Inhibition of Nodal suppresses angiogenesis and growth of human gliomas

Abstract

Angiogenesis is the hallmark of malignant gliomas positively correlated with the vascular endothelial growth factor (VEGF) expression. We previously reported that expression levels of Nodal, a member of transforming growth factor-β super family, correlate with the malignant invasive behavior of human glioma cells. In this study, we show that knockdown of Nodal suppresses glioma angiogenesis by inhibition of VEGF. In human primary glioma specimens, expression of Nodal positively correlates with WHO glioma tumor grades and expression of VEGF in the corresponding glioma specimens. In human U87MG glioma cells, knockdown of endogenous Nodal by RNA interference (RNAi) significantly decreases colony formation and secretion of VEGF. In vivo, cellular depletion of Nodal in U87MG inhibited brain glioma growth and prolonged the survival of mice with U87MG/shNodal glioma compared with controls. Inhibition of Nodal suppressed tumor vessel growth in U87MG gliomas. Using Nodal inhibitor (SB431542), silencing Nodal, or overexpressing Nodal in the U87MG, GBM8401, and GBM glioma cells, our further experiments revealed that Nodal-induced VEGF expression might, at least in part, mediate through the ERK1/2-HIF-1α-mediated signaling pathway. Taken together, our data revealed that alteration of Nodal expression in glioma cells resulted in changes to VEGF secretion, and subsequent colony formation, in vivo tumor growth, and angiogenesis, all of which are consistent with the regulation of VEGF through the ERK1/2-HIF-1α-mediated signaling, suggesting that Nodal may serve as a potential therapeutic target for the treatment of human gliomas.

Embryonic Protein Nodal Promotes Breast Cancer Vascularization

“…In accordance with previous studies in glioma, Nodal promoted VEGF and PDGF expression in all of the human breast cancer cell lines tested (14). However, we found that there were differences in protein expression between lysate and conditioned media within a particular cell type, suggesting that Nodal may be involved in regulation of protein trafficking, protein stability, or secretion.…”

“…In addition, a mesenchymallike subclass of high-grade gliomas has been shown to exhibit elevated expression of proangiogenic factors, including VEGF and PECAM (CD31), and a recent study revealed that glioma stem cell-like populations promote vascularization via a combinatorial mechanism involving the secretion of VEGF and stromal derived factor-1 (12,13). Lastly, one study has reported that Nodal regulates VEGF expression and vessel density in gliomas (14). However, this latter study did not directly assess the role of Nodal in the regulation of angiogenesis or vasculogenesis.…”

Lefty inhibits glioma growth by suppressing Nodal-activated Smad and ERK1/2 pathways

“…Lee et al [11] showed that Nodal over-expression increased the secretion of MMP-2, enhanced cell invasiveness, and promoted cell proliferation in vitro, as well as increased tumor growth in vivo. A subsequent report indicated that Nodal stimulated the angiogenesis in U87 glioblastoma cells, and that ERK1/2-HIF-1α signaling pathway was involved in this process [16].…”

Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment

“…These data indicate that higher levels of Nodal are found within TNBC even when compared to invasive receptor positive tumors (summarized in Table 1), and are in agreement with studies that have reported correlations with Nodal expression and aggressive cancer-related characteristics. 13,15,[18][19][20][21][22][23] Collectively, our results demonstrate the robust presence of Nodal in TNBC samples, representing a potential new target for this disease.…”