Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth.

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.