Open AccessDickkopf‐1‐promoted vasculogenic mimicry in non‐small cell lung cancer is associated with EMT and development of a cancer stem‐like cell phenotype
Author(s) -
Yao Lingli,
Zhang Danfang,
Zhao Xiulan,
Sun Baocun,
Liu Yanrong,
Gu Qiang,
Zhang Yanhui,
Zhao Xueming,
Che Na,
Zheng Yanjun,
Liu Fang,
Wang Yong,
Meng Jie
Publication year - 2016
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12862
Subject(s) - vasculogenic mimicry , lung cancer , phenotype , cancer research , cancer , cell , biology , immunology , medicine , pathology , metastasis , genetics , gene
To characterize the contributions of Dickkopf‐1 ( DKK 1) 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 DKK 1 was detected in 133 cases. Notably, DKK 1 was positively associated with VM . Statistical analysis showed that VM and DKK 1 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 CD 44), VM ‐related proteins ( MMP 2, MMP 9, and vascular endothelial‐cadherin), and β‐catenin‐nu were all elevated in VM ‐positive and DKK 1‐positive tumours, whereas the epithelial marker (E‐cadherin) was reduced in the VM ‐positive and DKK 1‐positive groups. Non‐small cell lung cancer cell lines with overexpressed or silenced DKK 1 highlighted its role in the restoration of mesenchymal phenotypes and development of CSC characteristics. Moreover, DKK 1 significantly promotes NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that DKK 1 enhances the growth of transplanted human tumours cells, as well as increased VM formation, mesenthymal phenotypes and CSC properties. Our results suggest that DKK 1 can promote VM formation via induction of the expression of EMT and CSC ‐related proteins. As such, we feel that DKK 1 may represent a novel target of NSCLC therapy.