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Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors

Oncogene volume 24, pages 5589–5605 (2005)Cite this article

Abstract

Patients with neurofibromatosis type 1 develop aggressive Schwann cell neoplasms known as malignant peripheral nerve sheath tumors (MPNSTs). Although tumor suppressor gene mutations play an important role in MPNST pathogenesis, it is likely that dysregulated signaling by as yet unidentified growth factors also contributes to the formation of these sarcomas. To test the hypothesis that neuregulin-1 (NRG-1) growth factors promote mitogenesis in MPNSTs, we examined the expression and action of NRG-1 in human MPNSTs and neurofibromas, the benign precursor lesions from which MPNSTs arise. Multiple α and β transmembrane precursors from the class II and III NRG-1 subfamilies are present in both tumor types. Neoplastic Schwann cells within these neoplasms variably express the erbB kinases mediating NRG-1 responses (erbB2, erbB3 and/or erbB4). Human MPNST cell lines (Mash-1, YST-1, NMS-2 and NMS-2PC cells) similarly coexpress multiple NRG-1 isoforms and erbB receptors. These MPNST lines are NRG-1 responsive and demonstrate constitutive erbB phosphorylation. Treatment with PD168393 and PD158780, two structurally and mechanistically distinct erbB inhibitors, abolishes erbB phosphorylation and reduces DNA synthesis in these lines. These findings suggest that autocrine and/or paracrine NRG-1/erbB signaling promotes neoplastic Schwann cell proliferation and may be an important therapeutic target in neurofibromas and MPNSTs.

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Acknowledgements

We thank Dr Kevin A Roth (Department of Pathology, UAB) for helpful comments on this manuscript. This work was supported by National Institute of Neurological Disorders and Stroke Grant R01 NS048353.

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Authors and Affiliations

  1. Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, 35294-0017, AL, USA

    Mark S Stonecypher & Steven L Carroll

  2. Department of Pathology, The University of Alabama at Birmingham, Birmingham, 35294-0017, AL, USA

    Stephanie J Byer, William E Grizzle & Steven L Carroll

  3. The Medical Scientist Training Program, The University of Alabama at Birmingham, Birmingham, 35294-0017, AL, USA

    Mark S Stonecypher

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  1. Mark S Stonecypher
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Correspondence to Steven L Carroll.

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Stonecypher, M., Byer, S., Grizzle, W. et al. Activation of the neuregulin-1/ErbB signaling pathway promotes the proliferation of neoplastic Schwann cells in human malignant peripheral nerve sheath tumors. Oncogene 24, 5589–5605 (2005). https://doi.org/10.1038/sj.onc.1208730

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