Abstract
Vasculogenic mimicry (VM) is a nonangiogenesis-dependent pathway that promotes tumor growth and disease progression. Nodal signaling has several vital roles in both embryo development and cancer progression. However, the effects of Nodal signaling on VM formation in breast cancer and its underlying mechanisms are ill-defined. We analyzed the relationship between Nodal signaling and VM formation in one hundred human breast cancer cases and the results showed that the expression of Nodal was significantly correlated with VM formation, tumor metastasis, differentiation grade, TNM stage and poor prognosis. Furthermore, up-regulation of Nodal expression promoted VM formation of breast cancer cells in vitro and in vivo. Knockdown of Nodal expression restrained VM formation. In addition, Nodal induced EMT and up-regulated the expression of Slug, Snail and c-Myc. We found that blocking the Smad2/3 pathway by administering SB431542 inhibited VM formation in breast cancer cell lines and xenografts. Taken together, Nodal signaling through the Smad2/3 pathway up-regulated Slug, Snail and c-Myc to induce EMT, thereby promoting VM formation. Our study suggests that the Nodal signaling pathway may serve as a therapeutic target to inhibit VM formation and improve prognosis in breast cancer patients.
Highlights
Breast cancer is the most frequently diagnosed malignant tumor among women worldwide [1]
We analyzed the relationship between Nodal signaling and Vasculogenic mimicry (VM) formation in one hundred human breast cancer cases and the results showed that the expression of Nodal was significantly correlated with VM formation, tumor metastasis, differentiation grade, TNM stage and poor prognosis
We investigated the role of Nodal and demonstrated for the first time that Nodal signaling facilitated VM formation in breast cancer
Summary
Breast cancer is the most frequently diagnosed malignant tumor among women worldwide [1]. The tumor microenvironment and vascular network formation may play important roles in these differences [2]. Nodal is a member of the TGF-β superfamily and has several critical roles in embryo development It is normally expressed during embryogenesis, and promotes mesendoderm specification and left-right asymmetry www.impactjournals.com/oncotarget [16,17,18]. Nodal expression is correlated with tumor progression, poor prognosis and angiogenesis [16, 23,24,25]. Recent studies have shown that Nodal may regulate breast cancer progression and metastasis [24, 26]. We focused on determining the function of Nodal in VM formation and the role of the Smad2/3 pathway in this process. Nodal might serve as a therapeutic target for inhibiting VM formation and improving the prognosis in breast cancer
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