Macrophage migration inhibitory factor promotes vasculogenic mimicry formation induced by hypoxia via CXCR4/AKT/EMT pathway in human glioblastoma cells.

Xing Guo,Jian Wang,Wei Qiu,Shugang Xu,Hao Xue,Xiao Gao,Gang Li,Zihang Chen,Xiaofan Guo,Mingyu Qian,Jinsen Zhang

doi:10.18632/oncotarget.18673

Abstract

Macrophage migration inhibitory factor (MIF) is over-expressed and secreted in various cancer cells in particular in response to hypoxia. Recent studies have shown that, under hypoxic conditions, glioblastoma (GBM) cells display the ability to drive blood-perfused vasculogenic mimicry (VM). The aim of this study was to investigate the underlying mechanism of MIF in the regulation of hypoxia-induced VM in GBM cells. By analyzing clinical specimens, we observed the co-localization of MIF, C-X-C motif chemokine receptor 4 (CXCR4) and VM in hypoxic regions of gliomas. In vitro, the exposure of GBM cells (U87 and U251) to hypoxia increased the expression of MIF and CXCR4 and induced VMs. Other data demonstrated that ectogenic rhMIF promoted VMs in GBM cells and knock-down endogenous MIF attenuated hypoxia-induced VMs. In addition, we demonstrated that MIF augmented VM formation ability by enhancing the epithelial mesenchymal transition (EMT) through the CXCR4-AKT pathway. Moreover, in vivo, the subcutaneous injection of rhMIF resulted in the progression of EMT and VMs formation. On the contrary, CXCR4-AKT pathway inhibitors blocked the effects of rhMIF on EMT and VMs formation. Collectively, our results support a critical role for the MIF-CXCR4 signaling axis in regulating hypoxia-induced VMs formation, indicating the potential usefulness of MIF as a notable target for the anti-vascularization treatment of GBM.

Highlights

Glioblastoma multiforme (GBM) is the most common and deadly type of malignant brain tumor
Further linear regression analysis showed that the expression of migration inhibitory factor (MIF) and CXCR4 were positively correlated with the level of HIF1α individually (Figure 1C)
To illustrate that hypoxia is a direct inducer of MIF and CXCR4, we performed double immunofluorescence staining in GBM specimens to detect the co-localization of HIF1α with MIF and CXCR4

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and deadly type of malignant brain tumor. The average overall survival for patients with glioblastoma has improved slowly in the standard of care [1]. Especially by anti-VEGF agents, was considered a hopeful strategy to overcome the malignant progression of GBM. Antiangiogenic therapies were well tolerated in patients with GBM and clinical trial evidence indicated that it had no significant effect on prolonging long-term survival for patients with primary GBM [3]. The mechanisms of resistance to anti-angiogenic therapies are complicated and poorly understood. There must be some salvageneovascularization instead of angiogenesis to rescue and contribute to the malignant progression of GBM under hypoxic conditions. A better understanding of the molecular mechanisms of salvage-neovascularization is needed to develop more specific therapeutic strategies

Objectives

Methods

Results

Conclusion