Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs
Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs
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DOI：
10.1073/pnas.1209310110
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发表时间：
2013-01-08
影响因子：
11.1
通讯作者：
Cao, Yihai
中科院分区：
文献类型：
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作者：
Hedlund, Eva-Maria Eleonora;Yang, Xiaojuan;Cao, Yihai
胎盘生长因子（PlGF）在调节肿瘤血管生成和肿瘤生长中的作用仍然是一个谜。此外，在临床前肿瘤模型中，抗PlGF治疗在肿瘤血管生成和肿瘤生长中仍然存在争议。在这里，我们表明，在人类和小鼠肿瘤中，PlGF诱导形成扩张和正常化的血管网络，对抗VEGF和抗VEGFR-2治疗过敏，导致大量无血管肿瘤的休眠。在人绒毛膜癌中使用plgf shRNA的功能丧失显著加速肿瘤生长速率并获得对抗VEGF药物的抗性，而在小鼠肿瘤中PlGF的功能获得增加抗VEGF敏感性。此外，我们表明，VEGFR-2和VEGFR-1阻断抗体显示对肿瘤血管生成的相反作用。VEGFR-1阻断和VEGFR-1酪氨酸激酶结构域的基因缺失导致肿瘤血管生成增强。这些发现表明，肿瘤衍生的PlGF负调节肿瘤血管生成和肿瘤生长，并可能作为抗VEGF癌症治疗的预测标志物。
The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.