Angiopoietin-2 Levels Are Associated with Disease Progression in Metastatic Malignant Melanoma
Angiopoietin-2 Levels Are Associated with Disease Progression in Metastatic Malignant Melanoma
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DOI：
10.1158/1078-0432.ccr-08-1615
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发表时间：
2009-02-15
影响因子：
11.5
通讯作者：
Augustin, Hellmut G.
中科院分区：
文献类型：
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作者：
Helfrich, Iris;Edler, Lutz;Augustin, Hellmut G.
目的：血管去稳定化Tie 2配体血管生成素-2（Ang-2）与血管内皮生长因子/血管内皮生长因子受体系统协同作用以控制肿瘤进展期间的血管组装。我们假设，循环可溶性血管紧张素-2（sAng-2）可能参与黑色素瘤的进展实验设计：血清样本（n = 98）从黑色素瘤患者（美国癌症联合委员会阶段I-IV），活检相应的患者，和人黑色素瘤细胞系进行了分析的Ang-2和S100 β的表达。在从III期进展至IV期期间，检测了33例患者的子队列的多份血清。结果：循环中sAng-2水平与黑色素瘤患者的肿瘤进展（P < 0.0001）和患者生存期（P = 0.007）相关。在从III期到IV期的过渡期间对血清样品的分析鉴定出sAng-2增加高达400%。比较分析显示，sAng-2作为预测标志物优于已建立的标志物S100 β 56%。免疫组织化学和逆转录-PCR证实了肿瘤相关内皮细胞的Ang-2的显著表达，但确定Ang-2也作为黑色素瘤细胞本身的分泌产物。相应的细胞实验表明，人黑色素瘤分离的肿瘤细胞Tie 2阳性，并认为Ang-2作为黑色素瘤细胞的迁移和invasion.Conclusions的自分泌调节：实验建立sAng-2作为黑色素瘤的进展和转移的生物标志物与肿瘤负荷和总生存率。控制黑色素瘤迁移和侵袭的自分泌血管生成素/Tie环的鉴定保证了进一步的功能实验，并验证了血管生成素/Tie系统作为人类黑色素瘤的有前途的治疗靶点。
Purpose: The blood vessel-destabilizing Tie2 ligand angiopoietin-2 (Ang-2) acts in concert with the vascular endothelial growth factor/vascular endothelial growth factor receptor system to control vessel assembly during tumor progression. We hypothesized that circulating soluble Ang-2 (sAng-2) may be involved in melanoma progression.Experimental Design: Serum samples (n = 98) from melanoma patients (American Joint Committee on Cancer stages I-IV), biopsies of corresponding patients, and human melanoma cell lines were analyzed for expression of Ang-2 and S100 beta. Multiple sera of a subcohort of 33 patients were tested during progression from stage III to IV. Small interfering RNA-based loss-of-function experiments were done to assess effects of Ang-2 on melanoma cells.Results: Circulating levels of sAng-2 correlate with tumor progression in melanoma patients (P < 0.0001) and patient survival (P = 0.007). Analysis of serum samples during the transition from stage III to IV identified an increase of sAng-2 up to 400%. Comparative analyses revealed a 56% superiority of sAng-2 as predictive marker over the established marker S100 beta. Immunohistochemistry and reverse transcription-PCR confirmed the prominent expression of Ang-2 by tumor-associated endothelial cells but identified Ang-2 also as a secreted product of melanoma cells themselves. Corresponding cellular experiments revealed that human melanoma-isolated tumor cells were Tie2 positive and that Ang-2 acted as an autocrine regulator of melanoma cell migration and invasion.Conclusions: The experiments establish sAng-2 as a biomarker of melanoma progression and metastasis correlating with tumor load and overall survival. The identification of an autocrine angiopoietin/Tie loop controlling melanoma migration and invasion warrants further functional experiments and validate the angiopoietin/Tie system as a promising therapeutic target for human melanomas.