Nodal signaling promotes vasculogenic mimicry formation in breast cancer via the Smad2/3 pathway
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Wenchen Gong1,*, Baocun Sun1,2,3,*, Xiulan Zhao1,2, Danfang Zhang1,2, Junying Sun1, Tieju Liu1,2, Qiang Gu1,2, Xueyi Dong1, Fang Liu1, Yong Wang1, Xian Lin1, Yanlei Li1
1Department of Pathology, Tianjin Medical University, Tianjin, 300070, China
2Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China
3Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, 300060, China
*These authors contributed equally to this work
Baocun Sun, email: [email protected]
Keywords: Nodal signaling, Smad2/3 pathway, VM, EMT, breast cancer
Received: April 18, 2016 Accepted: September 14, 2016 Published: September 21, 2016
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.
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