title: 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.affiliation: Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yao
authors.forename: Xiumin
authors.initials: X
authors.lastname: Wu
authors.forename: Guanglei
authors.initials: G
authors.lastname: Zhuang
authors.forename: Ian M
authors.initials: IM
authors.lastname: Kasman
authors.forename: Tobias
authors.initials: T
authors.lastname: Vogt
authors.forename: Vernon
authors.initials: V
authors.lastname: Phan
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Napoleone
authors.initials: N
authors.lastname: Ferrara
authors.forename: Carlos
authors.initials: C
authors.lastname: Bais
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000209:etiology / Q000276:immunology* / Q000628:therapy*; D009389:Neovascularization, Pathologic; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D000072483:Placenta Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1