血清血管内皮生长因子-A作为上皮性卵巢癌的预后生物标志物

Serum Vascular Endothelial Growth Factor-A as a Prognostic Biomarker for Epithelial Ovarian Cancer.

作者信息

Komatsu Hiroaki, Oishi Tetsuro, Itamochi Hiroaki, Shimada Muneaki, Sato Shinya, Chikumi Jun, Sato Seiya, Nonaka Michiko, Sawada Mayumi, Wakahara Makoto, Umekita Yoshihisa, Harada Tasuku

机构信息

*Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago; †Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Morioka; and ‡Department of Pathology, Tottori University School of Medicine, Yonago, Japan.

出版信息

Int J Gynecol Cancer. 2017 Sep;27(7):1325-1332. doi: 10.1097/IGC.0000000000001027.

DOI:10.1097/IGC.0000000000001027

PMID:28557832

Abstract

BACKGROUND

Bevacizumab, which targets vascular endothelial growth factor (VEGF)-A, has recently been proven to be effective for the treatment of epithelial ovarian cancer (EOC). Thus, interest in VEGF-A has increased. There are few reports on concomitant detection of both ligands and its soluble receptors in serum samples, and the significance of serum VEGF-A in EOC is unclear, unlike the situation with tissue samples. We conducted the present study to explore the levels of serum VEGF family and its receptors and to evaluate their utility as prognostic biomarkers.

METHODS

A total of 128 patients with EOC, who were consecutively treated at Tottori University Hospital between 2006 and 2012, were included. Blood samples were collected before initial surgery. Serum concentrations of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assay. We also examined the mRNA and protein expression of VEGF-A in tumor tissue from 30 cases by real-time reverse transcription polymerase chain reaction and immunohistochemistry.

RESULTS

The levels of VEGF-A in patients with stage III/IV disease were significantly higher than those with stage I/II disease (P = 0.0036). On the other hand, the level of VEGFR-2 in stage III/IV was significantly lower than that in stage I/II (P = 0.0026). With the cutoff value of VEGF/VEGFRs at the median level, the overall survival (OS) for patients with high VEGF-A levels was significantly lower than those with low levels (P = 0.015). Patients with high VEGFR-2 levels showed better prognosis than those with low VEGFR-2 levels (P = 0.023). Multivariate analysis revealed that International Federation of Gynecology and Obstetrics stage and serum VEGF-A were independent prognostic factors for OS [hazard ratio 2.01, 95% confidence interval (1.13-3.63), P = 0.017]. There was no significant correlation between mRNA or protein expression and serum levels of VEGF-A.

CONCLUSIONS

Serum VEGF-A is an independent prognostic factor for OS in patients with EOC, implying that serum VEGF-A is a prognostic biomarker for EOC. Further study to validate the data is needed.

摘要

背景

贝伐单抗靶向血管内皮生长因子（VEGF）-A，最近已被证明对上皮性卵巢癌（EOC）治疗有效。因此，对VEGF-A的关注度有所增加。关于血清样本中配体及其可溶性受体同时检测的报道较少，与组织样本的情况不同，EOC中血清VEGF-A的意义尚不清楚。我们开展本研究以探究血清VEGF家族及其受体的水平，并评估其作为预后生物标志物的效用。

方法

纳入2006年至2012年期间在鸟取大学医院连续接受治疗的128例EOC患者。在初次手术前采集血样。采用酶联免疫吸附测定法分析血清中VEGF-A、VEGF-C、VEGFR-1和VEGFR-2的浓度。我们还通过实时逆转录聚合酶链反应和免疫组织化学检测了30例患者肿瘤组织中VEGF-A的mRNA和蛋白表达。

结果

III/IV期疾病患者的VEGF-A水平显著高于I/II期疾病患者（P = 0.0036）。另一方面，III/IV期的VEGFR-2水平显著低于I/II期（P = 0.0026）。以VEGF/VEGFRs的中位数水平为临界值，VEGF-A水平高的患者总生存期（OS）显著低于水平低的患者（P = 0.015）。VEGFR-2水平高的患者预后优于VEGFR-2水平低的患者（P = 0.023）。多因素分析显示，国际妇产科联盟分期和血清VEGF-A是OS的独立预后因素[风险比2.01，95%置信区间（1.13 - 3.63），P = 0.017]。VEGF-A的mRNA或蛋白表达与血清水平之间无显著相关性。