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Large-Scale Molecular Comparison of Human Schwann Cells to Malignant Peripheral Nerve Sheath Tumor Cell Lines and Tissues

Divisions of ¹ Experimental Hematology and ² Biomedical Informatics, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, Ohio; ³ Department of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany; ⁴ Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom; Departments of ⁵ Pediatric Neurology, Neuroscience, and ⁶ Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida; ⁷ Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa; and Departments of ⁸ Pathology and Immunology and ⁹ Neurology, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Nancy Ratner, Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 7013, Cincinnati, OH 45229. Phone: 513-636-9469; Fax: 513-636-3549; E-mail: Nancy.Ratner{at}cchmc.org.

Malignant peripheral nerve sheath tumors (MPNST) are highly invasive soft tissue sarcomas that arise within the peripheral nerve and frequently metastasize. To identify molecular events contributing to malignant transformation in peripheral nerve, we compared eight cell lines derived from MPNSTs and seven normal human Schwann cell samples. We found that MPNST lines are heterogeneous in their in vitro growth rates and exhibit diverse alterations in expression of pRb, p53, p14^Arf, and p16^INK4a proteins. All MPNST cell lines express the epidermal growth factor receptor and lack S100ß protein. Global gene expression profiling using Affymetrix oligonucleotide microarrays identified a 159-gene molecular signature distinguishing MPNST cell lines from normal Schwann cells, which was validated in Affymetrix microarray data generated from 45 primary MPNSTs. Expression of Schwann cell differentiation markers (SOX10, CNP, PMP22, and NGFR) was down-regulated in MPNSTs whereas neural crest stem cell markers, SOX9 and TWIST1, were overexpressed in MPNSTs. Previous studies have implicated TWIST1 in apoptosis inhibition, resistance to chemotherapy, and metastasis. Reducing TWIST1 expression in MPNST cells using small interfering RNA did not affect apoptosis or chemoresistance but inhibited cell chemotaxis. Our results highlight the use of gene expression profiling in identifying genes and molecular pathways that are potential biomarkers and/or therapeutic targets for treatment of MPNST and support the use of the MPNST cell lines as a primary analytic tool. (Cancer Res 2006; 66(5): 2584-91)

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