Yang Yue, He Jianxin, Long Feng, Liu Yongqi, Lin Li, Wei Hulai
Key Laboratory of Environmental Ecology and Population Health in Northwest Minority Areas, State Ethnic Affairs Commission, Northwest Minzu University Lanzhou 730000, Gansu, China.
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University Lanzhou 730000, Gansu, China.
Am J Transl Res. 2025 Jul 15;17(7):4952-4963. doi: 10.62347/RKYL8675. eCollection 2025.
To investigate the mechanisms by which mesenchymal stem cells (MSCs) contribute to erlotinib resistance in non-small cell lung cancer (NSCLC).
HCC827 NSCLC cells were treated with MSC-conditioned medium (MSC-CM). Cell viability and apoptosis were evaluated using MTT assays and flow cytometry, respectively. Protein and mRNA expression levels were assessed by western blotting and quantitative real-time PCR. For validation, a xenograft model was established by co-injecting HCC827 cells and MSCs into NOD/SCID mice.
MSC-CM significantly increased cell viability and reduced apoptosis in HCC827 cells following erlotinib treatment, indicating enhanced drug resistance. Mechanistically, MSC-secreted hepatocyte growth factor (HGF) activated AKT and ERK1/2 phosphorylation, thereby bypassing EGFR inhibition by erlotinib. Neutralization of HGF restored erlotinib sensitivity in MSC-CM-treated HCC827 cells. Furthermore, osteopontin (OPN) was transcriptionally upregulated and acted as a resistance enhancer. Inhibition of OPN attenuated MSC-CM-mediated resistance. , tumors derived from co-injected MSCs and HCC827 cells exhibited significantly greater volume and weight after erlotinib treatment compared to control tumors.
This study identifies a novel MSC-mediated resistance mechanism in which MSC-derived HGF activates compensatory AKT/ERK1/2 signaling, circumventing EGFR blockade by erlotinib. Concurrent upregulation of OPN in NSCLC cells forms a synergistic survival axis under erlotinib pressure. These findings suggest that targeting MSC-derived HGF and tumor-derived OPN may offer promising strategies to overcome erlotinib resistance in NSCLC.
研究间充质干细胞（MSC）导致非小细胞肺癌（NSCLC）对厄洛替尼耐药的机制。
用MSC条件培养基（MSC-CM）处理HCC827 NSCLC细胞。分别使用MTT法和流式细胞术评估细胞活力和凋亡情况。通过蛋白质印迹法和定量实时PCR评估蛋白质和mRNA表达水平。为进行验证，将HCC827细胞和MSC共同注射到NOD/SCID小鼠体内建立异种移植模型。
厄洛替尼处理后，MSC-CM显著提高了HCC827细胞的活力并减少了凋亡，表明耐药性增强。机制上，MSC分泌的肝细胞生长因子（HGF）激活了AKT和ERK1/2磷酸化，从而绕过了厄洛替尼对EGFR的抑制作用。中和HGF可恢复MSC-CM处理的HCC827细胞对厄洛替尼的敏感性。此外，骨桥蛋白（OPN）转录上调并作为耐药增强因子发挥作用。抑制OPN可减弱MSC-CM介导的耐药性。与对照肿瘤相比，共同注射MSC和HCC827细胞产生的肿瘤在厄洛替尼处理后体积和重量显著更大。
本研究确定了一种新的MSC介导的耐药机制，其中MSC衍生的HGF激活代偿性AKT/ERK1/2信号传导，规避了厄洛替尼对EGFR的阻断。NSCLC细胞中OPN的同时上调在厄洛替尼压力下形成了协同生存轴。这些发现表明，靶向MSC衍生的HGF和肿瘤衍生的OPN可能为克服NSCLC对厄洛替尼的耐药性提供有前景的策略。
