Abstract
A further understanding of tumor angiogenesis is urgently needed due to the limited therapeutic efficacy of anti-angiogenesis agents. However, the origin of endothelial cells (EC) in tumors remains widely elusive and controversial. Snail has been thoroughly elucidated as a master regulator of the epithelial–mesenchymal transition (EMT), but its role in endothelium generation is not yet established. In this study, we reported a new and unexpected function of Snail in endothelium generation by breast cancer cells. We showed that high Snail-expressing breast cancer cells isolated from patients showed more endothelium generated from these cells. Expression of Snail was positively correlated with endothelial markers in breast cancer patients. The ectopic expression of Snail induced endothelial marker expression, tube formation and DiI-AcLDL uptake of breast cancer cells in vitro, and enhanced tumor growth and microvessel density in vivo. Snail-mediated endothelium generation depended on VEGF and Sox2. Mechanistically, Snail promoted the expression of VEGF and Sox2 through recruiting the p300 activator complex to these promoters. We showed the dual function of Snail in tumor initiation and angiogenesis in vivo and in vitro through activation of Sox2 and VEGF, suggesting Snail may be an ideal target for cancer therapy.
Highlights
Tumor angiogenesis is a crucial step for tumor growth, progression, and metastasis
Tumor angiogenesis is a hallmark of cancer development, which has been considered as an attractive therapeutic target[3]
Accumulating evidences suggest that the pathway of regulating cancer stem cell-like (CSC) and angiogenesis are closely related, which may provide new targets for cancer therapy[24,25]
Summary
Tumor angiogenesis is a crucial step for tumor growth, progression, and metastasis. As the major regulator of angiogenesis, the vascular endothelial growth factor (VEGF) pathway represents an ideal therapeutic target for cancer therapy[1,2]. It was thought that tumor blood vessels originate from nearby normal vessels or by recruiting circulating endothelial and other cells into the tumor[6,7]. Increasing researches proposed that cancer stem cell-like (CSC) cells in breast cancer, ovarian cancer, and glioblastomas have the potential to differentiate into EC8–11. It was reported that CSCs, and tumor cells, have the potential to give rise to endothelial phenotypes and directly participate in tumor angiogenesis.
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