Document Detail


Tumor cell-derived placental growth factor sensitizes antiangiogenic and antitumor effects of anti-VEGF drugs.
MedLine Citation:
PMID:  23267058     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Eva-Maria Eleonora Hedlund; Xiaojuan Yang; Yin Zhang; Yunlong Yang; Masabumi Shibuya; Weide Zhong; Baocun Sun; Yizhi Liu; Kayoko Hosaka; Yihai Cao
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-12-24
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-09     Completed Date:  2013-03-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  654-9     Citation Subset:  IM    
Affiliation:
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Angiogenesis Inhibitors / metabolism*
Animals
Antibodies, Blocking / pharmacology
Antineoplastic Agents / metabolism*
Cell Line, Tumor
Choriocarcinoma / genetics*,  metabolism
DNA Primers / genetics
Drug Resistance, Neoplasm / drug effects
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Humans
Male
Mice
Mice, Inbred C57BL
Neovascularization, Pathologic / chemically induced*,  metabolism
Pregnancy Proteins / metabolism,  pharmacology*
RNA, Small Interfering / genetics,  pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Antibodies, Blocking; 0/Antineoplastic Agents; 0/DNA Primers; 0/Pregnancy Proteins; 0/RNA, Small Interfering; 0/Vascular Endothelial Growth Factor A; 144589-93-5/placenta growth factor; EC 2.7.10.1/Vascular Endothelial Growth Factor Receptor-2
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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