Abstract |
Recruitment of bone marrow-derived myelomonocytic cells plays a fundamental role in tumor angiogenesis and metastasis. Placental growth factor (PlGF) is a potent cytokine that can attract myelomonocytic cells to the tumor. However, the underlying mechanism remains obscure. In this study, we demonstrate that tumor-derived PlGF activates NFAT1 via vascular endothelial growth factor receptor 1 in both murine and human myelomonocytic cells. Activation of NFAT1 is crucial for PlGF-induced myelomonocytic cell recruitment as shown by the in vitro transwell migration assay, transendothelial migration assay, and PlGF-overexpressing tumor models in mice, respectively. TNF-alpha is upregulated by PlGF in myelomonocytic cells in an NFAT1-dependent manner, which in turn contributes to PlGF-induced myelomonocytic cell recruitment. Blockade of TNF-alpha expression by RNA interference or neutralization of secreted TNF-alpha with its Ab attenuates PlGF-induced myelomonocytic cell migration and transendothelial migration. Furthermore, the inhibitory effect of NFAT1 RNA interference on PlGF function is rescued by exogenously added TNF-alpha. Taken together, we demonstrate that NFAT1 mediates PlGF-induced myelomonocytic cell recruitment via the induction of TNF-alpha. Our present studies discover a novel role of the NFAT1-TNF-alpha pathway in tumor inflammation, which may provide potential targets to diversify current cancer therapy.
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Authors | Yanping Ding, Yujie Huang, Nan Song, Xiaobin Gao, Shaopeng Yuan, Xiaofeng Wang, Hongchen Cai, Yan Fu, Yongzhang Luo |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 184
Issue 5
Pg. 2593-601
(Mar 01 2010)
ISSN: 1550-6606 [Electronic] United States |
PMID | 20097868
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- NFATC Transcription Factors
- Oligopeptides
- PGF protein, human
- Pgf protein, mouse
- Pregnancy Proteins
- Tumor Necrosis Factor-alpha
- VIVIT peptide
- Placenta Growth Factor
- Cyclosporine
- Vascular Endothelial Growth Factor Receptor-1
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Topics |
- Animals
- Cell Line
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cyclosporine
(pharmacology)
- Fluorescent Antibody Technique
- Humans
- Immunoblotting
- Mice
- Mice, Inbred C57BL
- Monocytes
(cytology, metabolism)
- Myeloid Cells
(cytology, metabolism)
- NFATC Transcription Factors
(antagonists & inhibitors, genetics, metabolism)
- Neoplasms, Experimental
(genetics, metabolism, pathology)
- Oligopeptides
(pharmacology)
- Placenta Growth Factor
- Pregnancy Proteins
(genetics, metabolism)
- RNA Interference
- Transfection
- Transplantation, Heterologous
- Tumor Necrosis Factor-alpha
(genetics, metabolism)
- Vascular Endothelial Growth Factor Receptor-1
(genetics, metabolism)
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