title: Dickkopf-1-promoted vasculogenic mimicry in non-small cell lung cancer is associated with EMT and development of a cancer stem-like cell phenotype.
abstract: To characterize the contributions of Dickkopf-1 (DKK1) towards the induction of vasculogenic mimicry (VM) in non-small cell lung cancer (NSCLC), we evaluated cohorts of primary tumours, performed in vitro functional studies and generated xenograft mouse models. Vasculogenic mimicry was observed in 28 of 205 NSCLC tumours, while DKK1 was detected in 133 cases. Notably, DKK1 was positively associated with VM. Statistical analysis showed that VM and DKK1 were both related to aggressive clinical course and thus were indicators of a poor prognosis. Moreover, expression of epithelial-mesenchymal transition (EMT)-related proteins (vimentin, Slug, and Twist), cancer stem-like cell (CSC)-related proteins (nestin and CD44), VM-related proteins (MMP2, MMP9, and vascular endothelial-cadherin), and β-catenin-nu were all elevated in VM-positive and DKK1-positive tumours, whereas the epithelial marker (E-cadherin) was reduced in the VM-positive and DKK1-positive groups. Non-small cell lung cancer cell lines with overexpressed or silenced DKK1 highlighted its role in the restoration of mesenchymal phenotypes and development of CSC characteristics. Moreover, DKK1 significantly promotes NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that DKK1 enhances the growth of transplanted human tumours cells, as well as increased VM formation, mesenthymal phenotypes and CSC properties. Our results suggest that DKK1 can promote VM formation via induction of the expression of EMT and CSC-related proteins. As such, we feel that DKK1 may represent a novel target of NSCLC therapy.
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Danfang
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Xiulan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, China.|Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Baocun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanrong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.|Department of Pathology, Tianjin General Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Department of Pathology, Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Na
authors.initials: N
authors.lastname: Che
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Tianjin Medical University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Meng
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D048430:Cell Shape; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000098:blood supply* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018716:Molecular Mimicry; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering
keywords: DKK1; cancer stem-like cell; epithelial-mesenchymal transition; non-small cell lung cancer; vasculogenic mimicry