IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis
IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis
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DOI：
10.4049/jimmunol.175.9.6177
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发表时间：
2005-11-01
影响因子：
4.4
通讯作者：
Sasaki, H
中科院分区：
文献类型：
--
作者：
Numasaki, M;Watanabe, M;Sasaki, H
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不同NSCLC细胞系的一系列血管生成CXC趋化因子的分泌，包括CXCL 1、CXCL 5、CXCL 6和CXCL 8，但不增加血管生成抑制趋化因子的分泌。内皮细胞趋化活性（作为净血管生成潜力的量度）在对来自用11-17刺激的NSCLC的条件培养基的响应中与来自未刺激的NSCLC的条件培养基相比增加。增强的趋化活性可被CXCL 1、CXCL 5和CXCL 8或CXCR-2的中和mAb抑制，但不被血管内皮生长因子-A的中和mAb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。这种IL-17引起的NSCLC生长增强与肿瘤血管分布增加相关。此外，用抗小鼠CXCR-2中和抗体治疗显著减弱了SCID小鼠中新霉素磷酸转移酶基因转染和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表达经常在积聚和浸润的炎性细胞中检测到，并且高水平的IL-17表达与肿瘤血管分布增加相关。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). Although 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 different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with 11-17 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 vascular endothelial growth factor-A. 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 enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected 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 in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor 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.