title: Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.
abstract: The role of placental growth factor (PlGF) in modulation of tumor angiogenesis and tumor growth remains an enigma. Furthermore, anti-PlGF therapy in tumor angiogenesis and tumor growth remains controversial in preclinical tumor models. Here we show that in both human and mouse tumors, PlGF induced the formation of dilated and normalized vascular networks that were hypersensitive to anti-VEGF and anti-VEGFR-2 therapy, leading to dormancy of a substantial number of avascular tumors. Loss-of-function using plgf shRNA in a human choriocarcinoma significantly accelerated tumor growth rates and acquired resistance to anti-VEGF drugs, whereas gain-of-function of PlGF in a mouse tumor increased anti-VEGF sensitivity. Further, we show that VEGFR-2 and VEGFR-1 blocking antibodies displayed opposing effects on tumor angiogenesis. VEGFR-1 blockade and genetic deletion of the tyrosine kinase domain of VEGFR-1 resulted in enhanced tumor angiogenesis. These findings demonstrate that tumor-derived PlGF negatively modulates tumor angiogenesis and tumor growth and may potentially serve as a predictive marker of anti-VEGF cancer therapy.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology,  Karolinska Institute, 171 77 Stockholm,  Sweden.
authors.forename: Eva-Maria Eleonora
authors.initials: EM
authors.lastname: Hedlund
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Yang
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Yang
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
authors.forename: Weide
authors.initials: W
authors.lastname: Zhong
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hosaka
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism*; D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000378:metabolism; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D019138:Antibodies, Blocking; D000970:Antineoplastic Agents; D017931:DNA Primers; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2