Dickkopf‐1‐promoted vasculogenic mimicry in non‐small cell lung cancer is associated with EMT and development of a cancer stem‐like cell phenotype

摘要

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 style="fixed-case">DKK1‐positive tumours, whereas the epithelial marker (E‐cadherin) was reduced in the style="fixed-case">VM‐positive and style="fixed-case">DKK1‐positive groups. Non‐small cell lung cancer cell lines with overexpressed or silenced style="fixed-case">DKK1 highlighted its role in the restoration of mesenchymal phenotypes and development of style="fixed-case">CSC characteristics. Moreover, style="fixed-case">DKK1 significantly promotes style="fixed-case">NSCLC tumour cells to migrate, invade and proliferate. In vivo animal studies demonstrated that style="fixed-case">DKK1 enhances the growth of transplanted human tumours cells, as well as increased style="fixed-case">VM formation, mesenthymal phenotypes and style="fixed-case">CSC properties. Our results suggest that style="fixed-case">DKK1 can promote style="fixed-case">VM formation via induction of the expression of style="fixed-case">EMT and style="fixed-case">CSC‐related proteins. As such, we feel that style="fixed-case">DKK1 may represent a novel target of style="fixed-case">NSCLC therapy.