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

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.

Selective Internal Radiotherapy Alters the Profiles of Systemic Extracellular Vesicles in Hepatocellular Carcinoma

“…These findings indicate a proinflammatory status induced by SIRT. Immune cell-derived EVs play crucial roles in intercellular communication and regulation of specific mechanisms of both adaptive and innate immune responses [42][43][44]. Similar to our results, previous research by Tung et al demonstrated the influence of EVs on dendritic cell activity and mobility through the study of dendritic cell interaction with exosomes derived from regulatory T cells (Tregs).…”

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases

“…Third, macrophages play a significant role in promoting chemotherapy resistance or radiation resistance in lung cancer cells through release of exosomes. For instance, the resistance of non-small cell lung cancer cells to epidermal growth factor receptor (EGFR)-targeted drugs could be attributed to the reactivation of AKT, ERK1/2, and signal transducer and activator of transcription 3 (STAT3) signaling pathways facilitated by exosomes released from macrophages ( Yuan et al, 2022 ). Moreover, M2 macrophages can activate the MAPK signaling pathway via exosomes, leading to resistance against the EGFR-targeted drug osimertinib ( Wan et al, 2022 ).…”

Landscape of tumor and immune system cells-derived exosomes in lung cancer: mediators of antitumor immunity regulation

“…On the other hand, exosomes released by macrophages themselves are also relevant, it was found that M2 TAMs secrete exosomes containing miR-155 and miR-196a-5p that can promote EMT, cell migration, cell invasion and cell viability in NSCLC ( 68 ). TAM-derived exosomes can also favor EGFR-TKI resistance in NSCLC via activation of AKT, ERK1/2 and STAT3 signaling pathways ( 69 ). On the contrary, macrophages themselves and other immune cells, even some diseased cells, can polarize the naïve macrophages via exosomes toward a M1 phenotype ( 70 ).…”