Impaired Pten expression in human malignant peripheral nerve sheath tumours.

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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e47595 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23139750 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neurofibromin 1
• Simvastatin
• Ribosomal Protein S6 Kinases, 70-kDa
• PTEN Phosphohydrolase
• PTEN protein, human
• Sirolimus

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Drug Synergism
• Fibroblasts (drug effects, metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Nerve Sheath Neoplasms (enzymology, genetics, pathology)
• Neurofibroma (enzymology, genetics, pathology)
• Neurofibromin 1 (metabolism)
• PTEN Phosphohydrolase (genetics, metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Simvastatin (pharmacology)
• Sirolimus (pharmacology)