TY - GEN T1 - Impaired pten expression in human malignant peripheral nerve sheath tumours. AU - Bradtmöller, Maren AU - Hartmann, Christian AU - Zietsch, Jan AU - Jäschke, Sebastian AU - Mautner, Victor-F. AU - Kurtz, Andreas AU - Park, Su-Jin AU - Baier, Michael AU - Harder, Anja AU - Reuss, David AU - Deimling, Andreas von AU - Heppner, Frank L. AU - Holtkamp, Nikola AB - Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten downregulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF12/2 and NF1+/+Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms. KW - Animals KW - Humans KW - Mice KW - Blotting Western KW - Cell Line Tumor KW - Drug Synergism KW - Fibroblasts/drug effects KW - Fibroblasts/metabolism KW - Fibroblasts/pathology KW - Gene Expression Regulation Neoplastic/drug effects KW - Nerve Sheath Neoplasms/enzymology KW - Nerve Sheath Neoplasms/genetics KW - Nerve Sheath Neoplasms/pathology KW - Neurofibroma/enzymology KW - Neurofibroma/genetics KW - Neurofibroma/pathology KW - Neurofibromin 1/metabolism KW - PTEN Phosphohydrolase/genetics KW - PTEN Phosphohydrolase/metabolism KW - Ribosomal Protein S6 Kinases 70-kDa/metabolism KW - Simvastatin/pharmacology KW - Sirolimus/pharmacology KW - 610 Medizin PY - 2012 LA - eng PB - Robert Koch-Institut VL - 7 IS - 11 DO - 10.1371/journal.pone.0047595 ER -