Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium.
J Hepatol. 2013 Feb;58(2):319-28. doi: 10.1016/j.jhep.2012.09.032. Epub 2012 Oct 6.
BACKGROUND & AIMS: The placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family known to stimulate endothelial cell growth, migration and survival, attract angiocompetent macrophages, and determine the metastatic niche. Unlike VEGF, genetic studies have shown that PlGF is specifically involved in pathologic angiogenesis, thus its inhibition would not affect healthy blood vessels, providing an attractive drug candidate with a good safety profile.
We assess whether inhibition of PlGF could be used as a potential therapy against hepatocellular carcinoma (HCC), by using PlGF knockout mice and monoclonal anti-PlGF antibodies in a mouse model for HCC. In addition, the effect of PlGF antibodies is compared to that of sorafenib, as well as the combination of both therapies.
We have found that both in a transgenic knockout model and in a treatment model, targeting PlGF significantly decreases tumor burden. This was achieved not only by inhibiting neovascularisation, but also by decreasing hepatic macrophage recruitment and by normalising the remaining blood vessels, thereby decreasing hypoxia and reducing the prometastatic potential of HCC.
Considering the favourable safety profile and its pleiotropic effect on vascularisation, metastasis and inflammation, PlGF inhibition could become a valuable therapeutic strategy against HCC.
胎盘生长因子（PlGF）是血管内皮生长因子（VEGF）家族的一员，已知其能刺激内皮细胞生长、迁移和存活，吸引血管生成能力的巨噬细胞，并决定转移灶的微环境。与 VEGF 不同，遗传研究表明 PlGF 特异性参与病理性血管生成，因此其抑制不会影响健康血管，为具有良好安全性特征的药物候选物提供了一个有吸引力的选择。
我们通过 PlGF 基因敲除小鼠和单克隆抗 PlGF 抗体在 HCC 小鼠模型中，评估抑制 PlGF 是否可作为治疗肝细胞癌（HCC）的潜在疗法。此外，我们比较了 PlGF 抗体的作用与索拉非尼的作用，以及两种疗法的联合作用。
我们发现，在转基因敲除模型和治疗模型中，靶向 PlGF 均可显著降低肿瘤负担。这不仅通过抑制新生血管生成来实现，还通过减少肝巨噬细胞募集和使剩余血管正常化来实现，从而降低缺氧程度并降低 HCC 的促转移潜力。
考虑到其有利的安全性特征及其对血管生成、转移和炎症的多效性作用，PlGF 抑制可能成为治疗 HCC 的有价值的治疗策略。
