Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 34, Pages 13932-13937Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309629110
Keywords
VEGF receptor signaling; neovascularization; antiangiogenic therapy
Categories
Funding
- Swedish Research Council
- Swedish Cancer Foundation
- Karolinska Institute Foundation
- Karolinska Institute Distinguished Professor Award
- Torsten Soderbergs Foundation
- Soderbergs Stiftelse
- Tianjin Natural Science Foundation (CMM-Tianjin) Grant [09ZCZDSF04400]
- ImClone/Eli Lilly
- European Union [222741]
- European Research Council Advanced ANGIOFAT Grant Project [250021]
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Placental growth factor (PIGF) remodels tumor vasculatures toward a normalized phenotype, which affects tumor growth, invasion and drug responses. However, the coordinative and spatiotemporal relation between PIGF 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 PIGF-expressing tumors resulted in (i) accelerated tumor growth rates and angiogenesis and (ii) complete attenuation of PIGF-induced vascular normalization. Thus, PIGF 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 PIGF and VEGF in modulation of tumor growth and angiogenesis, and have conceptual implication for antiangiogenic cancer therapy.
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