Transfer of functional microRNAs between glioblastoma and microvascular endothelial cells through gap junctions.

Dominique Thuringer,Carmen Garrido,Eric Solary,Laurent Cronier,Jonathan Boucher,Nicolas Pernet,Gaetan Jego,Arlette Hammann

doi:10.18632/oncotarget.12136

Abstract

Extensive invasion and angiogenesis are hallmark features of malignant glioblastomas. Here, we co-cultured U87 human glioblastoma cells and human microvascular endothelial cells (HMEC) to demonstrate the exchange of microRNAs that initially involve the formation of gap junction communications between the two cell types. The functional inhibition of gap junctions by carbenoxolone blocks the transfer of the anti-tumor miR-145-5p from HMEC to U87, and the transfer of the pro-invasive miR-5096 from U87 to HMEC. These two microRNAs exert opposite effects on angiogenesis in vitro. MiR-5096 was observed to promote HMEC tubulogenesis, initially by increasing Cx43 expression and the formation of heterocellular gap junctions, and secondarily through a gap-junction independent pathway. Our results highlight the importance of microRNA exchanges between tumor and endothelial cells that in part involves the formation of functional gap junctions between the two cell types.

Highlights

Among all brain cancers arising from transformed glial cells, grade IV glioblastoma (GBM), as defined by the World Health Organization, is the most prevalent and aggressive [1]
MiR-5096 was observed to promote human microvascular endothelial cells (HMEC) tubulogenesis, initially by increasing Cx43 expression and the formation of heterocellular gap junctions, and secondarily through a gap-junction independent pathway.Our results highlight the importance of microRNA exchanges between tumor and endothelial cells that in part involves the formation of functional gap junctions between the two cell types
We demonstrate the ability of gap junctions to drive miRs exchange between HMEC and the U87 human glioblastoma cell line and to modulate the behavior of target cells

Summary

Introduction

Among all brain cancers arising from transformed glial cells, grade IV glioblastoma (GBM), as defined by the World Health Organization, is the most prevalent and aggressive [1]. The diffusely invasive nature of these tumors precludes their complete surgical resection, which inevitably leads to tumor recurrence and patient death [2]. Glioblastoma cells migrate onto normal brain microvessels for invasion and tumor growth [3]. They communicate directly with surrounding normal cells such as astrocytes, glia and endothelial cells, through the formation of gap junctions. These cell-to-cell interactions modify astrocyte phenotype [4,5,6] and promote tumor angiogenesis and tumor growth [7]. Gap junctions and their signaling are proposed as potential therapeutic targets in these patients

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