Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 5; pp. 2584 - 2591
• Main Authors: MILLER, Shyra J, RANGWALA, Fatima, MAUTNER, Victor, UPADHYAYA, Meena, MUIR, David, WALLACE, Margaret, HAGEN, Jussara, QUELLE, Dawn E, WATSON, Mark A, PERRY, Arie, GUTMANN, David H, RATNER, Nancy, WILLIAMS, Jon, ACKERMAN, Peter, KONG, Sue, JEGGA, Anil G, KAISER, Sergio, ARONOW, Bruce J, FRAHM, Silke, KLUWE, Lan
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-03-2006
• Subjects: Antineoplastic agents; Apoptosis - physiology; Biological and medical sciences; Cell Line, Tumor; Cell Movement - physiology; Drug Resistance, Neoplasm; Gene Expression Profiling; Humans; Medical sciences; Nerve Sheath Neoplasms - genetics; Nerve Sheath Neoplasms - metabolism; Nerve Sheath Neoplasms - pathology; Neurology; Nuclear Proteins - biosynthesis; Nuclear Proteins - genetics; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; RNA, Small Interfering - genetics; Schwann Cells - metabolism; Schwann Cells - physiology; Transfection; Tumors; Tumors of the nervous system. Phacomatoses; Twist-Related Protein 1 - biosynthesis; Twist-Related Protein 1 - genetics; Human; Peripheral nerve; Nervous system diseases; Schwann cell; Neuroglia; Established cell line; Neurinoma; Benign neoplasm; Malignant tumor; In vitro; Comparative study
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-3330

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 S100beta 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.