Tanaka Fumihiro, Ishikawa Shinya, Yanagihara Kazuhiro, Miyahara Ryo, Kawano Yozo, Li Mio, Otake Yosuke, Wada Hiromi
Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, 606-8507 Japan.
Cancer Res. 2002 Dec 1;62(23):7124-9.
Angiopoietin (Ang)-1 and -2 have been recently identified as potent angiogenic factors which function in concert with vascular endothelial growth factor (VEGF), but no detailed clinical study on Ang expression has been reported. To assess the clinical significance of Ang expression in non-small cell lung cancer (NSCLC), a total of 236 patients with pathological stage-I-IIIA disease were retrospectively reviewed. Expression of Ang-1, Ang-2, or VEGF was examined immunohistochemically; intratumoral microvessel density (IMVD) was examined with immunohistochemical staining against CD34, a marker of pan-endothelial cells (CD34-IMVD), and that against CD105, a marker of proliferative endothelial cells (CD105-IMVD). Positive expression of Ang-1 and that of Ang-2 were seen in 101 (42.8%) and 40 patients (16.9%), respectively. There was no significant correlation between Ang-1 expression and CD34-IMVD or CD105-IMVD. In contrast, the average CD105-IMVD for Ang-2-positive tumor was significantly higher than that for Ang-2-negative tumor (56.7 versus 38.5; P = 0.032). More interestingly, such an angiogenic effect of Ang-2 was seen only when VEGF expression was high; when VEGF expression was high, the average CD105-IMVD for Ang-2-positive tumor was significantly higher than that for Ang-2-negative tumor (89.1 versus 63.6; P = 0.045); when VEGF expression was low, the average CD105-IMVD for Ang-2-positive tumor and that for Ang-2-negative tumor were almost the same (27.4 and 27.1, respectively). Moreover, positive expression of Ang-2, not Ang-1, was a significant factor to predict a poor postoperative survival (5-year survival rates for Ang-2-positive patients and -negative patients were 53.5 and 70.3%, respectively; P = 0.027), which was confirmed by a multivariate analysis. The influence of Ang-2 status on postoperative survival was enhanced when VEGF expression was high. That said, the 5-year survival of Ang-2-positive and VEGF-high patients was extremely low (41.4%) as compared with that for Ang-2-negative and VEGF-low patients (66.6%), as compared with that for Ang-2-positive and VEGF-low patients (63.6%), and as compared with that for Ang-2-negative and VEGF-low patients (71.8%). In conclusion, positive Ang-2 expression was significantly correlated with a poor prognosis, as well as with aggressive angiogenesis in resected NSCLC that was enhanced in the presence of high VEGF expression.
血管生成素（Ang）-1和-2最近被确认为有效的血管生成因子，它们与血管内皮生长因子（VEGF）协同发挥作用，但尚未有关于Ang表达的详细临床研究报道。为评估Ang表达在非小细胞肺癌（NSCLC）中的临床意义，我们对236例病理分期为I-IIIA期的患者进行了回顾性研究。采用免疫组织化学方法检测Ang-1、Ang-2或VEGF的表达；通过针对全内皮细胞标志物CD34（CD34-IMVD）和增殖内皮细胞标志物CD105（CD105-IMVD）的免疫组织化学染色来检测肿瘤内微血管密度（IMVD）。Ang-1和Ang-2的阳性表达分别见于101例（42.8%）和40例（16.9%）患者。Ang-1表达与CD34-IMVD或CD105-IMVD之间无显著相关性。相比之下，Ang-2阳性肿瘤的平均CD105-IMVD显著高于Ang-2阴性肿瘤（56.7对38.5；P = 0.032）。更有趣的是，只有当VEGF表达较高时，Ang-2才具有这种血管生成作用；当VEGF表达较高时，Ang-2阳性肿瘤的平均CD105-IMVD显著高于Ang-2阴性肿瘤（89.1对63.6；P = 0.045）；当VEGF表达较低时，Ang-2阳性肿瘤和Ang-2阴性肿瘤的平均CD105-IMVD几乎相同（分别为27.4和27.1）。此外，Ang-2而非Ang-1的阳性表达是预测术后生存不良的重要因素（Ang-2阳性和阴性患者的5年生存率分别为53.5%和70.3%；P = 0.027），多因素分析证实了这一点。当VEGF表达较高时，Ang-2状态对术后生存的影响增强。也就是说，如果与Ang-2阴性和VEGF低表达患者（66.6%）、Ang-2阳性和VEGF低表达患者（63.6%）以及Ang-2阴性和VEGF高表达患者（71.8%）相比，Ang-2阳性和VEGF高表达患者的5年生存率极低（41.4%）。总之，Ang-2阳性表达与预后不良显著相关，同时也与切除的NSCLC中活跃的血管生成相关，且在高VEGF表达情况下这种相关性增强。
