ZEB1‐mediated vasculogenic mimicry formation associates with epithelial–mesenchymal transition and cancer stem cell phenotypes in prostate cancer

Abstract

The zinc finger E‐box‐binding homeobox 1 (ZEB1) induced the epithelial–mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid–Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1‐induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT‐related and CSC‐associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p‐Src527 level but not p‐Src416 level, while ZEB1 knockdown also down‐regulated the level of p‐Src527 in PC3 and DU‐145 cells. PP2 treatment also significantly reduced the expression of VE‐cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression.

Hypoxia promotes vasculogenic mimicry formation by vascular endothelial growth factor A mediating epithelial‐mesenchymal transition in salivary adenoid cystic carcinoma

“…Similarly, the high level of ZEB1, another EMT-related transcription factor, was strongly associated with the presence of VM in 96 prostate cancer samples (P < 0.05) 37. Similarly, the high level of ZEB1, another EMT-related transcription factor, was strongly associated with the presence of VM in 96 prostate cancer samples (P < 0.05) 37.…”

Vasculogenic mimicry in carcinogenesis and clinical applications

“…VE-cadherin is a VM biomarker and plays a crucial role in the process of VM formation [23,43]. Some EMT-associated transcription factors including Snail1, Slug (Snail2) [45], Zinc finger E-box binding homeobox 1 (ZEB1) [18,46], ZEB2 [13] and Twist1 [11]. These transcription factors can bind to the E-cadherin promoter to regulate transcriptional activity, and the decreased levels of E-cadherin result in decreased cell adhesion and increased cell invasion and metastasis [22,30].…”

“…Additionally, in prostate cancer, ZEB1 regulates VM formation and alters the expression of CSC-associated protein CD133. Furthermore, the follow-up experiments revealed that ZEB1 knockdown reduces the level of p-Src [527], the results showed ZEB1 is essential to CSC phenotype and VM formation by Src signaling [18]. Recently, in hepatocellular carcinoma, Zhao et al found that LncRNA n339260 promotes VM formation in HCC by inducing CSC-like phenotype and the knockdown of n339260 reduced VM and CSCs.…”

“…Moreover, VM is associated with high tumor grade, invasion, metastasis, and poor prognosis in patients with malignant tumors [3][4][5][6]. In recent years, VM has been reported in a variety of malignant tumors, such as melanoma, glioblastoma, osteosarcoma, hepatocellular carcinoma (HCC), breast cancer, lung cancer, gastric cancer, colorectal cancer, and prostate cancer [7][8][9][10][11][12][13][14][15][16][17][18][19]. VM has emerged as a promising new target for anti-tumor therapy [20,21].…”

Cancer Stem Cells and Its Role in Angiogenesis and Vasculogenic Mimicry in Gastrointestinal Cancers

“…Interestingly, tumor cells associated to VM structures acquire an undifferentiated phenotype as well as ECs characteristics (80). Nowadays, CSCs have been involved in VC formation in cancer (81)(82)(83)(84)(85)(86)(87). For instance, in salivary adenoid cystic carcinoma (ACC) specimens CD133 is positively associated with VM formation.…”