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

Abstract

Objectives To investigate the role of hypoxia in vasculogenic mimicry (VM) of salivary adenoid cystic carcinoma (SACC) and the underlying mechanism involved. Materials and methods Firstly, wound healing, transwell invasion, immunofluorescence and tube formation assays were performed to measure the effect of hypoxia on migration, invasion, EMT and VM of SACC cells, respectively. Then, immunofluorescence and RT‐PCR were used to detect the effect of hypoxia on VE‐cadherin and VEGFA expression. And pro‐vasculogenic mimicry effect of VEGFA was investigated by confocal laser scanning microscopy and Western blot. Moreover, the levels of E‐cadherin, N‐cadherin, Vimentin, CD44 and ALDH1 were determined by Western blot and immunofluorescence in SACC cells treated by exogenous VEGFA or bevacizumab. Finally, CD31/ PAS staining was performed to observe VM and immunohistochemistry was used to determine the levels of VEGFA and HIF‐1α in 95 SACC patients. The relationships between VM and clinicopathological variables, VEGFA or HIF‐1α level were analysed. Results Hypoxia promoted cell migration, invasion, EMT and VM formation, and enhanced VE‐cadherin and VEGFA expression in SACC cells. Further, exogenous VEGFA markedly increased the levels of N‐cadherin, Vimentin, CD44 and ALDH1, and inhibited the expression of E‐cadherin, while the VEGFA inhibitor reversed these changes. In addition, VM channels existed in 25 of 95 SACC samples, and there was a strong positive correlation between VM and clinic stage, distant metastases, VEGFA and HIF‐1α expression. Conclusions VEGFA played an important role in hypoxia‐induced VM through regulating EMT and stemness, which may eventually fuel the migration and invasion of SACC.

The EMT transcription factor, Twist1, as a novel therapeutic target for pulmonary sarcomatoid carcinomas

“…Previous studies have demonstrated that VM occurs in highly invasive tumours and is associated with a high histological grade, invasion, metastasis and a short survival in patients with malignant tumours (14,15). Previous studies by the authors of this study and others (16)(17)(18)(19) have demonstrated that VM channel formation in highly aggressive human tumour cells has a close association with the EMT process. Therefore, both EMT and The EMT transcription factor, Twist1, as a novel therapeutic target for pulmonary sarcomatoid carcinomas VM are synonymous with tumour plasticity, the transdifferentiation of epithelial cells to a mesenchymal phenotype, tumour aggressiveness and metastasis.…”

Myeloid derived suppressor cells contribute to the malignant progression of oral squamous cell carcinoma

“…EMT has been proved to contribute to the VM which is described as a process that aggressive tumor cells mimic the endothelial cells to form microvascular tubes and has been reported to promote progression of cancer [42]. Our previous work found that the VEGFA induced VM formation through regulating EMT to fuel the migration and invasion of salivary adenoid cystic carcinoma [43]. Recently, several studies have revealed that immune cells are involved in the VM.…”

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

“…Moreover, albeit that the expression of VEGFR, a main regulator of neo angiogenesis, was not modified in GB7 cells comparing the hypoxia and normoxia conditions, after M2 agonist treatment the expression of VEGFR transcript levels appeared significantly reduced. This suggest that M2 receptor stimulation may significantly impair the ability of tumor cells to modulate the formation of new vessels or counteracting the vasculogenic mimicry, a property of GSCs to differentiate in endothelium cells to form new tumoral blood vessels [27], contributing to increase the O 2 levels in deprived microenvironment.…”