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Astrocytes promote glioma invasion via the gap junction protein connexin43

Oncogene volume 35, pages 1504–1516 (2016)Cite this article

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Abstract

Reactive astrocytes are integral to the glioma microenvironment. Connexin43 (Cx43) is a major gap junction protein in astrocytes and its expression is enhanced significantly in glioma-associated astrocytes, especially at the peri-tumoral region. Although downregulation of Cx43-mediated intercellular communication is associated with increased malignancy in tumor cells, the role of Cx43 in stromal cells in glioma progression is not defined. Using a mouse model consisting of syngeneic intracranial implantation of GL261 glioma cells into Nestin-Cre:Cx43fl/fl mice where Cx43 was eliminated in astrocytes, we demonstrate a role of astrocytic Cx43 in the dissemination of glioma cells from the tumor core. To determine whether heterocellular communication between astrocytes and glioma cells is essential for reduced invasion in the absence of astrocytic Cx43, we abolished channel formation between glioma cells and astrocytes by either knocking down Cx43 in glioma cells with short hairpin RNA (shRNA) or overexpressing a dominant-negative channel-defective Cx43-T154A mutant in these cells. Although Cx43shRNA in glioma cells reduced invasion, expression of Cx43-T154A had no effect on glioma invasion, suggesting tumoral Cx43 may influence motility independently from its channel function. Alteration in astrocytic Cx43 function, such as by replacing the wild-type allele with a C-terminal truncated Cx43 mutant exhibiting reduced intercellular coupling, is sufficient to reduce glioma spreading into the brain parenchyma. Our results reveal a novel role of astrocytic Cx43 in the formation of an invasive niche and raise the possibility to control glioma progression by manipulating the microenvironment.

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Acknowledgements

We thank Lina Wang, Elodie Montaudon, Kushal Kolar, Xu Qiu Guo, Aishah Tul-Firdaus Binte Abdul Khalid and Jose Luis Vega for providing technical support for this project. We also wish to thank Maxence Le Vasseur for critical review of the manuscript. This study was supported by two operating grants (MOP-102489 and MOP-93572) to WCS and CCN from the Canadian Institutes of Health Research. CCN holds a Canada Research Chair. QA was supported by a postgraduate scholarship from the National Sciences and Engineering Research Council of Canada.

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  1. Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, Vancouver, BC, Canada

    W C Sin, Q Aftab, J F Bechberger, J H Leung, H Chen & C C Naus

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  1. W C Sin
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  2. Q Aftab
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Sin, W., Aftab, Q., Bechberger, J. et al. Astrocytes promote glioma invasion via the gap junction protein connexin43. Oncogene 35, 1504–1516 (2016). https://doi.org/10.1038/onc.2015.210

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  • DOI: https://doi.org/10.1038/onc.2015.210

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