Overexpression of C-X-C chemokine receptor type 4 (CXCR4) has been shown in several cancers, including non-small cell lung cancer (NSCLC) and is linked to early metastasis and worse prognosis. The crosstalk between cancer cells and tumor stroma promotes the growth and metastasis and CXCR4 signaling is a key element of this crosstalk. To test the effects of CXCR4 overexpression (CXCR4-OE), we transduced the human NSCLC cell line A549 by using a lentiviral vector. A 3D cell culture model showed generations of tumorspheres and the effects derived by the co-culturing of lung fibroblasts. Using a xenograft mouse model, we also studied the effects of CXCR4-OE in pulmonary cell engraftment and tumor burden in vivo. Our data indicate that CXCR4-OE leads to increased tumorsphere formation and epithelial-mesenchymal transition (EMT). CXCR4-OE by A549 cells resulted in a significant increase in the production of the CXCR4-ligand macrophage migration inhibitory factor (MIF) compared to those transduced with an empty vector (EV) or in which the CXCR4 expression was deleted (KO). In our in vitro system, we did not detect any production of the canonical CXCR4 ligand CXCL12. Autocrine MIF production and CXCR4 signaling are part of a self-perpetuating loop that amplifies tumor growth and EMT. Co-culture with lung fibroblasts further increased tumorsphere formation, partially driven by an increase in IL-6 production. When A549 cells were injected into murine lungs, we observed more abundant and significantly larger tumor lesions in recipients of CXCR4-OE A549 cells compared to those receiving EV or KO cells, consistent with our in vitro findings. Treatment of mice with the MIF antagonist ISO-1 resulted in significantly less tumor burden. In conclusion, our data highlight the role of the CXCR4-OE/MIF/IL-6 axis in epithelial mesenchymal crosstalk and NSCLC progression.

中文翻译：

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CXCR4/MIF 轴放大非小细胞肺癌中的肿瘤生长和上皮间充质相互作用。

CXC 趋化因子受体 4 (CXCR4) 的过度表达已在包括非小细胞肺癌 (NSCLC) 在内的多种癌症中显示出来，并且与早期转移和较差的预后有关。癌细胞和肿瘤基质之间的串扰促进了生长和转移，而 CXCR4 信号是这种串扰的关键因素。为了测试 CXCR4 过表达 (CXCR4-OE) 的影响，我们使用慢病毒载体转导了人 NSCLC 细胞系 A549。一个 3D 细胞培养模型显示了肿瘤球的产生和肺成纤维细胞共培养所产生的影响。使用异种移植小鼠模型，我们还研究了 CXCR4-OE 在肺细胞植入和体内肿瘤负荷中的影响。我们的数据表明 CXCR4-OE 导致肿瘤球形成和上皮间质转化 (EMT) 增加。与用空载体 (EV) 转导或其中 CXCR4 表达被删除 (KO) 的那些相比，A549 细胞的 CXCR4-OE 导致 CXCR4 配体巨噬细胞迁移抑制因子 (MIF) 的产生显着增加。在我们的体外系统中，我们没有检测到任何经典 CXCR4 配体 CXCL12 的产生。自分泌 MIF 的产生和 CXCR4 信号是放大肿瘤生长和 EMT 的自我延续循环的一部分。与肺成纤维细胞共培养进一步增加了肿瘤球的形成，部分原因是 IL-6 产生的增加。当 A549 细胞被注射到鼠肺中时，我们观察到与接受 EV 或 KO 细胞的接受者相比，接受 CXCR4-OE A549 细胞的接受者的肿瘤病变更丰富，而且明显更大，这与我们的体外发现一致。用 MIF 拮抗剂 ISO-1 治疗小鼠显着减少了肿瘤负荷。总之，我们的数据强调了 CXCR4-OE/MIF/IL-6 轴在上皮间充质串扰和 NSCLC 进展中的作用。