Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype.

Dan Liu,Howard Colman,Nahir Cortes-Santiago,Jing Xu,Ok-Hee Lee,Candelaria Gomez-Manzano,Vanesa Martin,Kenneth Aldape,Marta M Alonso,Juan Fueyo

doi:10.18632/oncotarget.204

Dan Liu, Howard Colman + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.204

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Abstract

Malignant gliomas are the prototype of highly infiltrative tumors and this characteristic is the main factor for the inevitable tumor recurrence and short survival after most aggressive therapies. The aberrant communication between glioma cells and tumor microenvironment represents one of the major factors regulating brain tumor dispersal. Our group has previously reported that the tyrosine kinase receptor Tie2/TEK is expressed in glioma cells and brain tumor stem cells and is associated with the malignant progression of these tumors. In this study, we sought to determine whether the angiopoietin 1 (Ang1)/Tie2 axis regulates crosstalk between glioma cells and endothelial cells. We found that Ang1 enhanced the adhesion of Tie2-expressing glioma and brain tumor stem cells to endothelial cells. Conversely, specific small interfering RNA (siRNA) knockdown of Tie2 expression inhibited the adhesion capability of glioma cells. Tie2 activation induced integrin β1 and N-cadherin upregulation, and neutralizing antibodies against these molecules inhibited the adhesion of Tie2-positive glioma cells to endothelial cells. In 2D and 3D cultures, we observed that Ang1/Tie2 axis activation was related to increased glioma cell invasion, which was inhibited by using Tie2 siRNA. Importantly, intracranial co-implantation of Tie2-positive glioma cells and endothelial cells in a mouse model resulted in diffusely invasive tumors with cell clusters surrounding glomeruloid vessels mimicking a tumoral niche distribution. Collectively, our results provide new information about the Tie2 signaling in glioma cells that regulates the cross-talk between glioma cells and tumor microenvironment, envisioning Tie2 as a multi-compartmental target for glioma therapy.

Highlights

Tumor microenvironment plays an important role in tumor progression and invasion
0 U251-3.1 U251-Tie2 current study, we investigated whether the Angiopoietin 1 (Ang1)/Tie2 axis regulates the crosstalk between glioma cells and the tumor microenvironment
Treatment with Tie2 small interfering RNA (siRNA) significantly abolished Ang1induced adhesion of U-87 MG cells to endothelial cells (EC) (Figure 1E). These results indicate that the angiopoietin 1 (Ang1)/Tie2 axis plays a major role in mediating the adhesion of glioma cells and brain tumor stem cell (BTSC) to ECs

Summary

INTRODUCTION

Tumor microenvironment plays an important role in tumor progression and invasion. Interaction of tumor cells with the extracellular matrix and stromal cells is crucial for tumor formation including survival, invasion and maintenance of tumor-initiating cells [1]. Malignant gliomas are the most common type of primary brain tumor, and the prognosis for patients with these tumors remains dismal [2]. The tyrosine kinase receptor Tie2/TEK was initially reported as a specific vascular receptor present in both normal and tumoral endothelial cells (EC), including ECs in astrocytomas, and its levels correlate positively with increasing malignancy [4,5,6,7,8]. In these processes, Tie and its ligands, angiopoietins, are critical to angiogenic remodeling [9]. Examining in vitro and in vivo models of gliomas, we found that glial Tie is involved in enhancing the adhesion of glioma cells to ECs, and critically participates in the development of the invasive phenotype of gliomas

RESULTS

DISCUSSION

MATERIALS AND METHODS