FGF18 as a prognostic and therapeutic biomarker in ovarian cancer
FGF18 as a prognostic and therapeutic biomarker in ovarian cancer
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DOI：
10.1172/jci70625
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发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Birrer, Michael J.
中科院分区：
文献类型：
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作者：
Wei, Wei;Mok, Samuel C.;Birrer, Michael J.
高通量基因组技术已经确定了卵巢癌的生物标志物和潜在的治疗靶点。需要对这些生物标志物的生物学和临床意义进行全面的功能验证研究，以将其推向临床应用。染色体区域5 q31 -5q35.3的扩增已被用于预测晚期、高级别浆液性卵巢癌患者的不良预后。在这项研究中，我们进一步分析了这个大的扩增子，并确定了FGF 18的过表达作为该患者人群中不良临床结局的独立预测标志物。利用细胞培养和异种移植模型，我们发现FGF 18信号通过调节卵巢肿瘤的侵袭性和微侵袭性促进肿瘤进展。FGF 18通过NF-κ B活化，增加致癌细胞因子和趋化因子的产生，控制卵巢癌细胞的迁移、侵袭和致瘤性。这导致肿瘤微环境的特征在于增强的血管生成和增强的肿瘤相关巨噬细胞浸润和M2极化。来自卵巢癌患者的肿瘤具有增加的FGF 18表达水平以及微血管密度和M2巨噬细胞浸润，证实了我们的体外结果。这些发现表明，FGF 18对一部分卵巢癌很重要，并可作为治疗靶点。
High-throughput genomic technologies have identified biomarkers and potential therapeutic targets for ovarian cancer. Comprehensive functional validation studies of the biological and clinical implications of these biomarkers are needed to advance them toward clinical use. Amplification of chromosomal region 5q31-5q35.3 has been used to predict poor prognosis in patients with advanced stage, high-grade serous ovarian cancer. In this study, we further dissected this large amplicon and identified the overexpression of FGF18 as an independent predictive marker for poor clinical outcome in this patient population. Using cell culture and xenograft models, we show that FGF18 signaling promoted tumor progression by modulating the ovarian tumor aggressiveness and microenvironrnent. FGF18 controlled migration, invasion, and tumorigenicity of ovarian cancer cells through NF-kappa B activation, which increased the production of oncogenic cytokines and chemokines. This resulted in a tumor microenvironment characterized by enhanced angiogenesis and augmented tumor-associated macrophage infiltration and M2 polarization. Tumors from ovarian cancer patients had increased FGF18 expression levels with microvessel density and M2 macrophage infiltration, confirming our in vitro results. These findings demonstrate that FGF18 is important for a subset of ovarian cancers and may serve as a therapeutic target.