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Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro

Oncogene volume 18, pages 6692–6699 (1999)Cite this article

Abstract

The neu/erbB2 protooncogene is overexpressed in numerous human cancers and is mutationally activated in N-ethyl-N-nitrosourea (ENU)-induced rodent tumors of the Schwann cell lineage. We investigated whether expression of activated neu in Schwann cells is sufficient to initiate their immortalization and transformation. Clones of embryonic dorsal root ganglia cells infected with a retrovirus bearing activated neu (NID cells) were selected based on their expression of Schwann cell-specific markers. Compared to embryonic Schwann cells infected with a virus encoding empty vector, we found that NID cells have altered shapes and disorganized cytoskeletons, grow in the absence of growth factors required for normal Schwann cell survival and proliferation, and can be repeatedly passaged. Furthermore, NID cells are invasive in an in vitro matrix invasion assay and form metastatic tumors when injected into syngeneic animals. The neu-induced growth and invasive phenotypes could be reversed by drugs that inhibit Ras and Src activity. Interestingly, later stage Schwann cells infected with activated neu failed to become immortalized. These findings indicate that constitutive activation of erbB2 is sufficient to initiate the immortalization and transformation of immature Schwann cells, and support the notion that Schwann cells have particular developmental stages during which they are susceptible to immortalizing and transforming events.

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Acknowledgements

We thank Tanja Schüler and Saikumar Karyala for technical assistance, Norma Howells for assistance with animal breeding, and Helmut Ponta for helpful discussions and ideas. We are also grateful to Paul Edwards from the Department of Pathology at the University of Cambridge for the ψ-2 pINA-neu and ψ-2 pINA cell lines, to Mark Marchionni from Cambridge Neuroscience for the rh-GGF2, to Jackson Gibbs and Nancy Krohl from Merck Sharp and Dohme Research Laboratories for the L-739,749. This work was supported by NIH NS28840 to N Ratner, NRSA NS10297 to L Sherman and He551/8-2 from the Deutsche Forschungsgemeinschaft to P Herrlich.

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  1. Department of Cell Biology, Neurobiology and Anatomy, University of Cincinnati College of Medicine, 231 Bethesda Avenue, Cincinnati, 45267-0521, Ohio, OH, USA

    Larry Sherman, Robert F Hennigan & Nancy Ratner

  2. Institut für Genetik, Forschungszentrum Karlsruhe, Postfach 3640, 76021, Karlsruhe, Germany

    Jonathan P Sleeman & Peter Herrlich

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  1. Larry Sherman
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Sherman, L., Sleeman, J., Hennigan, R. et al. Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro. Oncogene 18, 6692–6699 (1999). https://doi.org/10.1038/sj.onc.1203055

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