Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13932-7. doi: 10.1073/pnas.1309629110. Epub 2013 Aug 5.
Placental growth factor (PlGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PlGF and VEGF in modulation of tumor angiogenesis and vascular remodeling is less understood. Here we report that PlGF positively and negatively modulate tumor growth, angiogenesis, and vascular remodeling through a VEGF-dependent mechanism. In two independent tumor models, we show that PlGF inhibited tumor growth and angiogenesis and displayed a marked vascular remodeling effect, leading to normalized microvessels with infrequent vascular branches and increased perivascular cell coverage. Surprisingly, elimination of VEGF gene (i.e., VEGF-null) in PlGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PlGF-induced vascular normalization. Thus, PlGF positively and negatively modulates tumor growth, angiogenesis, and vascular remodeling through VEGF-dependent spatiotemporal mechanisms. Our data uncover molecular mechanisms underlying the complex interplay between PlGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.
胎盘生长因子（PlGF）重塑肿瘤血管，使其向正常表型发展，从而影响肿瘤生长、侵袭和药物反应。然而，PlGF 和 VEGF 之间在调节肿瘤血管生成和血管重塑方面的协调和时空关系还不太清楚。在这里，我们报告 PlGF 通过 VEGF 依赖性机制正向和负向调节肿瘤生长、血管生成和血管重塑。在两个独立的肿瘤模型中，我们表明 PlGF 抑制肿瘤生长和血管生成，并显示出明显的血管重塑作用，导致正常化的微血管，血管分支较少，周细胞覆盖增加。令人惊讶的是，消除 PlGF 表达肿瘤中的 VEGF 基因（即 VEGF 缺失）导致（i）肿瘤生长速度和血管生成加快，以及（ii）PlGF 诱导的血管正常化完全减弱。因此，PlGF 通过 VEGF 依赖性时空机制正向和负向调节肿瘤生长、血管生成和血管重塑。我们的数据揭示了 PlGF 和 VEGF 之间在调节肿瘤生长和血管生成方面的复杂相互作用的分子机制，并为抗血管生成癌症治疗提供了概念上的启示。
