NFAT1 Mediates Placental Growth Factor-Induced Myelomonocytic Cell Recruitment via the Induction of TNF-α

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.