Investigation of the role for novel angiogenic factor IL-17 in human non-small cell lung cancer-induced tumor angiogenesis

在这项研究中，我们研究了IL-17对人非小细胞肺癌（NSCLC）的生物学作用。虽然IL-17对NSCLC的体外生长速率没有直接影响，但IL-17选择性地增加了三种NSCLC细胞系的一系列血管生成CXC趋化因子（包括CXCL 1、CXCL 5、CXCL 6和CXCL 8）的分泌，但不增加血管生成抑制趋化因子的分泌。与未受刺激的NSCLC相比，IL-17刺激的NSCLC条件培养基的内皮细胞趋化活性（作为净血管生成潜力的测量）增加。增强的趋化活性被针对CXCL 1、CXCL 5和CXCL 8或CXCR-2的中和mAb抑制，但不被VEGF抑制。用IL-17转染NSCLC对体外生长没有影响，而当移植到SCID小鼠中时，与对照相比，IL-17转染子生长更快。IL-17诱导的NSCLC生长增强与肿瘤血管分布增加相关。此外，用抗小鼠CXCR-2中和Ab治疗显著减弱了SCID小鼠中Neo和IL-17转染的NSCLC肿瘤的生长。IL-17在调节人NSCLC表型中的潜在作用得到以下发现的支持：在原发性NSCLC组织中，IL-17表达通常仅在积聚和浸润的炎性细胞中检测到，并且高水平的IL-17表达与血管分布增加相关。这些结果表明，IL-17通过促进CXCR-2依赖性血管生成来增加NSCLC的净血管生成活性和体内生长，并且表明靶向CXCR-2信号传导可能是治疗NSCLC患者的新的有希望的策略。

In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). While IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively augmented the secretion of an array of angiogenic CXC chemokines including CXCL1, CXCL5, CXCL6 and CXCL8, but not angiostatic chemokines, by three NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned media from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1 CXCL5 and CXCL8 or to CXCR-2, but not to VEGF. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhanced NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2 neutralizing Ab significantly attenuated the growth of both Neo-and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected only in accumulating and infiltrating inflammatory cells and high levels of IL-17 expression were associated with increased vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.