Purpose

Previously, inflammation has been found to be associated with the development of lung cancer. Despite their well-characterized pro-inflammatory functions, the putative roles of interleukin-17 (IL-17) cytokine family members in tumorigenesis have remained controversial. While IL-17A exhibits both pro- and anti-tumor effects, IL-17F has been suggested to serve as a candidate for cancer therapy. Thus, we aimed at clarifying the involvement of IL-17A/F in lung cancer.

Methods

IL-17 receptor expression in human and murine lung cancer cells was assessed using immunofluorescence. The effect of IL-17A/F stimulation on lung cancer cell viability (SRB assay) and metabolism (glucose consumption and lactate production) was evaluated under normoxic and hypoxic conditions. Characterization of IL-17A/F-stimulated macrophages was performed by flow cytometry and ELISA. The effect of conditioned media (CM) from IL-17A/F-stimulated macrophages was evaluated on lung cancer cell migration. The effect of CM-stimulated macrophages on lung tumor growth, proliferation and angiogenesis was evaluated in vivo using a chicken chorioallantoic membrane (CAM) assay.

Results

No alterations in lung cancer cell viability or metabolism were observed upon direct stimulation with IL-17A/F. We found, however, that CM from IL-17A/F-stimulated macrophages promoted both murine and human lung cancer cell progression through an increased migration capacity in vitro and enhanced in vivo tumor growth, proliferation and angiogenesis. These findings were supported by an increased polarization of human macrophages towards a M2-like phenotype.

Conclusions

Our data indicate that IL-17A/F act through immune cell orchestration, i.e., of macrophages, to promote lung cancer cell growth and progression. In addition, our data provide a link between IL-17A/F activity and lung cancer cell-macrophage crosstalk.

中文翻译：

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IL-17A和IL-17F编排巨噬细胞以促进肺癌。

目的

以前，已经发现炎症与肺癌的发展有关。尽管它们具有明确的促炎功能，但是白介素17（IL-17）细胞因子家族成员在肿瘤发生中的假定作用仍存在争议。尽管IL-17A既表现出抗肿瘤作用又表现出抗肿瘤作用，但已提出IL-17F可以作为癌症治疗的候选药物。因此，我们旨在阐明IL-17A / F与肺癌的关系。

方法

使用免疫荧光评估人和鼠肺癌细胞中的IL-17受体表达。在常氧和低氧条件下，评估了IL-17A / F刺激对肺癌细胞生存力（SRB分析）和新陈代谢（葡萄糖消耗和乳酸产生）的影响。通过流式细胞仪和ELISA对IL-17A / F刺激的巨噬细胞进行表征。评估了IL-17A / F刺激的巨噬细胞的条件培养基（CM）对肺癌细胞迁移的影响。使用鸡绒膜尿囊膜（CAM）测定法在体内评估了CM刺激的巨噬细胞对肺肿瘤生长，增殖和血管生成的影响。

结果

用IL-17A / F直接刺激后，未观察到肺癌细胞活力或代谢的改变。然而，我们发现，IL-17A / F刺激的巨噬细胞中的CM通过增加体外迁移能力并增强体内肿瘤生长，增殖和血管生成，促进了鼠和人肺癌细胞的进程。这些发现得到了人类巨噬细胞向M2样表型的日益极化的支持。

结论

我们的数据表明，IL-17A / F通过免疫细胞编排（即巨噬细胞）起作用，以促进肺癌细胞的生长和进程。此外，我们的数据提供了IL-17A / F活性与肺癌细胞-巨噬细胞串扰之间的联系。