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The Journal of Neuroscience, June 1, 2002, 22(11):4302-4311

Connexin 43 Enhances the Adhesivity and Mediates the Invasion of Malignant Glioma Cells

Jane H.-C. Lin¹, Takahiro Takano², Maria Luisa Cotrina², Gregory Arcuino², Jian Kang², Shujun Liu², Qun Gao², Li Jiang², Fanshu Li², Hella Lichtenberg-Frate³, Sandra Haubrich³, Klaus Willecke³, Steven A. Goldman⁴, and Maiken Nedergaard²

Departments of ¹ Pathology and ² Anatomy and Cell Biology, New York Medical College, Valhalla, New York 10595, ³ Institut für Genetik, Abteilung Molekulargenetik, University of Bonn, 53117 Bonn, Germany, and ⁴ Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021

A hallmark of astrocytic tumors is their infiltrative nature. Although their aggressive and typically widespread dispersal in the adult brain differs fundamentally from that of other brain tumors, little is known about their cellular basis. Astrocytic tumors express the gap junction protein connexin 43 (Cx43), and we show here that Cx43 expression induced the morphological transformation of glioma cells into an epithelial phenotype. In a short-term aggregation assay, Cx43 expression was associated with a several-fold increase in the competence of glioma cells to aggregate. Antibodies directed against the extracellular domain of Cx43 restored the connexin-deficient phenotype, as manifested by a dose-dependent reduction in aggregation. Apart from their role in gap junction formation, connexins may therefore be considered a distinct class of membrane proteins with adhesive properties. Moreover, implanted Cx43-expressing glioma cells established functional gap junction channels with host astrocytes and dispersed through a substantially greater volume of brain parenchyma than mock- and mutant Cx43-transfected sister cells. Cx43 expression therefore may modulate not only the adhesion of astrocytes to one another, but the spread of glial tumor cells throughout astrocytic syncytia. These observations widen our concept of the potential interactions between tumor cells and their surroundings and suggest that both connexin proteins and their derived gap junctions are critical determinants of the invasiveness of central gliomas.

Key words: cell motility; astrocyte; gap junction; bystander death; brain tumor; rat

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22114302-10$05.00/0

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