Impaired Pten expression in human malignant peripheral nerve sheath tumours

• Verfasst von: Bradtmöller, Maren [VerfasserIn]
• Verfasst von: Hartmann, Christian [VerfasserIn]
• Verfasst von: Reuss, David [VerfasserIn]
• Verfasst von: Deimling, Andreas von [VerfasserIn]
• Titel: Impaired Pten expression in human malignant peripheral nerve sheath tumours
• Verf.angabe: Maren Bradtmöller, Christian Hartmann, Jan Zietsch, Sebastian Jäschke, Victor-F. Mautner, Andreas Kurtz, Su-Jin Park, Michael Baier, Anja Harder, David Reuss, Andreas von Deimling, Frank L. Heppner, Nikola Holtkamp
• Jahr: 2012
• Umfang: 9 S.
• Fussnoten: Published: November 6, 2012 ; Gesehen am 12.06.2018
• Titel Quelle: Enthalten in: PLOS ONE
• Ort Quelle: San Francisco, California, US : PLOS, 2006
• Jahr Quelle: 2012
• Band/Heft Quelle: 7(2012,11) Artikel-Nummer e47595, 9 Seiten
• ISSN Quelle: 1932-6203
• DOI: doi:10.1371/journal.pone.0047595
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Cell cultures
• Sach-SW: Cultured fibroblasts
• Sach-SW: DNA methylation
• Sach-SW: Fibroblasts
• Sach-SW: Metastasis
• Sach-SW: Neurofibromatosis type 1
• Sach-SW: Polymerase chain reaction
• Sach-SW: Schwann cells
• K10plus-PPN: 1576271129

Abstract

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 down-regulation 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 NF1−/− 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.