Expression of a functional VEGFR-1 in tumor cells is a major determinant of anti-PlGF antibodies efficacy.

Abstract

PlGF, one of the ligands for VEGFR-1, has been implicated in tumor angiogenesis. However, more recent studies indicate that genetic or pharmacological inhibition of PlGF signaling does not result in reduction of microvascular density in a variety of tumor models. Here we screened 12 human tumor cell lines and identified 3 that are growth inhibited by anti-PlGF antibodies in vivo. We found that efficacy of anti-PlGF treatment strongly correlates with VEGFR-1 expression in tumor cells, but not with antiangiogenesis. In addition, PlGF induced VEGFR-1 signaling and biological responses in tumor cell lines sensitive to anti-PlGF, but not in refractory tumor cell lines or in endothelial cells. Also, genetic ablation of VEGFR-1 signaling in the host did not affect the efficacy of PlGF blockade. Collectively, these findings suggest that the role of PlGF in tumorigenesis largely consists of promoting autocrine/paracrine growth of tumor cells expressing a functional VEGFR-1 rather than stimulation of angiogenesis.

• Authors: Jenny Yao, Xiumin Wu, Guanglei Zhuang, Ian M Kasman, Tobias Vogt, Vernon Phan, Masabumi Shibuya, Napoleone Ferrara, Carlos Bais
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 28 Pg. 11590-5 (Jul 12 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21709213 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• PGF protein, human
• Pgf protein, mouse
• Pregnancy Proteins
• RNA, Small Interfering
• Placenta Growth Factor
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage)
• Cell Line, Tumor
• Endothelial Cells (drug effects, metabolism)
• Female
• Gene Knockdown Techniques
• Humans
• MAP Kinase Signaling System
• Mice
• Mice, Inbred BALB C
• Mice, Knockout
• Mice, Nude
• Neoplasms (blood supply, etiology, immunology, therapy)
• Neovascularization, Pathologic
• Placenta Growth Factor
• Pregnancy Proteins (antagonists & inhibitors, immunology, pharmacology)
• RNA, Small Interfering (genetics)
• Signal Transduction
• Stromal Cells (metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors, genetics, metabolism)