title: Nodal signaling promotes vasculogenic mimicry formation in breast cancer via the Smad2/3 pathway.
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.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Wenchen
authors.initials: W
authors.lastname: Gong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China.|Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, 300060, China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Tieju
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, 300052, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Xueyi
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Yanlei
authors.initials: Y
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001943:Breast Neoplasms / Q000098:blood supply* / Q000473:pathology; D004149:Dioxoles / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D055457:Nodal Protein / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; C526007:NODAL protein, human; D055457:Nodal Protein; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein
keywords: EMT; Nodal signaling; Smad2/3 pathway; VM; breast cancer