NFAT1 mediates placental growth factor-induced myelomonocytic cell recruitment via the induction of TNF-alpha.
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.
Ding
Yanping
Y
National Engineering Laboratory for Antitumor Protein Therapeutics, Beijing Key Laboratory for Protein Therapeutics, and Cancer Biology Laboratory, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, People's Republic of China.
Huang
Yujie
Y
Song
Nan
N
Gao
Xiaobin
X
Yuan
Shaopeng
S
Wang
Xiaofeng
X
Cai
Hongchen
H
Fu
Yan
Y
Luo
Yongzhang
Y
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
D050778:NFATC Transcription Factors; D009842:Oligopeptides; C000608036:PGF protein, human; C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D014409:Tumor Necrosis Factor-alpha; C121611:VIVIT peptide; D000072483:Placenta Growth Factor; D016572:Cyclosporine; D040281:Vascular Endothelial Growth Factor Receptor-1