Placenta Growth Factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers

Abstract

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.

Down-Regulation of Placenta Growth Factor by Promoter Hypermethylation in Human Lung and Colon Carcinoma

“…Our preliminary study showed that PlGF expression level was low in lung and colorectal tumor tissues, and this prompted us to study the mechanisms that inhibited the expression of PlGF in these two tumor types. Second, the role of PlGF in tumor angiogenesis and progression is controversial; some published studies suggest that PlGF inhibits tumor angiogenesis and growth (8,9), indicating that PlGF functions as a tumor suppressor gene. Aberrant promoter methylation has been shown to be a common mechanism that regulates tumor suppressors in non -small cell lung cancer and colorectal cancer.…”

“…(5-7) showed that PlGF enhances tumor angiogenesis; on the contrary, studies from Cao et al (8,9) showed that PlGF inhibits the angiogenic effect of VEGF by forming inactive PlGF/VEGF heterodimers. Our recent studies showed that the overexpression of PlGF inhibits human lung and colon carcinoma growth, angiogenesis, and metastasis in orthotopical mouse models, which indicates that PlGF functions as a tumor suppressor gene in the progression of human lung and colorectal carcinomas (10).…”

“…The role of PlGF in pathologic angiogenesis is controversial. Although some studies showed that PlGF enhances pathologic angiogenesis by initiating crosstalk between VEGFR-1 and VEGFR-2 (5-7), others showed that PlGF inhibits tumor growth and angiogenesis (8,9). Our recent studies showed that overexpression of PlGF inhibits tumor growth, angiogenesis, and metastasis in human lung and colon orthotopical tumor models (10).…”

Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis

“…Immunomhistochemical staining was performed according to previously published methods [39][40][41] . Paraffin-embedded tumour issue sections (5 mm) were double-stained with anti-endomucin (1:400; eBioscience, 14-5851-85) and anti-aSMA (1:200; DAKO, M0851) antibodies, followed by staining with a mixture of secondary antibodies comprised of Alexa Fluor 555-labelled goat anti-rat (1:400; Molecular Probes) and Alexa Fluor 488-labelled donkey anti-mouse (1:400; Molecular Probes).…”

Vascular endothelial growth factors (VEGF): role in pathological processes

“…Многие патологические и физиологические процессы в органах и тканях протекают с участием этих факторов (см. рисунок) [9].…”