356. https://doi.org/10.3892/ol.2022.13476
Copy and paste a formatted citation
x
Spandidos Publications style
Yuan S, Chen W, Yang J, Zheng Y, Ye W, Xie H, Dong L and Xie J: Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways. Oncol Lett 24: 356, 2022.
APA
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H. ... Xie, J. (2022). Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways. Oncology Letters, 24, 356. https://doi.org/10.3892/ol.2022.13476
MLA
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H., Dong, L., Xie, J."Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways". Oncology Letters 24.4 (2022): 356.
Chicago
Yuan, S., Chen, W., Yang, J., Zheng, Y., Ye, W., Xie, H., Dong, L., Xie, J."Tumor‑associated macrophage‑derived exosomes promote EGFR‑TKI resistance in non‑small cell lung cancer by regulating the AKT, ERK1/2 and STAT3 signaling pathways". Oncology Letters 24, no. 4 (2022): 356. https://doi.org/10.3892/ol.2022.13476
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