Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers.
Tumor growth and metastasis require concomitant growth of new blood vessels, which are stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), secreted by most tumors. Whereas the angiogenic property and molecular mechanisms of VEGF have been well studied, the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1 in VEGF-producing tumor cells results in the formation of PlGF-1/VEGF heterodimers and depletion of the majority of mouse VEGF homodimers. The heterodimeric form of PlGF-1/VEGF lacks the ability to induce angiogenesis in vitro and in vivo. Similarly, PlGF-1/VEGF fails to activate the VEGFR-2-mediated signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas and early hepatic metastases. Our data demonstrate that PlGF-1, a member of the VEGF family, acts as a natural antagonist of VEGF when both factors are synthesized in the same population of cells. The underlying mechanism is due to the formation of functionally inactive heterodimers.
Eriksson
Anna
A
Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77, Stockholm, Sweden.
Cao
Renhai
R
Pawliuk
Robert
R
Berg
Sanna Maria
SM
Tsang
Monica
M
Zhou
Danielle
D
Fleet
Christina
C
Tritsaris
Katerina
K
Dissing
Steen
S
Leboulch
Philippe
P
Cao
Yihai
Y
D043925:Angiogenesis Inducing Agents / Q000502:physiology; D000818:Animals; D002633:Chemotaxis; D016510:Corneal Neovascularization / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016228:Endothelial Growth Factors / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008222:Lymphokines / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D000072483:Placenta Growth Factor; D010957:Plasmids; D011257:Pregnancy Proteins / Q000502:physiology*; D020033:Protein Isoforms; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D016228:Endothelial Growth Factors; D007295:Inositol Phosphates; D008222:Lymphokines; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D020033:Protein Isoforms; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor